Clinical trial NCT02584959
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire
Start date: 2015-11-01; Completion date: 2017-07-24
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the efficacy and safety of subcutaneous administration of a liquid formulation of C1 esterase inhibitor for the prevention of angioedema attacks in adolescent and adult subjects with hereditary angioedema.

Detailed description:

Arms: arm 1: Subjects will be randomized to receive C1 Esterase Inhibitor in the 1st Treatment period and then switch to Placebo in the 2nd treatment period. arm 2: Subjects will be randomized to receive a placebo treatment in the 1st Treatment period and then switch to receive C1 Esterase Inhibitor in the 2nd treatment period. arm 3: Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period
Interventions: intervention 1: C1 esterase inhibitor [human] liquid intervention 2: Placebo
Intervention descriptions: intervention 1: C1 Esterase Inhibitor \[Human\] Liquid administered Subcutaneously as specified on specified days intervention 2: Placebo

Protocol documents:
Prot_003.pdf: 
PROTOCOL: SHP616-300
TITLE:
A 
Phase 
3, 
Randomized, 
Double-blind, 
Placebo-controlled, 
Two-period, Three-sequence, Partial Crossover Study to Evaluate the 
Efficacy and Safety of Subcutaneous Administration of 2000 IU of 
C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention 
of Angioedema Attacks in Adolescents and Adults with Hereditary 
Angioedema
DRUG:
SHP616, C1 esterase inhibitor [human] liquid for injection
IND:
16516
EUDRACT NO.:
2015-002478-19
SPONSOR: 
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
INVESTIGATORS: Multicenter
PROTOCOL 
HISTORY:
Amendment 3: 11 Jan 2016 (Signatory Approval)
Amendment 2: 03 Sep 2015
Amendment 1: 22 Jul 2015
Original Protocol: 28 May 2015
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used solely for the 
purposes for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Shire ViroPharma, Inc.


Shire ViroPharma. Inc. 
Protocol SHP616-300 
CONFIDENTIAL 
Version 4.0. FINAL 
PROTOCOL SIGNATURE PAGE 
ll Jan 2016 
Page 2 of 106 
Sponsor's (Shire ViroPharma, Inc.) Approval 
Sign•ture: 
 MD 
Date: 
Jm·estiga tor's Acknowledgement 
I have read this protocol for Shire ViroPharma Study SHP616-300. 
Title: A Phase 3, randomized, double-blind, placebo-conrrolled, two-period, three-sequence. 
partial crossover study to evaluate the efficacy and safety of subcutaneous administration of 
2000 IU of C 1 esterase inhibitor [human] liquid for injection for the prevention of 
angioedema attacks in adolescems and adults with hereditary angioedema. 
I have fully discussed the objecrive(s) of this study and rhe contents of this protocol vvith rhe 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed. 
other lhan to those di1·ectly involved in the execution or the scientil:ic/ethical review of the 
study, without written authorization from the sponsor. It is, however. permissible to provide 
the information contained herein to a 
in order to obtain their consent to participate. 
I agree to conduct this sntdy according to this protocol and to comply with its requirements, 
to ethical and safety considerations and guidelines. and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whate,·er reason: such a decision will be communicated to me in writing. Conversely. 
should I decide to withdraw ti'om execution of the study I will communicate my intention 
immediately in \Hiring to the sponsor. 
Investigator Name and Address: 
(please hand print or 1ype) 
Signature: -------------------------------- Date: 
PPD
PPD
PPD
PPD


Shire ViroPharma, Inc.
CONFIDENTIAL
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Protocol SHP616-300
Version 4.0, FINAL
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Amendment 3 to Protocol SHP616-300 incorporates the following major changes:
•
Allow subjects (adolescent or adult) the option to self-administer investigational product 
with or without supervision after receiving appropriate training by the investigator or 
designee. Adolescent subjects self-administering investigational product will be 
supervised by a parent/legal guardian/caregiver (if home health professional and/or study 
site personnel is not present).
•
Subjects who elect to self-administer investigational product will be instructed on 
investigational product transport, storage, treatment compliance, and retention of all used 
and unused product vials for drug accountability purposes. Written instructions on 
investigational product and self-administration procedures will be provided to subjects at 
the screening or first dosing visit.
•
Revised schedule for assessment of SC injection site reactions during Treatment Periods 1 
and 2; the assessments will be less frequent and only occur when investigational product 
is administered at the investigative site. An overall assessment of the impact on daily 
living and duration of injection sites reaction will occur at the last visit of each treatment 
period.
•
In order to prevent subjects from missing a scheduled dose of investigational product, 
additional guidance on the dosing interval has been provided.
•
For subjects without documented C1 INH antigen level and/or C1 INH functional activity 
as part of eligibility criteria to confirm HAE diagnosis, a blood sample will be collected at 
screening and sent to a local or central laboratory (as appropriate). 
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
11 Jan 2016
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Allow subjects (adolescent or adult) to self-administer investigational 
product with or without supervision (qualified home health professional 
and/or study site personnel) after receiving appropriate training by the 
investigator or designee. Adolescent subjects self-administering 
investigational 
product 
will 
be 
supervised 
by 
a 
parent/legal 
guardian/caregiver (if home health professional and/or study site 
personnel is not present). Alternatively, a parent/legal guardian/caregiver
is also allowed to administer investigational product to an adolescent 
subject with or without supervision. 
Synopsis, Section 3.1,
Section 6.2, Section 7.2.4.5
Information on self-administration of investigational product will be 
recorded in the electronic subject diary.
Synopsis, Section 3.1


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Added Firazyr (icatibant) to exclusion criterion #8 to exclude subjects 
with a history of an allergic reaction to icatibant from entering the study.
Synopsis, Section 4.2
Revised schedule for assessment of SC injection site reactions to occur 
only when investigational product is administered at the investigative site 
(Visits 1, 8, 16, 24, and 28 in each treatment period). An overall 
assessment of the impact on daily living and duration of injection site 
reactions will occur at the last visit of each treatment period (Visit 28a 
and 28b).
Table 1, Table 2,
Section 7.1.2.3, Section 7.1.3.3, 
Section 7.2.3.10
Updated safety endpoints and analyses to include the impact on daily 
living and duration of injection site reactions.
Synopsis, Section 9.9
In order to prevent subjects from missing a dose of investigational 
product (if the every 3 to 4 day interval cannot be followed), a less than 
3-day interval may occur with the recommendation of allowing at least 
24 hours between doses. 
Synopsis, Section 3.1,
Section 6.2
Vital sign measurements are not required at Visits 2, 3, and 4 in each 
treatment period for subjects self-administering investigational product 
without supervision (ie, assessment may not be possible).
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3
A PK/PD predose blood sample at Visit 2a and 2b is not required for 
subjects self-administering investigational product without supervision 
(ie, collection of sample may not be possible).
Table 4, Section 7.1.2.3,
Section 7.1.3.3
Provided details on the supply of commercial icatibant as rescue 
medication for the treatment of acute angioedema attacks. The product 
will be appropriately labeled for clinical trial use. Added recommended 
storage conditions for icatibant.
Section 5.2.1, Section 6.1
Subjects who self-administer investigational product (or when needed, 
icatibant as rescue medication) will be instructed on transport, storage, 
treatment compliance, and retention of all used and unused product vials 
for drug accountability purposes. Added details on investigational 
product and ancillary supplies to be provided to subjects at 
investigational site. Written instructions on investigational product and 
self-administration procedures will be provided to subjects at the 
screening or first dosing visit (Visit 1a).
Section 6.5.1, Section 6.6
For subjects without documented C1 INH antigen level and/or C1 INH 
functional activity as part of eligibility criteria to confirm HAE 
diagnosis, a blood sample will be collected at screening and sent to a 
local or central laboratory (as appropriate). Repeat blood sampling is 
allowed if the test is non-confirmatory despite a suspected diagnosis of 
HAE.
Section 7.1.1, Section 7.2.3.1, 
Section 7.2.3.5
Clarified that injection site reactions resulting from the administration of 
icatibant (as rescue medication for acute angioedema attacks) will be 
reported as an AE with causality linked to icatibant.
Section 7.2.3.10
Added “and/or other study product (eg, icatibant)” to clarify how the 
relatedness of AEs is to be captured in the CRF. 
Section 8.1.2
Updated product information for consistency with other patient 
instructions.
Appendix 1
See Appendix 6 for protocol history, including all amendments.


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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover) and are 
provided below. 
US and Canadian Sites
Fax:
Email: 
EU/ROW Sites
Fax:
Email: 
For protocol- or safety-related issues, the investigator must contact the Shire 
ViroPharma Medical Monitor:
, MD, 
, Clinical Development 
Office phone: 
Mobile phone: 
Fax: 
Email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire 
ViroPharma product (marketed or investigational) does not meet expectations (eg, inadequate 
or faulty closure, product contamination) or that the product did not meet the specifications 
defined in the application for the product (eg, wrong product such that the label and contents 
are different products). For instructions on reporting AEs related to product complaints, see 
Section 8.
Please report all Product Quality Complaints to:
PPD


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................3
EMERGENCY CONTACT INFORMATION ..........................................................................5
PRODUCT QUALITY COMPLAINTS ....................................................................................6
LIST OF TABLES....................................................................................................................11
LIST OF FIGURES..................................................................................................................12
LIST OF APPENDICES ..........................................................................................................12
ABBREVIATIONS..................................................................................................................13
STUDY SYNOPSIS.................................................................................................................15
STUDY SCHEDULES.............................................................................................................22
1.
BACKGROUND INFORMATION.............................................................................28
1.1
Indication and Current Treatment Options...................................................................28
1.2
Product Background and Clinical Information ............................................................29
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and with 
SC C1 Esterase Inhibitor [Human] Liquid for Injection........................................31
1.2.1.1
Clinical Safety.............................................................................................32
1.2.1.2
Clinical Efficacy..........................................................................................33
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid for 
Injection .................................................................................................................35
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response 
Analysis of CINRYZE ...................................................................................35
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid 
for Injection .................................................................................................39
1.2.2.3
Dose Selection.............................................................................................41
2.
STUDY OBJECTIVES AND PURPOSE....................................................................41
2.1
Rationale for the Study.................................................................................................41
2.2
Study Objectives...........................................................................................................42
2.2.1
Primary Objectives ................................................................................................42
2.2.2
Secondary Objectives ............................................................................................42
3.
STUDY DESIGN.........................................................................................................43


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3.1
Study Design and Flow Chart ......................................................................................43
3.2
Duration and Study Completion Definition .................................................................45
3.3
Sites and Regions .........................................................................................................45
4.
STUDY POPULATION...............................................................................................45
4.1
Inclusion Criteria..........................................................................................................46
4.2
Exclusion Criteria.........................................................................................................47
4.3
Reproductive Potential .................................................................................................47
4.3.1
Female Contraception............................................................................................47
4.3.2
Male Contraception................................................................................................48
4.4
Discontinuation of Subjects..........................................................................................48
4.4.1
Reasons for Discontinuation..................................................................................49
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit ..................................49
4.4.3
Anaphylactic Reaction...........................................................................................49
4.4.4
Thrombotic or Thromboembolic Event.................................................................49
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................50
5.1
Prior Treatment.............................................................................................................50
5.2
Concomitant Treatment and Medical/Surgical Procedures..........................................50
5.2.1
Management of Angioedema Attacks....................................................................51
5.2.2
Prohibited Treatment .............................................................................................52
5.2.3
Nonpharmacologic Treatments and Procedures ....................................................52
6.
INVESTIGATIONAL PRODUCT..............................................................................53
6.1
Identity of Investigational Product...............................................................................53
6.2
Administration of Investigational Product ...................................................................53
6.3
Allocation of Subjects to Treatment Sequence ............................................................54
6.4
Blinding of Treatment ..................................................................................................54
6.4.1
Unblinding the Treatment Assignment..................................................................55
6.5
Treatment Compliance .................................................................................................55
6.5.1
Self-Administration ...............................................................................................55
6.6
Packaging and Labeling ...............................................................................................56
6.7
Storage and Accountability ..........................................................................................56
6.8
Investigational Product Retention at Study Site...........................................................57
7.
STUDY PROCEDURES..............................................................................................57
7.1
Study Schedule.............................................................................................................57
7.1.1
Screening Period....................................................................................................57
7.1.2
Treatment Period 1.................................................................................................58


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7.1.2.1
Visit 1a (predose) ........................................................................................58
7.1.2.2
Visit 1a (postdose).......................................................................................59
7.1.2.3
Visit 2a through Visit 28a ...........................................................................59
7.1.3
Treatment Period 2.................................................................................................60
7.1.3.1
Visit 1b (predose) ........................................................................................60
7.1.3.2
Visit 1b (postdose).......................................................................................61
7.1.3.3
Visit 2b through Visit 28b...........................................................................61
7.1.4
Early Discontinuation Visit ...................................................................................62
7.1.5
Follow-up Period ...................................................................................................63
7.2
Study Evaluations and Procedures ...............................................................................64
7.2.1
Demographic and Other Baseline Characteristics .................................................64
7.2.2
Efficacy..................................................................................................................64
7.2.2.1
Definition of an Angioedema Attack ..........................................................64
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary...........64
7.2.2.3
Angioedema Activity Score ........................................................................65
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks .........65
7.2.3
Safety .....................................................................................................................66
7.2.3.1
Medical and Medication History.................................................................66
7.2.3.2
Physical Examination (Including Height and Weight)................................67
7.2.3.3
Adverse Event Collection............................................................................67
7.2.3.4
Vital Signs ...................................................................................................67
7.2.3.5
Clinical Laboratory Evaluations..................................................................67
7.2.3.6
Pregnancy Test ............................................................................................69
7.2.3.7
Electrocardiogram .......................................................................................69
7.2.3.8
Nonpharmacologic Treatments and Procedures..........................................69
7.2.3.9
Thrombotic or Thromboembolic Events.....................................................70
7.2.3.10 Injection Site Reactions...............................................................................70
7.2.4
Others.....................................................................................................................71
7.2.4.1
Clinical Pharmacology Assessments...........................................................71
7.2.4.2
Health-related Quality of Life Assessments................................................72
7.2.4.3
Health Resource Utilization Assessment ....................................................73
7.2.4.4
Survey of Acceptability of SC Administration ...........................................73
7.2.4.5
Self-administration Survey Assessment......................................................73
7.2.5
Volume of Blood to Be Drawn From Each Subject ..............................................74
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................75
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................75


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8.1.1
Severity Categorization..........................................................................................75
8.1.2
Relationship Categorization...................................................................................76
8.1.3
Outcome Categorization ........................................................................................76
8.1.4
Symptoms of the Disease Under Study .................................................................76
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................77
8.1.6
Pregnancy...............................................................................................................77
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................78
8.2
Serious Adverse Event Procedures...............................................................................79
8.2.1
Reference Safety Information................................................................................79
8.2.2
Reporting Procedures.............................................................................................79
8.2.3
Serious Adverse Event Definition .........................................................................79
8.2.4
Serious Adverse Event Collection Time Frame ....................................................80
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................80
8.2.6
Fatal Outcome........................................................................................................80
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................81
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................81
9.1
Data Collection.............................................................................................................81
9.2
Clinical Data Management...........................................................................................81
9.3
Data Handling Considerations......................................................................................81
9.4
Statistical Analysis Process..........................................................................................82
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........82
9.6
Sample Size Calculation and Power Considerations....................................................82
9.7
Study Population ..........................................................................................................83
9.8
Efficacy Analyses.........................................................................................................83
9.8.1
Primary Efficacy Endpoint ....................................................................................83
9.8.2
Secondary Efficacy Endpoints...............................................................................84
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................84
9.8.2.2
Other Secondary Efficacy Endpoints ..........................................................85
9.8.3
Exploratory Efficacy Endpoints.............................................................................85
9.9
Safety Analyses ............................................................................................................86
9.10
Other Analyses .............................................................................................................86
9.10.1 Pharmacokinetic and Pharmacodynamic Analyses ...............................................86
9.10.2 Health-related Quality of Life Analyses................................................................87
9.10.3 Surveys on SC Administration and Self-administration of Investigational 
Product...................................................................................................................87
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................87


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10.1
Sponsor’s Responsibilities ...........................................................................................87
10.1.1 Good Clinical Practice Compliance.......................................................................87
10.1.2 Public Posting of Study Information .....................................................................88
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................88
10.1.4 Study Suspension, Termination, and Completion .................................................88
10.2
Investigator’s Responsibilities .....................................................................................88
10.2.1 Good Clinical Practice Compliance.......................................................................88
10.2.2 Protocol Adherence and Investigator Agreement..................................................89
10.2.3 Documentation and Retention of Records.............................................................89
10.2.3.1 Case Report Forms......................................................................................89
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................90
10.2.3.3 Audit/Inspection..........................................................................................90
10.2.3.4 Financial Disclosure....................................................................................90
10.3
Ethical Considerations..................................................................................................91
10.3.1 Informed Consent ..................................................................................................91
10.3.2 Institutional Review Board or Ethics Committee..................................................91
10.4
Privacy and Confidentiality..........................................................................................92
10.5
Study Results/Publication Policy .................................................................................92
11.
REFERENCES.............................................................................................................94
12.
APPENDICES..............................................................................................................97
LIST OF TABLES
Table 1:
Schedule of Assessments – Treatment Period 1....................................................22
Table 2:
Schedule of Assessments – Treatment Period 2....................................................24
Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits..............................................................................................26
Table 4:
Blood Sample Collection for PK/PD Analyses .....................................................27
Table 5:
Exposure to SC CINRYZE.......................................................................................32
Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)...................................................................................................35
Table 7:
Treatment Sequences.............................................................................................54
Table 8:
Severity Scoring for Injection Site Reactions........................................................71
Table 9:
Approximate Volume of Blood to Be Drawn From Each Subject ........................74


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LIST OF FIGURES
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity .....................................................36
Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)..................................................37
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice-weekly Dose Regimen....................................................................38
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206)...............................................................................................39
Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103) .............40
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)........40
Figure 7:
Study Design Flow Chart.......................................................................................44
LIST OF APPENDICES
Appendix 1 Handling of Investigational Product for Subcutaneous Injection.........................98
Appendix 2 Subcutaneous Injection Site Selection and Preparation........................................99
Appendix 3 Wells Prediction Rule for the Diagnosis of Venous Thrombembolism .............100
Appendix 4 Algorithm For Suspected Venous Thromboembolism .......................................101
Appendix 5 Algorithm For Suspected Arterial Thromboembolism.......................................102
Appendix 6 Protocol History..................................................................................................103


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ABBREVIATIONS
AAS
Angioedema Activity Score
AE
adverse event
AE-QoL
angioedema quality of life (questionnaire)
ATE
arterial thromboembolism
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
C1 INH
C1 esterase inhibitor or C1 inhibitor
CI
confidence interval
CL
clearance
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
Cmin
minimum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAE
hereditary angioedema
β-hCG
beta human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRUA
health resource utilization assessment
ICH
International Conference on Harmonisation


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IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
λz
first order rate constant associated with the terminal (log-linear) portion of 
the curve
NNA
normalized number of attacks
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDS
Sheehan Disability Scale
t1/2
terminal half-life
T/TE
thrombotic/thromboembolic
TCSR
time-to-subject-assessed-complete-symptom resolution
TEAE
treatment-emergent adverse event
TISI
time-to-subject-assessed-initial-symptom improvement
tmax
time of maximum observed concentration sampled during a dosing 
interval
UK
United Kingdom
US
United States
VAS
Visual Analogue Scale
VTE
venous thromboembolism
VZ/F
apparent volume of distribution
WPAI-GH
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire)


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STUDY SYNOPSIS
Protocol number: SHP616-300
Drug: C1 esterase inhibitor [human] liquid for injection
Title of the study: A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, 
Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 
Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and 
Adults with Hereditary Angioedema.
Number of subjects (total and for each treatment arm):
Approximately 75 subjects will be screened
At least 66 subjects will be enrolled and randomized to ensure that 54 subjects complete both treatment periods
At least 26 subjects will be randomized to the treatment sequence 1 or 2, and at least 14 subjects will be 
randomized to the treatment sequence 3 
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites globally (North America and Europe)
Study period (planned):
2015-2017
Clinical phase:
3
Objectives:
Primary:  
To demonstrate the superior efficacy of subcutaneous (SC) administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
normalized number of attacks (NNA) during a treatment period.
Key Secondary:  
To demonstrate the superior efficacy of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for 
injection for the prevention of angioedema attacks relative to placebo as measured by the proportion of subjects 
meeting the criterion of at least 50% reduction in the NNA during the 2000 IU C1 esterase inhibitor [human] 
liquid for injection treatment period relative to the placebo period.
Other Secondary:

To assess the proportion of responders during treatment with 2000 IU C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo, where the proportion of responders is defined as achieving 
at least a 50% reduction in the NNA during a treatment period relative to the pretreatment assessment (ie, 
the subject’s attack rate without prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 IU C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of attack-free days during treatment with 2000 IU C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of angioedema attacks requiring acute treatment during treatment with 2000 IU C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo

To assess the safety and tolerability of SC administration of 2000 IU C1 esterase inhibitor [human] liquid 
for injection

To assess the immunogenicity of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for 
injection

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SC administration of 2000 IU 


Shire ViroPharma, Inc.
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Protocol SHP616-300
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C1 esterase inhibitor [human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment of acute 
angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS)

To evaluate subject experience with self-administration of SC 2000 IU C1 esterase inhibitor [human] liquid 
for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient population
Rationale:
Shire ViroPharma has developed a new, ready-to-use liquid formulation of CINRYZE® for SC administration. 
This product, C1 esterase inhibitor [human] liquid for injection, obviates the need for reconstitution by the 
patient or health care provider and, owing to its higher concentration, affords the opportunity for more rapid 
administration of the drug and may improve tolerability, without an expected change or compromise in efficacy. 
Subcutaneous administration represents a convenient alternative method of administering prophylaxis to 
hereditary angioedema (HAE) patients overall and for whom accessing peripheral veins is difficult or in patients 
where placement of central venous catheters are contraindicated, as well as a means to minimize the potential 
adverse effects of intravenous (IV) administration.                                                                                                     
Investigational product, dose, and mode of administration:

C1 esterase inhibitor [human] liquid for injection is supplied in clear glass vials containing 1000 IU of 
C1 INH in 2 mL of sterile liquid. Two (2) vials, a total 4 mL, are required per 2000 IU dose. The solution 
also contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection. No reconstitution or dilution is required. Vials must be stored at 2–8oC (36–46oF) and protected 
from light.

Placebo is supplied in the identical 2 mL presentation as the active investigational product minus the 
C1 INH protein. Two (2) vials, a total 4 mL, are required per dose. The inactive ingredients in the 2 mL 
solution are the same as the active product: sodium phosphate, sorbitol, glycine, and water for injection. 
No reconstitution or dilution is required. Vials must be stored at 2–8oC (36–46oF) and protected from light.
Blinded investigational product (Treatments A or B: 2000 IU C1 esterase inhibitor [human] liquid for injection 
or placebo) will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate treatment 
periods. Each dose of investigational product will be administered in the subject’s abdomen as a single 4 mL SC
injection.
Commercial icatibant labeled for clinical trial use will be supplied as rescue medication for the treatment of 
acute angioedema attacks.


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Methodology:
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial crossover study. 
This design was chosen as the best way to jointly address the protocol objectives of establishing efficacy 
(relative to placebo) and safety (ie, enrolling an adequate number of subjects for precision of estimation in 
detecting potential safety signals). Additionally, this design maximizes the number of subjects exposed to 
C1 esterase inhibitor [human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have a history (based 
on subject recall and medical records) of ≥2 attacks per month on average per inclusion criterion #3. At least 66 
eligible subjects will be randomized to 1 of 3 treatment sequences prior to the first dose of investigational 
product in Treatment Period 1 using interactive response technology (see table below). Randomization of 
subjects will be stratified by use of prophylactic therapy with C1 INH at the time enrollment.
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 
3 or 4 days) for 14 weeks.
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission of a washout 
period is to minimize the duration that subjects will be without active treatment. It is recommended that the 
twice weekly dosing schedule (every 3 or 4 days) be maintained between the last dose of investigational product 
in Treatment Period 1 and the first dose of investigational product in Treatment Period 2. Every effort should be 
made to complete scheduled dosing and to avoid situations where investigational product is not received. In
order to prevent a missed dose, a less than 3-day interval may occur, with the recommendation of allowing at 
least 24 hours between doses.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be blinded to 
treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be administered at the 
investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both treatment periods. Other doses may be 
administered by qualified blinded personnel at the investigational site or at the subject’s home or other agreed 
upon location or self-administered by the subject (adolescent or adult) with or without supervision (qualified 
home health professional and/or study site personnel), after receiving appropriate training by the investigator or 
designee. Adolescent subjects self-administering investigational product will be supervised by a parent/legal 
guardian/caregiver (if home health professional and/or study site personnel is not present). Alternatively, a 
parent/legal guardian/caregiver after receiving appropriate training, will be allowed to administer the 
investigational product to an adolescent subject with or without supervision. 
Throughout the study, an electronic subject diary will be used to record specific information regarding the 
subject’s symptoms of HAE and details on self-administration. This will include signs and symptoms of 
angioedema attacks, location (including whether mucosal or non-mucosal), triggers for angioedema attacks, 
medications used for the acute treatment of angioedema attacks, elective procedures, and interruptions in 
activities of daily living due to an angioedema attack. Additionally, quality of life questionnaires and surveys on 
SC administration of the investigational product will be also subject evaluated. Note: For adolescent subjects, a 
parent/legal guardian/caregiver is allowed to assist the subject in completing the electronic subject diary, 
including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product is administered. In addition, the investigator will report all SAEs that 
occur through 30 days after the last dose of investigational product to Shire Pharmacovigilance and the 


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respective Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last dose of 
investigational product in Treatment Period 2 for follow-up safety assessments. In addition, subjects will have 
blood samples collected for PK/PD and C1 INH antibody testing at 1 month (±2 days) after the last dose of 
investigational product. 
If a subject prematurely discontinues investigational product, early discontinuation visit procedures (Table 3) 
are to be performed as completely as possible. Whenever possible, all discontinued subjects should also 
complete the 1-week and 1-month post-treatment visits.  
The schedules of study procedures are provided immediately following the study synopsis:

Table 1: Clinical study assessments – Treatment Period 1 (Visits 1a to 24a).

Table 2: Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Table 3: Clinical study assessments – Early discontinuation visit, 1-week post-treatment and 1-month 
post-treatment visits.

Table 4: Blood sample collection schedule – PK/PD assessments.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 inhibitor (C1 INH) level less than 50% of 
normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in conjunction with the 
subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy with C1 INH, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving prophylactic therapy 
with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) during the 
3 consecutive months prior to the screening visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of attenuated androgens, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any angioedema attacks 
that occur during the study that, in the opinion of the healthcare care provider, requires medical 
intervention. Note: For subjects ≥12 to <18 years of age, standard of care therapy per local protocols 
should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) pregnancy test at 
the screening visit and must have a negative urine pregnancy test prior to the first dose of 
investigational product (Visit 1a), and agree to comply with any applicable contraceptive requirements 
of the protocol.
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, 
barrier control) from the screening visit through 2 months after the last dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide written informed 
consent before any study-specific procedures. 
OR


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If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study 
provide written informed consent for the child to participate in the study before any study-specific 
procedures are performed (with assent from the child when appropriate). Alternatively, certain 
sites/Independent Reviewing Authorities may permit adolescents who are <18 years of age to be 
informed of the nature of the study and provide written informed consent without consent from a 
parent(s)/legal guardian.
Exclusion Criteria:
1.
Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved dosing 
regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with C1 INH.
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose of 
investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention of angioedema 
attacks within 3 calendar days prior to the first dose of investigational product in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or hormone 
replacement therapy (ie, estrogen/progestin containing products) within 2 months prior to the 
screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism.
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies.
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of 
CINRYZE), or other blood products, or Firazyr (icatibant).
9.
Be pregnant or breastfeeding.
10.
Have received an investigational drug within 30 days prior to the first dose of investigational product in 
Treatment Period 1.
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical or medical 
condition that could interfere with the administration of investigational product or interpretation of 
study results.
Maximum duration of subject involvement in the study:
Individual participation from the screening visit through the 1-month post-treatment visit will be approximately 
9 months.

Planned duration of screening period: Up to 21 days

Planned duration of enrollment period: 6 months

Planned duration of treatment period: Treatment Periods 1 and 2 are 14 weeks each (total 28 weeks) with 
no washout between periods

Planned duration of follow-up: 1 month follow-up in total, with safety assessments at both 1-week and 
1-month post-treatment
Endpoints and statistical analysis:
Primary Efficacy Endpoint: The NNA recorded during each treatment period. The NNA is computed as the 
number of attacks per month (ie, 30.4 days) of exposure (NNA = 30.4 x [number of attacks during treatment 
period]/[days of treatment period]). If a subject discontinues during the treatment period, the denominator of the 
NNA will be the days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation. 
The primary analysis of the primary efficacy endpoint will test against the null hypothesis that the NNA of C1 
esterase inhibitor [human] liquid for injection is greater than or equal to the NNA of placebo 
(H0: µ C1 INH - µ placebo >0; H1: µ C1 INH - µ placebo <0). The primary efficacy endpoint will be analyzed by using a 


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mixed effect linear model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH),
and treatment as fixed effects, and subject nested within sequence as a random effect. The mean treatment 
difference (µ C1 INH - µ Placebo) will be estimated with a 95% confidence interval (CI).
To control the overall type 1 error, the primary and key secondary endpoints will be tested hierarchically, so that 
the significance of the key secondary endpoint is contingent on whether the primary endpoint is significant.
Key Secondary Efficacy Endpoint: The clinical response to treatment relative to placebo. This is defined as 
achieving a ≥50% reduction in the NNA (PR) during the 2000 IU C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion PR. The null 
hypothesis is that PR is less than or equal to 0.2 and the alternative hypothesis is that PR is greater than 0.2. The 
proportion meeting criterion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. 
Other Secondary Efficacy Endpoints:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA during a treatment 
period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity recorded for each 
angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every day of reported 
symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment during a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS during a treatment 
period, where the daily AAS is the sum of AAS items per day.

Results of the Angioedema Quality of Life (AE-QoL) questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema attack by:
-
Time to subject-assessed initial symptom improvement (TISI).
-
Time to subject-assessed complete symptom resolution (TCSR). 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC administration of C1 
esterase inhibitor [human] liquid for injection. The treatment differences in clinical responder rate, both of 
which are defined within treatments, will be analyzed using McNemar’s test for testing equality of proportions 
of responders within treatments. All other secondary endpoints will be analyzed using a linear mixed effect 
model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH), and treatment as 
fixed effects, and subject nested within sequence as a random effect. The results of all secondary efficacy 
analyses will be summarized by the point estimate of within-subject treatment differences or response rates and 
the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75% quartiles, and range) will be 
provided to summarize icatibant-related efficacy endpoints (TISI and TCSR) by treatment and icatibant-treated 
angioedema attack for all subjects in the Full Analysis Set. Where appropriate (for subjects ≥12 to <18 years of 
age) other rescue medications used to treat acute angioedema attacks will also be summarized using descriptive 
statistics. In addition, angioedema attacks will be summarized by the maximum symptom severity and treatment 
for all subjects in the Full Analysis Set.
Safety Endpoints:

Number of subjects experiencing AEs, including severity and causality. AEs will also be assessed by time 
of onset (eg, during administration of investigational product or within 24 hours after the end of injection of 
investigational product). 

Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings will be 
summarized by treatment and visit. Potentially clinically important findings will also be summarized or 


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listed. 

Incidence, severity (mild, moderate, severe), overall impact on daily living, and duration of SC injection 
site reactions. 

Results of C1 INH antibody testing will be reported for individual subjects and summarized. 

Tolerability of icatibant therapy for acute angioedema attacks will be summarized.
PK/PD Endpoints: Plasma concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
and C1q for individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics for values at each time point. C1q concentrations will only be assessed 
at baseline (ie, pre-injection, Dosing Visit 1a).
PK parameters will be calculated using observed and baseline-corrected concentration-vs-time data using non-
compartmental techniques for C1 INH antigen and functional activity, and results will be summarized using 
descriptive statistics.
Other Endpoints:

Results of the EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) health status instrument will 
be presented in accordance with the EQ-5D-5L user guide (Version 2.0). 

Results of the Work Productivity and Activity Impairment−General Health (WPAI-GH) questionnaire will 
be summarized. 

Results of the Sheehan Disability Scale (SDS) will be summarized.

Results of the survey of subject acceptability of SC administration of investigational product will be 
summarized.

Results of the survey of subject experience with self-administration of investigational product will be 
summarized. 


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STUDY SCHEDULES
Table 1:
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a 15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a 26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj




j
Acceptability surveyk

Self-administration surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c, n
c, n
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4


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Table 1:
Schedule of Assessments – Treatment Period 1
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report 
form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; HRUA=health 
resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; 
PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the 
injection. Note: Vital sign measurements are not required at Visits 2a, 3a, and 4a for subjects self-administering investigational product without supervision (ie, assessment may not be 
possible).
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
g HIV (single assay antibody/INNO-LIA) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28a the overall impact on daily living (yes/no) and the duration of 
injection site reactions will be assessed for each subject.
k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack. 
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see Table 4).


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Table 2:
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg




g
Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; 
INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan 
Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site.
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing 
days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.
Note: Vital sign measurements are not required at Visits 2b, 3b, and 4b for subjects self-administering investigational product without supervision (ie, assessment may not be 


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Table 2:
Schedule of Assessments – Treatment Period 2
possible).
d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28b, the overall impact on daily living (yes/no) and the duration 
of injection site reactions will be assessed for each subject. 
h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.


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Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits
Procedures
Early Discontinuation 
Visita
[If Applicable]
1-Week (±1 day)
Post-treatment 
Visit
[All Subjects]
1-Month (±2 days)
Post-treatment
Visit
[All Subjects]
Concomitant medications


Physical examination


Vital signs (BP, pulse)b


Safety labsc


UA with microscopy


Pregnancy testingd


Adverse events/ SAEs g



Angioedema attack monitoringe, f


AASe


Acceptability surveye

Self-administration surveye

AE-QoL questionnairee


EQ-5D-5Le


WPAI-GH and SDSe


HRUA-HAE

Immunogenicity (anti-C1 INH antibodies)



PK/PD



AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; 
BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level 
descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs 
that occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department.
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits. 
b Vital signs will be measured using standard methods at each investigational site. 
c Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer).  
d A urine pregnancy test will be performed for all female subjects of childbearing potential.
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation or at the 
1-week post-treatment visit.
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary.
g Serious Adverse Events (SAEs) are to be followed until 1 month post-treatment visit.


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Table 4:
Blood Sample Collection for PK/PD Analyses
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Pointsa
C1 INH Antigen, C1 INH Functional, C4
1a / Dose 1b
Predose 1 (within 15 min) 
2a / Dose 2c
Predose 2 (within 15 min)
8a / Dose 8
Predose 8 (within 15 min)
16a / Dose 16
Predose 16 (within 15 min) 
24a / Dose 24
Predose 24 (within 15 min)
Either 27a or 28a / Dose 27 or 28d
Predose 27 or 28 (within 15 min) 
48 hours postdose 27 or 28 (±3 hours)
TREATMENT PERIOD 2
1b / Dose 1
Predose 1 (within 15 min)
2b / Dose 2c
Predose 2 (within 15 min)
8b / Dose 8
Predose 8 (within 15 min)
16b / Dose 16
Predose 16 (within 15 min)
24b / Dose 24
Predose 24 (within 15 min)
28b / Dose 28
Predose 28 (within 15 min)
24 hours postdose 28 (±3 hours) – optional sampling time point
48 hours postdose 28 (±3 hours) 
72 hours postdose 28 (±6 hours) – optional sampling time point
96 hours postdose 28 (±6 hours)
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT
Early discontinuation
1-week (± 1 day)
1-month (± 2 days)
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for 
guidance is as an approximate value.
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a).
c Subjects who self-administer investigational product without supervision are not required to have a blood sample collected 
at Visit 2a or 2b.
d To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose 
sample to be collected at either Visit 27a or 28a. 


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Hereditary angioedema (HAE) is an autosomal dominant disease caused by a gene mutation 
on chromosome 11 that results in a quantitative or functional deficiency of C1 esterase 
inhibitor (C1 INH) protein (Bernstein 2011). C1 INH is produced mainly by hepatocytes and 
acts as a “suicide inhibitor” by forming complexes with target serine proteases that result in 
their inactivation and the consumption of C1 INH. C1 INH regulates the activity of several 
components of the complement, contact (bradykinin-forming), and fibrinolytic systems 
(Kaplan 2010). Dysregulation of these cascades (particularly the contact system) due to 
C1 INH deficiency causes the uninhibited production of bradykinin, which promotes 
inflammation through increased vascular permeability and excessive accumulation of fluid in 
body tissues (Kaplan and Joseph 2010). Thus, patients with HAE are susceptible to recurrent 
episodes of debilitating swelling throughout the body. During acute angioedema attacks, the 
plasma levels of bradykinin in HAE patients can increase from 2 to 12 times (18.0–90.0 pM) 
the upper limit of normal (0.2-7.1 pM; Cugno et al. 2003). Serum concentrations of C1 INH 
in patients with HAE are 5% to 30% of normal (Cicardi et al. 1987), thus necessitating C1 
INH replacement therapy to prevent manifestations of the disease.
The diagnosis of a C1 INH deficiency is suggested by a history that includes recurrent attacks 
of angioedema, characterized by non-itching swelling of the skin or mucosa. Serum C4, 
C1 INH antigen, and functional C1 INH levels can be measured to assist with the diagnosis of 
HAE. There are 2 main types of HAE: Type I HAE (85% of cases), characterized by a low 
level of C1 INH antigen, and Type II HAE (15% of cases), characterized by “normal” levels 
of functionally deficient C1 INH protein (Frank et al. 1976). There is no clinical difference 
between Type I and Type II HAE. A third form of HAE, where patients have normal C1 INH 
levels, was initially described and referred to as Type III (Bork et al. 2000a). Patients with this 
type of HAE, more frequently women, have normal complement levels (including normal 
C1 INH), but a well-defined history of angioedema in the absence of concurrent urticaria 
(Zuraw and Christiansen 2009; Bernstein 2011). Mutations in the gene for coagulation factor 
XII (F12) have been identified in a minority of affected families (Bork et al. 2007). There are 
subtle phenotypic differences between patients with HAE due to C1 INH deficiency and those 
with normal C1 INH levels, including age at symptom onset, attack location(s), period of 
disease-free intervals, and inheritance pattern (Zuraw et al. 2012). The pathogenesis of HAE 
with normal C1 INH remains to be fully elucidated.  
Hereditary angioedema with C1 INH deficiency can present as early as the first year of life 
(Ohela 1977; Farkas et al. 2002), however, the median age at onset of initial symptoms is 
between 9 and 12 years (Farkas et al. 2007). Nearly all affected individuals experience 
symptoms of the disease; however, the symptoms vary in both their frequency and severity 
throughout a patient’s lifetime (Gompels et al. 2005; Zuraw 2003). Angioedema attacks may 
or may not have a triggering event. Trauma, medical or dental procedures, psychological 
stress, menstruation, infections, oral contraceptive use, and the use of other medications, such 
as angiotensin-converting enzyme inhibitors have been identified as possible triggers (Georgy 


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and Pongracic 2012; Bowen et al. 2010). Angioedema attacks can affect the face, tongue,
larynx, gastrointestinal tract, genitourinary system, and extremities (Zuraw 2008). Laryngeal 
swelling can occlude the airway and cause death by asphyxiation, and these attacks primarily 
account for the mortality risk associated with C1 INH deficiency (Agostoni and Cicardi 1992; 
Bork et al. 2000b). Gastrointestinal involvement can mimic an acute surgical emergency, and 
misdiagnosis often results in unnecessary procedures to remove normal appendices and 
gallbladders (Weis 2009). Hence, angioedema attacks require prompt treatment, often in an 
emergency room.  
In addition to the impact on physical and mental health, the burden of illness in patients with 
HAE is considerable with respect to missed educational and career opportunities, work 
productivity, and a substantial economic burden for the cost of treatment (Lumry et al. 2010; 
Aygören-Pürsün et al. 2014). Hereditary angioedema not only causes short-term disability 
associated with attacks, but patients endure long-term effects on their daily lifestyle, 
emotional health, family life, and it may also affect caregivers’ quality of life (Bygum et al. 
2015). Effective management of HAE, including optimization of therapy, may reduce the 
clinical burden and have an overall favorable impact on the quality of life for individual HAE 
patients and their families (Banerji 2013; Caballero et al. 2014).
1.2
Product Background and Clinical Information
CINRYZE® (C1 esterase inhibitor [human]) was developed by the sponsor for the management 
of HAE. CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of C1 INH 
produced 
from 
human 
plasma. 
The 
manufacturing 
process 
includes 
3 
virus 
inactivation/removal 
steps: 
polyethylene 
glycol 
precipitation, 
pasteurization, 
and 
nanofiltration. CINRYZE is a normal human plasma protein that is not subject to cytochrome 
P450 metabolism, excretion, or pharmacokinetic (PK) drug-drug interactions exhibited by low 
molecular weight compounds. 
Intravenous (IV) administration of 1000 U of CINRYZE every 3 or 4 days is approved for 
routine prevention (prophylaxis) of angioedema attacks in patients with HAE in the United 
States (2008), European Union (2011), Australia (2012), Canada (2012), and Switzerland 
(2013). In several of these countries, CINRYZE is also approved for the acute treatment and 
preprocedure prevention of angioedema attacks.
The clinical efficacy of CINRYZE for the prevention of angioedema attacks in patients with 
HAE was demonstrated in 1
randomized, double-blind, placebo-controlled study 
(LEVP 2005-1/B) and 1 open-label study (LEVP 2006-4). Study LEVP 2005-1/B 
demonstrated that preventive therapy with CINRYZE resulted in both a statistically significant 
and clinically meaningful decrease in the rate, severity, and duration of acute attacks 
compared to placebo/on-demand therapy. Therapy with CINRYZE also increased antigenic 
C1 INH and functional C1 INH levels. These results were supported by Study LEVP 2006-4 
(that provided data for longer periods of preventive therapy across a wider age range of 
subjects), which demonstrated a reduction in the frequency of attacks while on CINRYZE
compared to a historical baseline. The open-label study also demonstrated that the efficacy of 


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CINRYZE for the prevention of angioedema attacks did not diminish over time periods of at 
least 1 year. 
The sponsor initiated a clinical development program for subcutaneous (SC) administration of 
CINRYZE for prevention of angioedema attacks using the same lyophilized formulation as that 
approved for IV injection. The initial program focused on safety, tolerability, and relative 
bioavailability of SC administration of CINRYZE (Studies 0624-100 and 0624-200). 
Preliminary assessments confirmed that CINRYZE can be absorbed after SC administration. 
However, because the exposure profile differed from that following IV administration, it was 
not known whether or to what extent SC administration would confer efficacy for the 
management of HAE.  
Based on results from nonsponsor studies conducted with recombinant human hyaluronidase 
(rHuPH20) and other injectable protein products, it was hypothesized that co-administration 
with rHuPH20 would increase dispersion and absorption of subcutaneously injected CINRYZE. 
Subsequently, 
the 
development 
program 
evaluated 
the 
safety, 
tolerability, 
PK/pharmacodynamics (PD), and efficacy of SC administration of CINRYZE with rHuPH20 
(Studies 0624-101, 0624-102, 0624-204, and 0624-206). However, in August 2013, the FDA 
directed the sponsor to stop administration of rHuPH20 in the ongoing Phase 2 study (0624-
206) of CINRYZE with rHuPH20 due to the development of anti-rHuPH20 antibodies in some 
patients. Dosing was also terminated in an ongoing Phase 1 healthy volunteer study (0624-
102) of CINRYZE with rHuPH20. Because the combination product (CINRYZE with rHuPH20) 
was being studied in these 2 trials, administration of CINRYZE was also discontinued. The 
FDA encouraged the sponsor to further the clinical development of CINRYZE alone 
administered via SC injection. Hence the evolution of the clinical development program with 
the new low volume, ready-to-use liquid formulation (C1 esterase inhibitor [human] liquid for 
injection) for SC administration. 
C1 esterase inhibitor [human] liquid for injection has been evaluated in an in vitro 
hemocompatibilitiy assay using human blood and plasma, a tissue irritation study in New 
Zealand White rabbits, and a 14-day repeat-dose toxicity study in Sprague Dawley rats. 
Incubation with whole blood at a concentration of 225 IU/mL C1 esterase inhibitor [human] 
liquid for injection did not elicit hemolysis nor did the same concentration induce 
flocculation, precipitation, or coagulation. In the tissue irritation study in rabbits, microscopic 
examination of the injection sites showed minimal to mild inflammation that was most 
pronounced for perivascular injection route, followed by SC and then IV injection routes. In 
the 14-day repeat-dose study in rats, doses of 0 (sodium phosphate, glycine, and sorbitol), 
200, 400, and 1000 IU/kg/day were administered subcutaneously once a day, while a fifth 
group of rats received 1000 IU/kg/day intravenously. The only signs of toxicity were related 
to the expected immunogenic response to a human protein. Therefore, the no observed 
adverse effect level is considered to be 1000 IU/kg/day of C1 esterase inhibitor [human] 
liquid for injection for both the SC and IV routes of administration. Therefore, the toxicity 
profile for this ready-to-use liquid formulation is generally comparable to the lyophilized 
product even when a higher dose of the new formulation was tested. 


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An initial clinical assessment of the new liquid formulation was conducted in a Phase 1 study 
in healthy volunteers (SHP616-103). This study evaluated the safety, tolerability, and relative 
bioavailability of the SC administration of 1000 IU and 2000 IU C1 esterase inhibitor 
[human] liquid for injection compared with the marketed formulation of CINRYZE (1000 U 
IV). This single-center, open-label study consisted of a single-dose IV administration of 
CINRYZE (lyophilized formulation) in Treatment Period 1 followed by a randomized, 
open-label, 2x2 crossover design (Treatment Periods 2 and 3) to evaluate SC C1 esterase 
inhibitor [human] liquid for injection. The safety and pharmacokinetic results from Study 
SHP616-103 are presented in Sections 1.2.1.1 and 1.2.2.2, respectively.
High-level summaries of the clinical experience with SC administration of both CINRYZE
(CINRYZE alone and CINRYZE + rHuPH20) and C1 esterase inhibitor [human] liquid for 
injection are provided below. Always refer to the latest version of the CINRYZE investigator’s 
brochure for the overall risk/benefit assessment and the most accurate and current information 
regarding the drug metabolism, pharmacokinetics, efficacy, and safety of CINRYZE and C1 
esterase inhibitor [human] liquid for injection. 
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and with SC 
C1 Esterase Inhibitor [Human] Liquid for Injection
Studies that evaluated SC administration of CINRYZE alone and CINRYZE with rHuPH20 
provided valuable data that informed key elements of this Phase 3 study of C1 esterase 
inhibitor [human] liquid for injection. Both programs enrolled healthy volunteers and subjects 
with HAE; 86 healthy volunteers (215 doses administered) and 72 subjects with HAE 
(1321 doses administered) have received 1 or more doses of SC CINRYZE in the development 
program to date (Table 5).


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Table 5:
Exposure to SC CINRYZE
Program
Study Number
Total Number of 
Subjects Exposed 
Number of SC Doses Administered
500 U
1000 U
2000 U
Total Doses
Healthy Volunteers
CINRYZE Alone
Study 0624-100a
9
1
0
14
15
Study 0624-102b
37 
0
37
0
37
CINRYZE with rHuPH20
Study 0624-101
24
0
0
47
47
Study 0624-102b
51 
0
116
0
116
Healthy Volunteers Total
86
1
153
61
215
Subjects with HAE
CINRYZE Alone
Study 0624-200
25
0
52
48
100
CINRYZE with rHuPH20
Study 0624-204
12 d
0
24
24
48
Study 0624-206
47
0
578
595
1173
Subjects with HAE Total
72
0
654
667
1321
OVERALL TOTAL
158
1
807
728
1536
HAE=hereditary angioedema; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
a CINRYZE via SC infusion and SC injection.
b A total of 53 subjects were enrolled in Study 0624-102 and received SC CINRYZE either alone (N=37) or co-administered 
with rHuPH20 (N=51).
c These 12 subjects received SC CINRYZE alone in Study 0624-200 and SC CINRYZE with rHuPH20 in Study 0624-204.
1.2.1.1
Clinical Safety 
Across the 2 studies of SC CINRYZE alone (Studies 0624-100 and 0624-200), 9 healthy adults 
and 25 subjects with HAE received CINRYZE doses of 1000 U and/or 2000 U. In healthy adult 
subjects, a single dose of 2000 U CINRYZE administered via the SC route was associated with 
mild injection/infusion site discomfort; however, no subjects were discontinued from study 
drug due to an AE. In HAE subjects, multiple doses of CINRYZE (1000 U or 2000 U) 
administered via the SC route were associated with generally mild to moderate injection site 
reactions, most notably pain, which was commonly characterized as burning or stinging. No 
subjects were discontinued from study drug due to an injection site reaction. No SAEs 
occurred during either SC study, and no subjects experienced a TEAE that was thrombotic or 
thromboembolic in nature. In addition, in both studies of SC CINRYZE, results of clinical 
laboratory evaluations and vital signs measurements were generally unremarkable and did not 
suggest any treatment-emergent abnormalities related to the administration of CINRYZE.
Across the 4 studies of SC CINRYZE + rHuPH20 (Studies 0624-101 0624-102, 0624-204 and 
0624-206), 77 healthy adults and 59 subjects with HAE received CINRYZE doses of 1000 U 


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and/or 2000 U. No SAEs occurred, no subjects were discontinued due to an AE, and no 
subjects experienced a TEAE that was thrombotic or thromboembolic in nature. The most 
commonly reported AEs were mild-moderate injection site reactions (eg, erythema, swelling, 
pain). Other safety parameters (clinical laboratory evaluations and vital signs measurements) 
were generally unremarkable and did not suggest any treatment-emergent abnormalities 
related to the administration of SC CINRYZE + rHuPH20. 
In Study 0624-206, a total of 21 (45%) subjects had detectable anti-rHuPH20 antibodies 
during the study, with 15 (32%) of the 21 subjects having a post-baseline titer of >1:20. All 
samples from these subjects were determined to be negative for rHuPH20-neutralizing 
activity. As requested by the FDA, the sponsor followed subjects who had treatment-emergent 
titers of ≥1:20 for 1 year post-treatment. There were no clinical sequelae observed in any 
subject and all titers declined during longitudinal follow-up. Three subjects in Study 0624-102 
had reportable anti-rHuPH20 antibodies at a titer ≥1:20; however, in all 3 cases, subjects had 
antibodies to rHuPH20 present at baseline (prior to the first dose of study drug). Subjects 
were not asked to participate in longitudinal follow-up, as anti-rHuPH20 antibody titers 
remained at or below the baseline level for each subject by the end of the study. 
In Study SHP616-103, a total of 26 healthy volunteers were enrolled in the study. Twenty-
three (23) subjects received a single SC dose of both 1000 and 2000 IU, and 1 subject only 
received a single SC dose of the 1000 IU C1 esterase inhibitor [human] liquid for injection. 
Therefore 24 unique subjects have been exposed to 47 doses of C1 esterase inhibitor [human] 
liquid for injection.
Subcutaneous administration of 1000 IU and 2000 IU C1 esterase inhibitor [human] liquid for 
injection was generally well tolerated and the clinical safety data were consistent with 
previous CINRYZE IV or SC studies. Overall 19 (73.1%) of the 26 subjects reported at least 1 
TEAE in the study: 62% (16/26), 29% (7/24), and 44% (10/23) of subjects administered 
1000 U IV CINRYZE, 1000 IU and 2000 IU of SC C1 esterase inhibitor [human] liquid for 
injection, respectively.
With regard to the local tolerability of SC administration of 1000 IU and 2000 IU C1 esterase 
inhibitor [human] liquid for injection, there was no clear difference in the overall incidence of 
injection site reactions with respect to dose (1000 IU versus 2000 IU). Twenty-three of 24 
(95.8%) subjects reported injection site reactions, all were mild (58.3%) to moderate (37.5%) 
in severity, and the majority resolved within 2 hours postdose. The majority of reported 
reactions were erythema (mild or moderate) and a warm sensation (all mild).
1.2.1.2
Clinical Efficacy
The Phase 2 dose-ranging, crossover Study 0624-206 was designed to determine if there was 
a difference in efficacy between 2 SC doses of CINRYZE (1000 U and 2000 U co-administered 
with rHuPH20). The study was terminated before enrollment was complete (at the request of 
FDA due to the detection of anti-rHuPH20 antibodies in some subjects). Of the 47 subjects 
enrolled, 22 completed both treatment periods. Thus, due to the early termination of the study, 
the final sample size of the intent-to-treat efficacy population was smaller than planned 


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(22/47, 47%). Regardless, the statistical advantage of a crossover study is that patients serve 
as their own control and the relative effect of the experimental treatments can be determined 
most efficiently with respect to within-patient differences.
The experimental results favored twice weekly SC administration of CINRYZE 2000 U + 
48,000 U rHuPH20 compared with CINRYZE 1000 U + 24,000 U rHuPH20 for the primary 
and all secondary efficacy endpoints during treatment, most notably in the within-subject 
treatment comparison.
An analysis of primary and secondary efficacy endpoints during treatment was performed for 
the mean difference between treatments (2000 U – 1000 U SC CINRYZE), within subjects in a 
treatment sequence and overall, as shown below in Table 6.
For the primary endpoint of normalized number of angioedema attacks during treatment, a 
treatment effect favoring the 2000 U compared with the 1000 U SC CINRYZE dose was 
observed for the within-subject treatment comparison; the overall mean difference (95% 
confidence interval [CI]) between treatments was -0.61 (-1.23, 0.01) and achieved borderline 
significance (p=0.0523).
With regard to secondary efficacy endpoints, statistically significant (p<0.05) treatment 
effects favoring the 2000 U compared with the 1000 U SC CINRYZE dose were observed for 
the within-subject treatment comparisons for both cumulative attack severity and for the 
number of attacks requiring acute treatment, with overall mean differences between 
treatments of -1.33 (p=0.0277) and -0.56 (p=0.0315), respectively.
No sequence effect was observed for the mean difference between the 2000 U and 1000 U SC 
CINRYZE doses within subjects in Sequences A/B or B/A for the primary or for any secondary 
endpoint (p-value for sequence effect across endpoints: ≥0.6290).
These findings indicated that CINRYZE at a dose of 2000 U SC was superior to a dose of 
1000 U in terms of clinical efficacy improvement. The results are more compelling in light of 
their arising from truncated enrollment and consequently, an underpowered study.


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Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)
Endpoints (Normalized)
Sequence A/B
Difference: B-A
N=12
Sequence B/A
Difference: B-A
N=10
Overall
Difference: B-A
N=22
Treatment
Comparison
p-valuea
Primary
Number of angioedema attacks
-0.72
(-1.71, 0.27)
-0.48
(-1.36, 0.40)
-0.61
(-1.23, 0.01)
0.0523
Secondary
Cumulative attack severity
-1.53
(-3.41, 0.35)
-1.09
(-2.74, 0.57)
-1.33
(-2.49, -0.16)
0.0277
Cumulative daily severity
-1.53
(-4.42, 1.36)
-2.19
(-6.06, 1.69)
-1.83
(-3.98, 0.32)
0.0912
Cumulative symptomatic days
-0.95
(-2.64, 0.74)
-0.87
(-3.35, 1.62)
-0.91
(-2.23, 0.41)
0.1660
Number of attacks requiring acute 
treatment
-0.67
(-1.20, -0.14)
-0.43
(-1.47, 0.62)
-0.56
(-1.06, -0.05)
0.0315
CI=confidence interval; ITT-E=intent-to-treat efficacy; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
Note: Data are presented as the mean (95% CI). Treatment A=1000 U SC CINRYZE + 24,000 U rHuPH20; 
Treatment B=2000 U SC CINRYZE + 48,000 U rHuPH20. Subjects who were dosed but did not have any attacks in the 
period were assigned a value of zero for each of the efficacy parameters.
a p-value for paired t-test.
b Only subjects who completed both treatment periods are included in the ITT-E population.
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid for 
Injection
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis of CINRYZE
Population PK and PK/PD modeling of C1 INH and C4 were developed based on data 
collected in 10 clinical studies with healthy volunteers and HAE patients who received IV or 
SC administrations of CINRYZE. Exposure-response analyses were performed based on 
2 studies for the use of CINRYZE for the prophylactic treatment to prevent HAE. 
The final population PK model of C1 INH was a 1-compartment model with endogenous 
C1 INH levels. The absorption of CINRYZE following SC dosing was characterized with a 
first-order rate and relative absorption fraction (Frel). Based on the population PK model, the 
relative bioavailability of CINRYZE following SC dosing without rHuPH20 was 38.8%. 
Typical CL of C1 INH was 0.0864 L/h (1.44 mL/min) in HAE patients with a typical body 
weight of 70 kg. The t1/2 of C1 INH in a typical 18.0, 36.6, and 80.0-year-old patient weighing 
70 kg were 32.0, 29.0, and 26.0 hours, respectively.
The effect of rHuPH20 on the rate and extent of absorption of C1 INH was included in the 
model. The use of rHuPH20 with SC administration appears to have little to no improvement 


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on C1 INH exposure. This was illustrated in the Phase 1 study with healthy volunteers 
(Study 0624-102) where CINRYZE 1000 U SC administered with 200, 2000, or 20,000 U 
rHuPH20 was not statistically different in Cmax and AUClast compared with CINRYZE alone. In 
addition, the population PK model estimated only a 10% increase in bioavailability with 
rHuPH20, which reached saturation with increasing rHuPH20 concentrations as presented in 
Figure 1.
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity
C1 INH=C1 esterase inhibitor; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
The population PK model was used to support the assessment of the exposure-response 
relationship of CINRYZE during prophylactic treatment of angioedema attacks for C1 INH and 
C4. The response criterion originally used in Study 0624-400 was used to define responder 
status, whereby a response was defined as ≤1 angioedema attack/month, since this criterion 
has been deemed clinically meaningful by both expert clinicians and patients with HAE. A 
logistic regression model was used to link Cmin values of C1 INH (continuous) with the 
probability of response (binary) following IV dosing of 1000 U of CINRYZE in studies LEVP 
2005-1/B and LEVP 2006-4 (Section 1.2). The exposure-response relationship of Cmin values 
of C1 INH following IV dosing of CINRYZE is presented in Figure 2.


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Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)
C1 INH=C1 esterase inhibitor; ROC=receiver-operating characteristic
Higher Cmin values of C1 INH were associated with a higher probability of response in 
patients with HAE (p<0.001). The above exposure-response relationship was to be used to 
predict the probability of response for any Cmin values of C1 INH in subjects with HAE. For 
example, typical Cmin values of 0.207, 0.289, 0.380, and 0.556 U/mL (corresponding to first, 
second, third, and fourth quartiles of Cmin of C1 INH, respectively) would be expected to 
result in response probabilities of 54.4%, 61.5%, 68.8%, and 80.5%, respectively. Typical C1 
INH plasma functional activity levels in HAE patients range from 5–30% of normal 
(0.05-0.3 U/mL) (Cugno et al. 1990).
Receiver-operating characteristic analysis was used to identify an optimal Cmin cutoff of C1 
INH that would optimize the probability of avoiding an angioedema attack. Based on data 
from study LEVP 2006-4 with IV administration of 1000 U CINRYZE approximately twice 
weekly, the optimal Cmin cutoff was 0.479 U/mL. When considering a 2-week period of delay, 
the optimal Cmin cutoff was 0.433 U/mL. Based on the above ROC analyses, a targeted 
C1 INH Cmin value of 0.45 U/mL was used to determine the expected response following SC 
dosing of 2000 U of CINRYZE. Based on the exposure-response model, a C1 INH Cmin value 
of >0.45 U/mL would achieve at least a 70% probability of success (≤1 angioedema 
attack/month).


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No statistically significant relationship was observed between minimum C4 concentrations 
and the probability of response.
The combination of the population PK model and exposure-response relationship model was 
used to simulate C1 INH Cmin following SC dosing of CINRYZE to support the dosing rationale 
and improve the likelihood of success at achieving an efficacious dose in patients with HAE 
(Figure 3).
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice-weekly Dose Regimen
C1 INH=C1 esterase inhibitor; HAE=hereditary angioedema
From these simulations, results show that a dose of 2000 U would maintain mean (blue line) 
functional C1 INH Cmin values above the targeted level of 0.45 U/mL (red horizontal line).
In studies LEVP 2005-1/B and LEVP 2006-4, in which subjects with HAE received IV doses 
of 1000 U CINRYZE approximately twice weekly, mean pre-infusion functional C1 INH 
concentrations ranged from 0.38-0.41 U/mL and 0.37-0.52 U/mL, respectively, during the 
treatment period. 
In the recent Phase 2 clinical study 0624-206, in which subjects with HAE received twice 
weekly SC doses of 1000 U CINRYZE with 24,000 U rHuPH20 or 2000 U CINRYZE with 
48,000 U rHuPH20 in two 8-week crossover periods, higher exposure with the 2000 U 
CINRYZE dose was observed (Figure 4). The mean baseline-corrected Cmax and AUC0-168 of 


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antigenic C1 INH for 2000 U SC CINRYZE + 48,000 U rHuPH20 were 1.8- and 2.3-fold 
higher, respectively, compared to those observed for 1000 U SC CINRYZE + 24,000 U 
rHuPH20. The mean baseline-corrected Cmax and AUC0-168 of functional C1 INH activity for 
2000 U SC CINRYZE + 48,000 U rHuPH20 were 2.0- and 2.6 fold higher, respectively, 
compared to their respective means for 1000 U SC CINRYZE + 24,000 U rHuPH20. The 
observed mean minimum concentration (Cmin) of functional C1 INH activity at steady-state 
for the 2000 U dose of SC CINRYZE with rHuPH20 was above the physiologically relevant 
level of 0.4 U/mL compared with 1000 U dose of SC CINRYZE with rHuPH20 (0.408 and 
0.319 U/mL, respectively). 
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206)
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid for Injection
In Study SHP616-103, new bioanalytical assays were developed and validated for the 
quantitative determination of C1 INH protein and functional binding of C1 INH in human 
plasma. These assays differed from those used in previous CINRYZE SC studies to determine 
plasma concentrations of C1 INH antigen and functional C1 INH activity. 
Following SC administration of 1000 IU and 2000 IU C1 esterase inhibitor [human] liquid for 
injection, injected C1 INH was slowly absorbed with median tmax ranging from 36–48 hours 
for both C1 INH antigen and functional C1 INH binding. Mean baseline-corrected Cmax and 


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AUClast PK parameters for both C1 INH antigen and functional C1 INH binding after IV and 
SC administration are shown in Figure 5 and Figure 6, respectively. 
Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Subcutaneous administration of C1 esterase inhibitor [human] liquid for injection was less 
than dose proportional, with a 2-fold increase in dose resulting in 1.76- and 1.58-fold increase 
in Cmax and AUClast respectively for C1 INH antigen, and 0.99- and 1.09-fold increase in Cmax
and AUClast respectively for functional C1 INH binding. 
The baseline-corrected point estimates of the AUClast ratios and 90% confidence intervals for 
C1 INH antigen and functional C1 INH binding was used to determine the relative 
bioavailability of 1000 and 2000 IU C1 esterase inhibitor [human] liquid for injection with 
1000 U IV CINRYZE. The relative bioavailabilities for the 1000 IU and 2000 IU SC dose of 
C1 esterase inhibitor [human] liquid for injection were approximately 69% (44–110%) and 
60% (38–95%) respectively for C1 INH antigen, and 67% (34–130%) and 39% (20–77%) 
respectively for C1 INH functional binding (in non-HAE subjects).


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1.2.2.3
Dose Selection
The approach for preventative therapy in HAE patients is to provide enough CINRYZE to 
achieve or exceed a threshold C1 INH functional activity concentration in plasma that has a 
>70% likelihood of preventing an angioedema attack. The combined data from prior SC 
CINRYZE studies (including the evaluation of bioavailability) along with the demonstration of 
similar bioavailability achieved in the completed Phase 1 single dose study of C1 esterase 
inhibitor [human] liquid for injection, support dose selection of 2000 IU C1 esterase inhibitor 
[human] liquid for injection for further evaluation in a Phase 3 study. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The sponsor has developed a new, ready-to-use liquid formulation of CINRYZE (C1 esterase 
inhibitor [human]). The CINRYZE liquid product (C1 esterase inhibitor [human] liquid for 
injection) is intended for the same indication as the licensed, lyophilized powder formulation 
of CINRYZE: routine prophylaxis against angioedema attacks in adolescent and adult patients 
with HAE. The route of administration will be SC injection, and the dosing regimen will be 
2000 IU every 3 or 4 days. Shire ViroPharma anticipates that patients will benefit from the 
inherent advantages of SC administration, as well as the ready-to-use liquid, lower volume 
product compared with one requiring reconstitution. In addition, the CINRYZE liquid product 
is more concentrated than the licensed CINRYZE product (500 vs 100 U/mL), which should 
enable more rapid administration of the drug and may improve tolerability, without an 
expected change or compromise in efficacy.
The sponsor has selected 2000 IU of C1 esterase inhibitor [human] liquid for injection as the 
appropriate active dose for this Phase 3 study. This dose is based on the results of a recently 
completed Phase 2, randomized, double-blind, dose-ranging, crossover study that evaluated 
SC administration of CINRYZE with rHuPH20 (a dispersing agent) for the prevention of 
angioedema attacks in adolescents and adults with HAE (Study 0624-206). Results revealed 
greater clinical benefit with 2000 U of CINRYZE compared with 1000 U. In addition, the 
2000 IU dose is supported by PK results from Study 0624-206, by the results of population 
PK and exposure-response modeling, and by PK data from a Phase 1 study (0624-102) that 
demonstrated the minimal influence of rHuPH20 on functional C1 INH activity when co-
administered with CINRYZE (Section 1.2.2.1). Finally, the 2000 IU dose is further supported 
by the PK and bioavailability data from the Phase 1 study of C1 esterase inhibitor [human] 
liquid for injection (Protocol SHP616-103).
The study design was chosen as the best way to jointly address the protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, adequate numbers of subjects for 
precision of estimation in detecting potential safety signals). Additionally, this design 
maximizes the number of patients exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes patient exposure to placebo while having adequate patient exposure 
to placebo to assess efficacy. Thus, the proposed study is described as a “partial” crossover 
because 2 treatment sequences involve crossing over to the other experimental agent and the 


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third sequence does not. All subjects will receive active treatment during this study and will 
have an overall two-thirds probability to be randomized to active drug in any treatment 
period.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to demonstrate superior efficacy of SC administration 
of 2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of 
angioedema attacks relative to placebo based on the normalized number of attacks (NNA) 
during a treatment period.
2.2.2
Secondary Objectives
The key secondary objective is to demonstrate the superior efficacy of SC administration of 
2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by the proportion of subjects meeting the criterion of 
at least 50% reduction in the NNA during the 2000 IU C1 esterase inhibitor [human] liquid 
for injection treatment period relative to the placebo period.
Other secondary objectives are:

To assess the proportion of responders during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo, where the 
proportion of responders is defined as achieving at least a 50% reduction in the NNA 
during a treatment period relative to the pretreatment assessment (ie, the subject’s 
attack rate without prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 IU C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of attack-free days during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of angioedema attacks requiring acute treatment during treatment 
with 2000 IU C1 esterase inhibitor [human] liquid for injection relative to treatment 
with placebo 

To assess the safety and tolerability of SC administration of 2000 IU C1 esterase 
inhibitor [human] liquid for injection

To assess the immunogenicity of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection 

To characterize the PK and PD of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection


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
To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the 
treatment of acute angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS) 

To evaluate subject experience with self-administration of SC 2000 IU C1 esterase 
inhibitor [human] liquid for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient 
population
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial 
crossover study (Figure 7). The design was chosen to optimally address the joint protocol 
objectives of establishing efficacy (relative to placebo) and safety (ie, enrolling an adequate 
number of subjects to have precision of estimation to detect or rule out safety signals). 
Additionally, this design maximizes the number of subjects exposed to C1 esterase inhibitor 
[human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have 
a history (based on subject recall and medical records) of ≥2 attacks per month on average per 
inclusion criterion #3. At least 66 eligible subjects will be randomized to 1 of 3 treatment 
sequences prior to the first dose of investigational product in Treatment Period 1 (ie, Dosing 
Day 1a) using interactive response technology (IRT). Randomization of subjects will be 
stratified by use of prophylactic therapy with C1 INH at the time enrollment. 


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Figure 7:
Study Design Flow Chart
Each treatment period will be 14 weeks, without a washout between the 2 periods. The 
omission of a washout period is to minimize the duration that subjects will be without active 
treatment. It is recommended that the twice weekly dosing schedule (every 3 or 4 days) be 
maintained between the last dose of investigational product in Treatment Period 1 and the first
dose of investigational product in Treatment Period 2. Every effort should be made to 
complete scheduled dosing and to avoid situations where investigational product is not 
received. In order to prevent a missed dose, a less than 3-day interval may occur, with the 
recommendation of allowing at least 24 hours between doses.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be 
blinded to treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be 
administered at the investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both 
treatment periods. Other doses may be administered by qualified blinded personnel at the 
investigational site or at the subject’s home or other agreed upon location or self-administered 
by the subject (adolescent or adult) with or without supervision (qualified home health 
professional or study site personnel), after receiving appropriate training by the investigator or 
designee. Adolescent subjects self-administering investigational product will be supervised by 
a parent/legal guardian/caregiver (if home health professional and/or study site personnel is 
not present). Alternatively, a parent/legal guardian/caregiver after receiving appropriate 
training, will be allowed to administer the investigational product to an adolescent subject 
with or without supervision.


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Throughout the study, an electronic subject diary will be used to record specific information 
regarding the subject’s symptoms of HAE and details on self-administration as described in 
Sections 7.2.2.2 and 6.5. Additionally, quality of life questionnaires and surveys on SC 
administration of the investigational product will be also subject evaluated. Note: For 
adolescent subjects, a parent/legal guardian/caregiver is allowed to assist the subject in 
completing the electronic subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days 
after the last dose of investigational product. This includes events occurring during the 
screening phase of the study, regardless of whether or not the investigational product is 
administered. In addition, the investigator will report all SAEs that occur through 30 days 
after the last dose of investigational product to Shire Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of the investigational product in Treatment Period 2 for follow-up safety assessments. In 
addition, subjects will have blood samples collected for PK/PD and C1 INH antibody testing 
at 1 month (±2) days after the last dose of the investigational product.
If a subject prematurely discontinues investigational product, regardless of the reason, the 
early discontinuation visit safety procedures listed in Table 3 are to be performed as 
completely as possible. Whenever possible, all discontinued subjects should also complete the 
1-week and 1-month post-treatment visits. 
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 9 months. 
The study will be completed in approximately 15 months. 
The Study Completion Date is defined as the date the final subject, across all sites, completes
their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. The Study Completion Date is used to ascertain timing for study
results posting and reporting.
3.3
Sites and Regions
Approximately 40 sites globally (North America and Europe) are expected to participate in 
this study.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.


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4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria
below.
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 INH level less than 50% 
of normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in 
conjunction with the subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy 
with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) 
during the 3 consecutive months prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving 
prophylactic therapy with C1 INH, have a history of ≥2.0 angioedema attacks 
per month (average) during the 3 consecutive months prior to the screening 
visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of 
attenuated androgens, have a history of ≥2.0 angioedema attacks per month 
(average) during the 3 consecutive months prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any 
angioedema attacks that occur during the study that, in the opinion of the healthcare 
care provider, require medical intervention. Note: For subjects ≥12 to <18 years of 
age, standard of care therapy per local protocols should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) 
pregnancy test at the screening visit and must have a negative urine pregnancy test 
prior to the first dose of investigational product (Visit 1a), and agree to comply with 
any applicable contraceptive requirements of the protocol. 
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control 
(eg, abstinence, barrier control) from the screening visit through 2 months after the last 
dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide 
written informed consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the 
nature of the study provide written informed consent for the child to participate in the 
study before any study-specific procedures are performed (with assent from the child 
when appropriate). Alternatively, certain sites/Independent Reviewing Authorities 


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may permit adolescents who are <18 years of age to be informed of the nature of the 
study and provide written informed consent without consent from a parent(s)/legal 
guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1.
Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved 
dosing regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with 
C1 INH.
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first 
dose of the investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or 
hormone replacement therapy (ie, estrogen/progestin containing products) within 
2 months prior to the screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition 
for thromboembolism. 
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH 
antibodies. 
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), other blood products, or Firazyr (icatibant). 
9.
Be pregnant or breastfeeding. 
10.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following 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 


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sexually active must agree to use acceptable contraception, as defined below, if they become 
sexually active during the period of the study and 30 days following the last dose of 
investigational product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and aged 
51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
Screening Visit and a negative urine pregnancy test prior to randomization (predose at 
Visit 1a). Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception 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 2 months prior to the Screening Visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to a hormonal contraceptive for 30 days.
4.3.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 2 months after the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Early Discontinuation Visit (Section 7.1.4) are to be performed as completely as possible. 
Whenever possible, all discontinued subjects should also complete the 1-week and 1-month 
Post-treatment visits. Comments (spontaneous or elicited) or complaints made by the subject 
must be recorded in the source documents. The reason for termination, date of stopping 


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investigational product, and the total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow up

Lack of efficacy

Other (specify) 
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.4.3
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, investigational product will be discontinued, 
and the subject will follow the schedule of assessments for early discontinuation (Table 3). 
Subjects already enrolled will continue with study drug administration and procedures. 
4.4.4
Thrombotic or Thromboembolic Event
If a thrombotic/thromboembolic (T/TE) event occurs in any subject, no further enrollment 
will occur pending a complete review of all available data. Already enrolled subjects will 
continue with investigational product administration and study procedures. Following a safety 
review of the T/TE event, study enrollment may be restarted if the medical monitor 
determines that the event was unrelated or unlikely to be related to investigational product or 
other C1 inhibitors, which may have been administered for an angioedema attack. Unblinding 
of the randomization code for that subject may be required (see below).


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If a T/TE event occurs in any subject, investigational product administration for that subject 
will be interrupted; however, other study procedures will continue, as clinically appropriate. 
Diagnosis and management of all suspected T/TE events should be per local standard of care; 
Appendix 4 and Appendix 5 present a suggested medical algorithm for diagnosis and 
management of such conditions. Investigators must also comply with all reporting and/or 
procedures for AEs/SAEs as indicated in the suggested algorithm. Following a complete 
medical review by the sponsor in conjunction with the investigator, and if determined safe to 
do so, dosing with investigational product may be resumed to complete a total of 28 doses in 
the treatment period that was interrupted. Study procedures, including PK/PD testing, will 
resume relative to dosing. If investigational product cannot be restarted within 30 days of the 
temporary interruption, the subject will be discontinued from treatment and will follow the 
schedule of assessments for early discontinuation (Table 3). If unblinding is required, a 
physician external to the study will review relevant safety information, including the subject’s 
assigned treatment. The unblinded physician will relay his or her findings and 
recommendations to the medical monitor, exercising caution not to reveal the subject’s 
randomization to anyone associated with the conduct of the study.
5.
PRIOR AND CONCOMITANT TREATMENT
Prior and concomitant medications that will be recorded on the appropriate CRF page include 
prescription medications, blood products (eg, albumin, packed red blood cells, whole blood, 
fresh frozen plasma, platelets), dietary supplements/vitamins, electrolyte supplementation, 
and over-the-counter medications. Topical medications (non-prescription) will be recorded 
only if used as treatment for an AE.
5.1
Prior Treatment
Any therapy received during the 12 months prior to randomization for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and 
the HAE indication (ie, acute treatment, long-term prevention, short-term [preprocedural] 
prevention).  
In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the CRF.
5.2
Concomitant Treatment and Medical/Surgical Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the 1-week post-treatment visit, inclusive. All prescription and 
over-the-counter medications being taken by subjects during this time period are regarded as 
concomitant treatments. For any medication that is administered, the investigator will 
document the drug name, amount, route of administration, frequency, and duration 
administered, as well as the reason for administering the medication on the appropriate CRF 
page.


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Elective procedures should be postponed, where possible. Medical/surgical procedures 
performed during the study will be recorded on the CRF, along with the date, time, and reason 
for the procedure. Pre-procedure prophylaxis may be provided (and documented as outlined 
above) if medically indicated and according to local standard of care.
5.2.1
Management of Angioedema Attacks 
If a subject (≥18 years of age) experiences an acute angioedema attack at any time during the 
study that in the opinion of the investigator requires medical intervention, icatibant should be 
administered to treat the attack. Commercial icatibant labeled for clinical trial use will be 
supplied in a single-dose pre-filled glass syringe delivering 3 mL of solution containing 
30 mg icatibant and should be stored at or below 25°C (must not be frozen). Icatibant is to be 
administered by the SC route in the abdominal area. The entire volume in the syringe should 
be administered and the injection should occur over at least 30 seconds. If response is 
inadequate or symptoms recur, additional injections of 30 mg may be administered at 
intervals of at least 6 hours. Do not administer more than 3 injections in 24 hours. The subject 
will be allowed to self-administer icatibant if already trained by a health care provider or after 
receiving instructions on the use and appropriate training by study site personnel or a 
qualified home health professional. If it is the opinion of the investigator that the subject still 
needs medication for his/her acute angioedema attack after icatibant administration, then other 
standard of care therapy (eg, C1 INH, ecallantide) may be provided per locally approved 
product information. 
For subjects ≥12 to <18 years of age standard of care therapy per local protocols should be 
provided, such as (where approved for adolescents) C1 esterase inhibitor (human), C1 
esterase inhibitor (recombinant), and ecallantide. 
The determination of the necessity for therapy to alleviate subject symptoms will be at the
discretion of the investigator. Administration of investigational product and study procedures 
will continue without alteration to the protocol schedule, even if a subject receives any 
treatment for an angioedema attack.
For all medications (including fluids, anti-emetics, analgesics) associated with management of 
acute angioedema attacks, study personnel will record start/stop dates, time of administration, 
dose, unit, frequency, and route of administration in the subject’s CRF page. Adverse events 
associated with medications used in the treatment of acute angioedema attacks will be 
captured on the AE CRF and attributed to the concomitant medication administered
(Section 8.1.2). 
Adult subjects receiving long-term prophylaxis with C1 INH prior to randomization may be 
randomized to treatment sequences that contain a placebo treatment period (ie, A/B or B/A); 
such subjects remain eligible for on-demand therapy as outlined above.  If, after receipt of at 
least 3 weeks of investigational product, the subject’s quality of life significantly deteriorates 
and interferes with daily living routines, and the subject experiences a 2-fold increase in 
attack frequency with greater severity (relative to the subject’s baseline without  prophylaxis), 


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following discussion of the investigator with the sponsor, subject may be discontinued from 
the treatment.  
The investigator will be responsible for entering information about the subject’s 
discontinuation from study drug in the CRF and where applicable, perform study related 
procedures as outlined in Table 3. The investigator will also ensure the subject receives 
appropriate treatment based on the subjects past HAE treatment and according to local 
standard of care.  Angioedema attacks will not be considered AEs; however, events satisfying 
the serious criteria should be recorded as a SAE and reported to Shire Pharmacovigilance 
(Section 8.1.4). Data on angioedema attacks will be collected separately from general reports 
of AEs and will be used in the evaluation of efficacy (Section 7.2.2). In addition, if applicable, 
subjects will record their response to icatibant therapy when used for treating an angioedema 
attack, as well as any associated side effects or tolerability issues. This information will be 
recorded in the electronic subject diary (Section 7.2.2.4).
5.2.2
Prohibited Treatment
Use of C1 INH therapy (other than investigational product) for prophylaxis against 
angioedema attacks is prohibited during this study (from the first dose of investigational 
product through the 1-month post-treatment visit). 
The initiation of androgen therapy is prohibited during the study (from the first dose of 
investigational product through the 1-month post-treatment visit). 
5.2.3
Nonpharmacologic Treatments and Procedures
To the extent possible, subjects will postpone elective procedures (eg, dental work) while 
participating in the study. In the event a procedure cannot be postponed, the subject will 
record this information in the subject diary and notify the site. Pre-procedure prophylaxis may 
be provided if medically indicated and according to local standard of care. 
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
during the treatment periods, as well as any medications associated with the procedure, will 
be recorded in the eCRF (see Section 5.2).


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is C1 esterase inhibitor [human] liquid for injection, which is supplied in 
clear glass vials containing 1000 IU of C1 INH in 2 mL of sterile liquid. The solution also 
contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection.
The reference product is placebo, which is supplied in an identical 2 mL presentation as the 
active investigational product minus the C1 INH protein. The inactive ingredients in the 
solution are the same as the active drug product: sodium phosphate, sorbitol, glycine, and 
water for injection.
No reconstitution or dilution is required for the test or reference product. Vials must be stored 
at 2–8oC (36–46oF) and protected from light.
Instructions for handling of investigational product and for SC injection site selection and 
preparation are provided in Appendix 1 and Appendix 2, respectively.
Commercial icatibant labeled for clinical trial use will be supplied as rescue medication for 
the treatment of acute angioedema attacks (Section 5.2.1).
6.2
Administration of Investigational Product
Blinded investigational product (C1 esterase inhibitor [human] liquid for injection or placebo) 
will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate 
treatment periods. Every effort should be made to complete scheduled dosing and to avoid 
situations where investigational product is not received. In order to prevent a missed dose, a 
less than 3-day interval may occur, with the recommendation of allowing at least 24 hours 
between doses. The contents of 2 vials of investigational products (a total volume of 4 mL) 
will be drawn into a silicone-free syringe for each SC injection. Following appropriate SC 
injection site selection and preparation (Appendix 2), the needle will be inserted in the 
subject’s abdominal area in order to administer the SC injection as quickly as tolerated by the 
subject. 
Investigational product will be administered at the investigational site for Dosing Visits 1, 8, 
16, 24, and 28 during both treatment periods. Other doses may be administered by qualified 
blinded personnel at the investigational site or at the subject’s home or other agreed upon 
location or self-administered by the subject (adolescent or adult) with or without supervision 
(qualified home health professional and/or study site personnel), after receiving appropriate 
training by the investigator or designee. Adolescent subjects self-administering investigational 
product will be supervised by a parent/legal guardian/caregiver (if a qualified home health 
professional and/or study site personnel is not present). Alternatively, a parent/legal 
guardian/caregiver after receiving appropriate training will be allowed to administer the 
investigational product to an adolescent subject with or without supervision.


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6.3
Allocation of Subjects to Treatment Sequence
This is a double-blind, placebo-controlled, two-period, 3-sequence, partial crossover study. At 
least 66 eligible subjects will be randomized to 1 of 3 treatment sequences (Table 7) prior to 
the first dose of investigational product in Treatment Period 1. The actual treatment sequence 
given to individual subjects is determined by a randomization schedule automatically assigned 
by the IRT. 
Table 7:
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects 
Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC 
twice weekly (every 3 or 4 days) for 14 weeks. 
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each level of use of prophylactic therapy with C1 INH across sites, the subject number is 
assigned to subjects according to the sequence of presentation for study participation. Subject 
number is unique within a protocol.
The randomization number represents a unique number corresponding to treatment sequence 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IRT at the baseline visit (predose Visit 1a) after subject eligibility has been 
confirmed using the randomization criteria. The randomization schedule will be stratified for 
use of prophylactic therapy with C1 INH at the time of enrollment versus no prophylactic 
therapy with C1 INH at the time of enrollment. Subjects will be randomized to the treatment 
sequence 1 (A/B), 2 (B/A), or 3 (A/A) in the randomization ratio of 2:2:1. 
The subject’s treatment sequence will be held in strict confidence. The treatment sequence for 
an individual subject may be broken in cases of emergency or for reasons of subject safety, as 
described in Section 6.4.1.
6.4
Blinding of Treatment
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence. 
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo will have 
an identical presentation, including its packaging and labeling, such that the contents of the 
glass vials within the prepackaged study kits will be indistinguishable from each other. As 
described in Section 6.6, investigational product will be identified only by a unique study 


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drug kit number. Each prepackaged study kit will contain 2x2 mL vials of investigational 
product (a total volume of 4 mL), which will be required to be drawn into a silicone-free 
syringe for each SC injection. If possible, a different individual should draw up the 
investigational product into the syringe than the individual administering the SC injection to
the study subject. 
Knowledge of the PK/PD data would compromise the study blind. As such, the independent 
external laboratory performing the PK/PD analyses will keep the results in strict confidence 
until the study is unblinded.
Additionally, a limited number of representatives of the sponsor responsible for the IRT and 
product labeling will be unblinded to treatment assignment in order to review drug 
accountability on an ongoing basis throughout the study (Section 6.7).
6.4.1
Unblinding the Treatment Assignment
The randomization code for an individual subject may only be broken by the investigator or 
the sponsor for reasons of subject safety or in an emergency when knowledge of the product 
administered would be important for the treatment of the subject. If the blind is broken by the 
investigator, he/she must notify the Shire ViroPharma Medical Monitor immediately and must 
document the date, time, and reason for the code break in a note to file.
6.5
Treatment Compliance
Investigational product will be administered either by study site personnel or a qualified home 
health professional or may occur under their direct supervision for subjects (or parent/legal 
guardian/caregiver) who elect to self-administer during Treatment Periods 1 and 2 
(Section 6.2). Therefore, full subject compliance with treatment is expected in this study.
6.5.1
Self-Administration
Instruction for subjects who elect to self-administer investigational product (or when needed, 
icatibant as rescue medication; see Section 5.2.1) with or without supervision (qualified home 
health professional and/or study site personnel), after receiving appropriate training by the 
investigator or designee will include:

Transportation and recommended storage conditions of investigational product from the 
study site to the home location.

Maintenance of accurate records regarding each administration of investigational product
including supply identification (ie, lot/kit number), date and time of injection, and if for 
any reason the SC injection could not be completed as instructed.

Retention of all used and unused vials of investigational product for drug accountability 
purposes.


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6.6
Packaging and Labeling
C1 esterase inhibitor [human] liquid for injection and placebo will be packaged and labeled 
such that the products will be indistinguishable from each other by the investigator, study site 
personnel, home health professionals, and subjects.
Investigational product will be supplied in a prepackaged study kit. Each study kit will 
contain 2 vials of investigational product (C1 esterase inhibitor [human] liquid for injection or 
placebo). Both the vials and carton (kit) will be appropriately labeled according to local 
regulations and bear the unique study drug kit number.  
The investigative site will also be provided with ancillary supplies including silicone-free 
syringes and needles. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection.
Subjects who elect to self-administer investigational product will be provided the following 
supplies at the investigational site:

4-week supply (8 study kits) of investigational product 

Ancillary supplies, including silicone-free syringes, needles, and a container for sharps
disposal

Transport container for investigational product

Subject accountability log to record investigational product storage conditions and 
administration details
All used and unused vials should be returned to the study kit cartons/boxes and transported to 
the site for drug accountability.
Written instructions on investigational product and self-administration procedures will be 
provided to subjects at the screening or first dosing visit (Visit 1a). Refer to the Pharmacy 
Manual for additional details on the investigational product and its administration. 
6.7
Storage and Accountability
Investigational product will shipped refrigerated to the study site at 2–8oC. Vials of 
investigational product must be stored at 2–8oC (36–46oF) and protected from light. Do not 
freeze investigational product.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log. The date and time of administration of the investigational product must be documented 
on the appropriate CRF.
The principal investigator, study site personnel, or qualified home health professional must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 


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loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.
6.8
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an investigational product 
returns process/policy, the sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the site regulatory binder.
If the investigational product is to be destroyed by the sites, sites must follow their own 
process/policy that describes such activities. Sites must retain copies of these documents 
within the site regulatory binder. Sites must ensure that the clinical trial material 
accountability and destruction log is complete, accurate, and ready for review and/or audit at 
each monitoring visit.
All manifests documenting shipments of investigational product must be retained, as well as 
copies of any investigational product return forms.
Refer to the Pharmacy Manual for additional details.
7.
STUDY PROCEDURES
Subjects may be enrolled in the study after the nature and purpose of the protocol has been 
explained, written informed consent to participate has been voluntarily granted, and the 
eligibility criteria listed in Sections 4.1 and 4.2 have been met.
7.1
Study Schedule
Table 1 (Treatment Period 1), Table 2 (Treatment Period 2), Table 3 (early discontinuation 
visit, 1-week and 1-month post-treatment follow-up visits), and Table 4 (blood sample 
collection for PK/PD Analyses) provide the timing of all study procedures and assessments. 
7.1.1
Screening Period
Informed consent must be obtained before any study-specific procedures are performed. Note 
that AEs will be collected from the time of informed consent through 7 days after the last dose 
of investigational product.
Subjects will have all screening procedures completed within 21 days prior to the first dose of 
investigational product (Visit 1a=Dosing Day 1) according to Table 1. The following 
procedures will occur:
•
Informed consent/assent


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•
Adverse events (collection begins from the time of informed consent through 7 days after 
the last dose of investigational product)
•
Inclusion/exclusion criteria
•
Medical history (includes HAE history with the documentation of attack rate for study 
entry criteria and if applicable, determination of C1 INH antigen level and/or C1 INH 
functional activity, Section 7.2.3.1)
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Virology screening 
•
Vital signs
•
ECG
•
Height and weight
•
Serum pregnancy test (in females of childbearing potential)
•
Recording of prior and concomitant medications
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 
7.1.2
Treatment Period 1
7.1.2.1
Visit 1a (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Randomization
•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications (needed for confirmation of subject eligibility)


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•
PK (C1 INH antigen, C1 INH functional, [includes measurement of C1q]) and PD (C4) 
sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody)
•
Angioedema quality of life (AE-QoL) questionnaire, EuroQol 5-dimensional 5-level 
descriptive system (EQ-5D-5L), Work Productivity and Activity Impairment-General 
Health (WPAI-GH) questionnaire, and Sheehan Disability Scare (SDS) assessments 
recorded in the electronic subject diary
•
Health resource utilization assessment (HRUA)-HAE
7.1.2.2
Visit 1a (postdose)
The following procedures will be performed after the administration of the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack (and the subject diary is to be updated daily; Section 7.2.2.2).
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.2.3
Visit 2a through Visit 28a
The following procedures will be performed throughout Treatment Period 1 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2a-28a)
•
Recording in the electronic subject diary daily any symptoms or occurrences of an 
angioedema attack (Visits 2a-28a)
•
Recording the daily AAS in the electronic subject diary (Visits 2a-28a)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2a, 3a, 4a, 8a, 16a, 24a, 28a). Note:  Vital sign measurements are not required at 
Visits 2a, 3a, and 4a for subjects self-administering investigational product without 
supervision (ie, assessment may not be possible).
•
Physical examination (Visits 8a, 16a, 24a, 28a)
•
Investigational product will be administered at each visit (2a-28a); Visits 8a, 16a, 24a, and 
28a must occur at the investigational site. 


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•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at Visits 8a, 16a, 24a, and 28a. At Visit 28a, the 
overall impact of injection site reactions on daily living (yes/no) and duration will be 
assessed.
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8a, 16a, 24a, 
and 28a
•
Urinalysis testing with microscopy at Visit 28a
•
Acceptability and self-administration survey assessment (recorded in the electronic
subject diary) at Visit 28a
•
Quality of life assessments recorded in the electronic subject diary: AE-QoL (Visits 9a, 
17a, 25a), EQ-5D-5L (Visit 24a and on each day that a subject experiences signs or 
symptoms of an angioedema attack), and WPAI-GH and SDS (Visits 3a, 5a, 7a, 9a, 11a, 
13a, 15a, 17a, 19a, 21a, 23a, 25a, 27a)
•
HRUA-HAE (Visits 8a, 16a, 24a)
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8a, 16a, 24a, 27a or 28a)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2a, 8a, 
16a, 24a, 27a or 28a [within ≈15 min], and 48 h postdose Visits 27a or 28a [±3 hours]). 
Note: A predose Visit 2a blood sample is not required for subjects self-administering 
investigational product without supervision (ie, sample collection may not be possible).
7.1.3
Treatment Period 2
7.1.3.1
Visit 1b (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product in Treatment Period 2 at Visit 1b:
•
Collection of AEs
•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications 
•
PK (C1 INH antigen, C1 INH functional) and PD (C4) sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody) blood sample collection


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•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS assessments recorded in the electronic subject 
diary
•
HRUA-HAE
7.1.3.2
Visit 1b (postdose)
The following procedures will be performed after the administration of investigational 
product at Visit 1b:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.3.3
Visit 2b through Visit 28b
The following procedures will be performed throughout Treatment Period 2 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2b-28b)
•
Recording in the subject diary daily any symptoms or occurrences of an angioedema 
attack (Visits 2b-28b)
•
Recording the daily AAS in the subject diary (Visits 2b-28b)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2b, 3b, 4b, 8b, 16b, 24b, 28b). Note:  Vital sign measurements are not required at 
Visits 2b, 3b, and 4b for subjects self-administering investigational product without 
supervision (ie, assessment may not be possible).
•
Physical examination (Visits 8b, 16b, 24b, 28b)
•
Investigational product will be administered at each visit (2b-28b); Visits 8b, 16b, 24b, 
and 28b must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at Visits 8b, 16b, 24b, and 28b. At Visit 28b, the 
overall impact of injection site reactions on daily living (yes/no) and duration will be 
assessed.


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•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8b, 16b, 24b, 
and 28b
•
Urinalysis testing with microscopy at Visit 28b
•
Quality of life assessments: AE-QoL (Visits 9b, 17b, 25b), EQ-5D-5L (Visit 24b and on 
each day that a subject experiences signs or symptoms of an angioedema attack), and 
WPAI-GH and SDS (Visits 3b, 5b, 7b, 9b, 11b, 13b, 15b, 17b, 19b, 21b, 23b, 25b, 27b) 
recorded in the electronic subject diary
•
HRUA-HAE (Visits 8b, 16b, 24b)
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments at Visit 28b
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8b, 16b, 24b, 28b)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2b, 8b, 
16b, 24b, and 28b [within ≈15 min], and 24 hours (±3 hours) (optional time point), 
48 hours (±3 hours), 72 h (±6 hours) (optional time point), and 96 hours (±6 hours) 
postdose Visit 28b). Note: A predose Visit 2b blood sample is not required for subjects 
self-administering investigational product without supervision (ie, sample collection may 
not be possible).
7.1.4
Early Discontinuation Visit
If a subject prematurely discontinues from investigational product, the following procedures 
are to be performed as completely as possible:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments


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•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
7.1.5
Follow-up Period
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of investigational product for follow-up safety assessments (Table 3). The following 
procedures will occur:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
A second post-treatment visit will occur at the investigative site 1 month (±2 days) after the 
last dose of investigational product. The following procedures will be performed at this visit:
•
HRUA-HAE
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to the Shire Pharmacovigilance Department.


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7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic details, medical history (including HAE history, Section 7.2.3.1), prior 
and concomitant medication data, vital signs, height, weight, physical examination, 12-lead 
ECG, biochemistry, hematology, coagulation, virology screening, and serum β-hCG
pregnancy test will be collected at the time of enrollment at the Screening Visit. 
7.2.2
Efficacy
Analyses of the efficacy endpoints in this study require documentation of specific information 
regarding the subject’s symptoms of any angioedema attacks they may experience during the 
study. 
7.2.2.1
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported indication of swelling or pain at 
any location following a report of no swelling or pain on the previous day (ie, there must be a 
full symptom-free calendar day preceding the onset of symptoms for an attack to be 
considered a new attack). Therefore, 

Attacks that progress from 1 site to another will be considered a single attack 

Attacks that begin to regress and then worsen before complete resolution will be 
considered 1 attack 

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar 
day reported after the appearance of resolution will also be considered 1 attack 
Note: An angioedema attack does not include swelling due to trauma, arthritis, or symmetrical 
nonpainful swelling of the lower extremities.
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary
During the study, subjects will use an electronic subject diary each day to record any 
symptoms or occurrences of an angioedema attack. The investigator will complete a separate 
angioedema attack CRF for each attack based upon their review of the data in the subject 
diary. Information will include the following:

Date and time of onset of angioedema attack symptoms

Characterization of whether swelling or pain is (indicate all that apply):

Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)

Non-mucosal (truncal, extremity, facial)


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
Location (site) of the swelling or pain (indicate all that apply):

Upper airway (includes laryngeal or pharyngeal)
Note: Pharyngeal or oral swelling that results in airway compromise will be 
classified as a laryngeal attack.
Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)

Genitourinary (including scrotum or vulva)

Cutaneous (facial)
Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, 
trunk])

Severity (intensity) of the sign/symptom at each location listed:

Absent
Mild: the angioedema attack sign/symptom(s) is noticeable but is easily 
tolerated by the subject and does not interfere with routine activities.
Moderate: the angioedema attack sign/symptom(s) interferes with the subject’s 
ability to attend work/school or participate in family life and social/recreational 
activities.
Severe: the angioedema attack sign/symptom(s) significantly limits the 
subject’s ability to attend work/school or participate in family life and 
social/recreational activities.

Visual Analogue Scale (VAS) pain measurement score

Angioedema attack trigger(s)

Answer to the question, “Was treatment administered for the attack?” If yes, record the 
date, time, and name of treatment administered.
7.2.2.3
Angioedema Activity Score
Subject self-assessment of disease activity will be assessed daily by the AAS. Subjects will 
respond to questions in the electronic subject diary about any swelling episode that has 
occurred within the previous 24 hours. Each AAS item (or question) is scored between 0 and 
3 points, with the minimum and maximum daily AAS ranging between 0 and 15 points 
(Weller et al. 2013).
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks
Efficacy endpoints are based on subject-assessed symptom improvement as a measure of 
response to icatibant therapy. When a subject receives treatment with icatibant for an acute 
angioedema attack, they will record the date and time of administration of the SC injection in 
the electronic subject diary and will monitor the following events:


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Initial Symptom Improvement

Report date and time when you feel that your symptoms start to improve.
Complete Symptom Resolution

Report date and time when you feel that your symptoms have completely resolved.
Tolerability

Report any side effects associated with administration of icatibant therapy.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical and Medication History
A medical history will be taken at the screening visit. All medical history findings that have 
been present/active within the 5 years prior to enrollment will be entered into the CRF 
regardless of clinical relevance or presence at study start. Medical history findings that have 
not been present within the 5 years prior to enrollment will be recorded if deemed clinically 
relevant by the investigator to the conduct of the study. The medical history should include 
any history of allergic reactions to drugs. 
HAE History
The following information associated with HAE history will be recorded in the CRF at the 
screening visit. If there is no documented C1 INH antigen level and/or C1 INH functional 
activity in the subject’s medical record, a blood sample can be collected at screening and sent 
to a local or central laboratory (as appropriate) to confirm HAE diagnosis (Type I or II).
Repeat blood sampling is allowed if the test is non-confirmatory despite a suspected diagnosis 
of HAE. (Note: the attack rate may be estimated based on subject or parent/caregiver recall as 
well as the subject’s medical records):  

HAE type (I or II)

Estimated date of last angioedema (swelling) attack prior to the screening visit

Any therapy received during the last 12 months for management of HAE (Section 5.1)

Total number, typical locations and average overall duration (days), and average overall 
severity of angioedema attacks experienced:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.

Typical score, estimated on a scale from 0-100, for the subject’s angioedema attack 
pain:


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
during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.
7.2.3.2
Physical Examination (Including Height and Weight)
The investigator or designee will perform physical examinations at the time points specified 
in Table 1, Table 2, and Table 3. General physical examinations will be performed in 
accordance with standard practices at the study site. Physical examination abnormalities 
observed prior to the screening visit will be entered into the medical history section of the 
CRF. Any new or worsening of pre-existing abnormalities noted at post-screening 
examinations should be captured as an AE on the AE CRF page, per investigator’s judgment. 
Body weight and height will be measured at the time points specified in Table 1 and Table 2. 
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed (Section 8.1).
7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse and will be measured at the time points specified 
in Table 1, Table 2, and Table 3. During the study, additional vital signs measurements will 
be performed if clinically indicated. Vital signs performed on a dosing day should be obtained 
immediately (≤30 minutes) before the start of the injection of investigational product, 
immediately after completion of the injection of investigational product (≤10 minutes), and 
then between 30 minutes and 1 hour after completion of the injection of investigational 
product. Every effort should be made to measure vital signs prior to any blood sample 
collection. Blood pressure should be determined by cuff (using the same method, the same 
arm, and in the same position throughout the study). Any clinically significant deviations 
from Baseline (predose Visit 1a) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. Reference ranges are to be supplied by the laboratory and will be used to assess 
the clinical laboratory data for clinical significance and out-of-range pathological changes. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.


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The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 6 mL) for biochemistry will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Aspartate aminotransferase (AST)
Albumin
Alanine aminotransferase (ALT)
Total protein
Alkaline phosphatase (ALP)
Glucose
Creatine phosphokinase (CPK)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Chloride
Carbon dioxide
Phosphorus
Hematology
Blood samples (approximately 2 mL) for hematology will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Hemoglobin
Red blood cell count
Hematocrit
Platelet count
White blood cell count – total and differential
Coagulation
Blood samples (approximately 3 mL) for coagulation will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
International normalized ratio (INR)
Prothrombin time (PT)
D-dimer a
Activated partial thromboplastin time (aPTT)
a In addition, D-dimer should be evaluated in any subject who presents with signs and symptoms consistent with 
suspected venous thromboembolism.


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Virology
Blood samples (approximately 6 mL) will be taken according to Table 1. The following 
parameters will be assessed:
Human immunodeficiency virus (HIV; single 
assay/INNO-LIA)
Hepatitis (hepatitis B surface antigen and 
hepatitis C antibody)
Urinalysis with microscopy
Urine samples (approximately 10 mL) will be taken according to Table 1, Table 2, and Table
3. The following parameters will be assessed:
pH
Specific gravity
Dipstick (protein, glucose, ketones, 
hemoglobin)
Microscopic evaluation (red blood cells, 
white blood cells, crystals, casts, bacteria)
In addition, a local or central laboratory (as appropriate) will be used for screening C1 INH 
diagnostic assessments for subjects without documented C1 INH antigen level and/or C1 INH 
functional activity in their medical history.
7.2.3.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all females of childbearing potential at the 
screening visit and a urine pregnancy test is performed thereafter according to the time points 
specified in Table 1, Table 2, and Table 3. Pregnancy test results must be confirmed as 
negative before subjects proceed in the study. 
7.2.3.7
Electrocardiogram 
Subjects will have a 12-lead ECG recorded at the screening visit, as specified in Table 1. 
During the study, additional ECGs will be performed if clinically indicated. The following 
ECG data will be entered into the CRF: heart rate, PR interval, QRS duration, and QT 
interval. The PQ interval may be used if the PR interval is not reported on the 12-lead ECG. 
The investigator will be responsible for providing the interpretation of all ECGs (clinically 
significant/not clinically significant). The subject’s ECG(s) should be consistently recorded in 
the same position (supine).
7.2.3.8
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
from the first dose of investigational product through the 1-week post-treatment visit will be 
recorded in the CRF (Section 5.2).


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7.2.3.9
Thrombotic or Thromboembolic Events
Monitoring for Venous Thromboembolism or Arterial Thromboembolism
Study personnel will actively monitor subjects for possible venous thromboembolism (VTE), 
encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), and 
arterial thromboembolism (ATE) with medical history, physical examinations, review of AEs, 
routine coagulation laboratory testing, and/or other diagnostic tests as applicable per local 
standard of care at the time points specified in Table 1, Table 2, and Table 3. 
Subjects will also receive instruction on how to recognize symptoms associated with potential 
thrombotic events and to seek medical attention for these symptoms in addition to informing 
their investigator. Treatment procedures, when applicable, will be provided per local standard 
of care.
Suspected Venous Thromboembolism or Arterial Thromboembolism
In subjects who present with signs and symptoms that are suspicious of a possible VTE (DVT 
or PE) based on clinical history and physical examination, the Wells Prediction Rules 
(Appendix 3) in conjunction with D-dimer assessment and/or other diagnostic tests, as 
applicable per local standard of care, are suggested to help guide the physician. Diagnostic 
and/or treatment procedures, when applicable, will be provided per local standard of care.
Based on the Wells Prediction Rule scores, the following procedures are recommended:

If the Wells Prediction DVT risk score is ≥1, coagulation studies and an imaging 
study (eg, lower extremity ultrasound or contrast venography) may be performed 
as described below. 

If the Wells Prediction PE risk score is ≥2, coagulation studies and 1 or more 
imaging studies (eg, ventilation-perfusion scan, multidetector helical computed 
axial tomography, or pulmonary angiography) may be performed as described 
below. 
In the setting of suspected VTE events, site personnel will complete the Wells Prediction Rule 
CRF.
Diagnosis and management of all suspected VTE and ATE events should be per local 
standard of care; Appendix 4 and Appendix 5 also presents a suggested medical algorithm for 
diagnosis and management of such conditions. Investigators must also comply with all 
reporting and/or concerning procedures for AEs/SAEs as indicated in the suggested 
algorithm. Confirmed diagnoses of T/TE events will be reported as SAEs (Section 8.2). 
However, superficial thrombophlebitis and catheter-related thrombosis will be reported as 
either a nonserious AE or an SAE based on investigator assessment and standard AE/SAE 
definitions.
7.2.3.10 Injection Site Reactions
Investigational product SC injection site reactions will be captured in the local tolerability 
CRF. Site personnel will distinguish between injection site reactions related to the procedure 


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(eg, will check for redness after needle is inserted and prior to investigational product 
administration) vs the actual investigational product. Injection site reactions that do not meet 
the criteria of an SAE will not need to be reported as an AE.
Subcutaneous injection site reactions will be assessed at the following post-injection time 
points in each treatment period: 15 minutes, 30 minutes, and 1 hour post-injection. Study 
personnel will examine injection sites for erythema or swelling and will question the subject 
to collect information on cutaneous pain, burning sensation, itching/pruritus, and warm 
sensation. The diameter of any erythema or swelling should be measured to obtain the 
severity grading. The injection site reactions will be graded as absent, mild, moderate, or 
severe using the scoring criteria shown in Table 8. Both the severity score and the 
measurement of any erythema or swelling are to be captured in the CRF. In addition, the 
overall impact of injection site reactions on daily living (yes/no) and duration will be assessed 
at the last visit of each treatment period (Visits 28a and 28b).
Table 8:
Severity Scoring for Injection Site Reactions
Reaction
Severity
Mild
Moderate
Severe
Erythema
>0 to 5 cm
>5 to 10 cm
>10 cm
Swelling
>0 to 5 cm
>5 to 10 cm
>10 cm
Cutaneous pain
Mild discomfort to touch
Discomfort with movement
Significant discomfort at rest
Burning sensation
Mild burning sensation, 
which is easily tolerated
Moderate burning sensation, 
causing some discomfort
Severe burning sensation, 
causing significant discomfort
Itching/pruritus
Mild itching/pruritus, 
which is easily tolerated
Moderate itching/pruritus, 
causing some discomfort
Severe itching/pruritus, causing 
significant discomfort
Warm sensation
Mild warmth to touch
Moderate warmth to touch
Significant warmth to touch
Injection site reactions resulting from the administration of icatibant (as rescue medication for 
acute angioedema attacks) will be reported as an AE with causality linked to icatibant.
7.2.4
Others
7.2.4.1
Clinical Pharmacology Assessments
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Subjects will have blood samples (7 mL) collected for the determination of plasma 
concentrations of C1 INH antigen, functional C1 INH, complement C4, and C1q at time 
points specified in Table 4. Serum samples (5 mL) will be collected prior to the first dose of 
investigational product on Visit 1a (Dose 1 of Treatment Period 1), Visit 1b (Dose 1 of 
Treatment Period 2), and throughout both treatment periods for the analysis of anti-C1 INH 
antibodies (Table 1 and Table 2). Additional blood samples for PK/PD and C1 INH antibody 
testing will be collected at the early discontinuation visit (if applicable) and the 1-week and 
1-month post treatment visits (Table 3). 


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The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH activity, complement C4 and C1q 
concentrations, and serum samples for the evaluation of anti-C1 INH antibodies will be 
analyzed using validated methods. All PK/PD and immunogenicity samples will be processed 
according to the procedure outlined in the laboratory manual.
Selected samples may be analyzed to investigate incurred sample reproducibility of the 
bioanalytical methods. These analyses are only to investigate the reproducibility of the 
bioanalytical methods used to determine C1 INH antigen and functional C1 INH 
concentrations in study samples. All incurred sample reproducibility results will be reported 
in a separate table in the bioanalytical report. Details of disposal will be documented and 
maintained with the study file at the analytical laboratory.
7.2.4.2
Health-related Quality of Life Assessments
Angioedema Quality of Life Questionnaire
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema (Weller et al. 2012). It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and food. Subjects will be asked how often 
they were restricted by—as well as the difficulties and problems that could be associated 
with—recurrent swellings (angioedema) during the previous 4 weeks. The AE-QoL will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3. Details about the use of the AE-QoL instrument are provided in a separate study 
manual. 
Health-related Quality of Life Questionnaire
The EQ-5D-5L1 is a descriptive system of health-related quality of life states consisting of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
of which can take 1 of 5 responses. The responses record 5 levels of severity within a 
particular dimension. The EQ-5D-5L will be completed in the electronic subject diary at the 
time points specified in Table 1, Table 2, and Table 3, as well as on each day that a subject 
experiences signs or symptoms of an angioedema attack. Details about the use and 
administration of the EQ-5D-5L instrument are provided in a separate study manual. 
Work Productivity and Activity Impairment-General Health Questionnaire
The WPAI-GH questionnaire includes 6 questions about work and activity impairment due to 
health problems during the past 7 days (Reilly et al. 1993). Outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less work or 
productivity. The WPAI-GH will be completed in the electronic subject diary at the time 
points specified in Table 1, Table 2, and Table 3. Details about the use of the WPAI-GH 
instrument are provided in a separate study manual.
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.


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Sheehan Disability Scale
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a 
subject’s disability due to an illness or health problem interferes with work/school, social 
life/leisure activities, and family life/home responsibilities (Sheehan 1983). The SDS will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3.
7.2.4.3
Health Resource Utilization Assessment
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. The Health Resource Utilization 
Assessment (HRUA-HAE) will be completed at the time points specified in Table 1, Table 2, 
and Table 3. Study personnel will enter the survey responses into the appropriate CRF.
7.2.4.4
Survey of Acceptability of SC Administration
Study personnel will ask subjects to rate their overall experience in receiving twice weekly 
SC injections of investigational product at the time points specified in Table 1, Table 2, and 
Table 3. For subjects who have previously received C1 INH products via IV administration, 
they will be asked to indicate the preferred route for medication administration. Study 
personnel will enter the subject’s survey responses into the electronic subject diary.
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) 
on the route to administer medications to prevent angioedema attacks. 
7.2.4.5
Self-administration Survey Assessment
After receiving appropriate training, subjects are allowed to self-administer investigational 
product during Treatment Periods 1 and 2 with or without direct supervision (qualified home 
health professional and/or study site personnel). Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/caregiver (if home health 
professional and/or study site personnel is not present). Alternatively, a parent/legal 
guardian/caregiver after having received appropriate training will be allowed to administer the 
investigational product to an adolescent subject with or without supervision. For those 
subjects who choose to self-administer or have a parent/legal guardian/caregiver administer 
the investigational product, study personnel will ask specific questions about their experience 
with self-administration of SC medication (Table 2 and Table 3). Study personnel will enter 
the subject’s survey responses into the electronic subject diary.


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7.2.5
Volume of Blood to Be Drawn From Each Subject
Table 9:
Approximate Volume of Blood to Be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
PK/PD 
7
20b
140
Immunogenicity (anti-C1 INH antibodies)
5
13
65
Safety
Biochemistry and -HCGa
6
13
78
Hematology
2
13
26
Coagulation
3
13
39
Virology
6
1
6
All assessments (mL)
354
Β-hCG=beta human chorionic gonadotrophin; C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a -hCG testing for females of childbearing potential at the Visit 1a (predose) only.
b Two of the 20 samples are optional as indicated in Table 4.
During this study, it is expected that maximum volume of blood to be drawn from each 
subject will be 354 mL, as shown in Table 9.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of 
blood drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 354 mL. When more than 1 blood assessment is done at 
the same time point/period, if they require the same type of tube, the assessments may be 
combined. 


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until 7 days after the last 
dose of investigational product. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE 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:
A type of AE that is usually alleviated with 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 subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product 
for each AE. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related.” The causality 
assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product and/or other study product (eg, icatibant) is compelling 
and/or follows a known or suspected response pattern to that product, and the event 
cannot be explained by the subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and/or other study 
product (eg, icatibant) and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (angioedema attacks) should not be captured as AEs as 
long as they are within the normal day-to-day fluctuation or expected progression of the 
disease and are part of the efficacy data to be collected in the study; however, events 


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satisfying the serious criteria should be recorded as a SAE and reported to Shire 
Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range (either 
while continuing treatment or after the end of treatment with the investigational product), and 
the range of variation of the respective parameter within its reference range must be taken into 
consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department 
using the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Shire ViroPharma 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 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire 
Clinical Trial Serious Adverse Event Form. Note: An elective abortion is not considered an 
SAE.


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In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event 
Form as well as the Shire Investigational and Marketed Products Pregnancy Report Form. The 
test date of the first positive serum/urine -hCG test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: This includes a situation where the investigational product is not used 
as directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
higher than the protocol-specified dose.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Medication errors should be collected and reported to the sponsor for all products under 
investigation. The following should be considered as examples of reportable medication 
errors:

The administration and/or use of the unassigned treatment

The administration and/or use of an expired investigational product

Violation of storage or refrigeration requirements for the investigational product
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
All investigational products administered to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, 
or medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 
Trial Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to 
the contract research organization (CRO)/Shire ViroPharma Medical Monitor using the 
details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as an SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 


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definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be 
reported to the Shire Pharmacovigilance Department and  Medical Monitor within 24 hours of 
the first awareness of the event until 30 days after the last dose of investigational product. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).


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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central Institutional Review Boards (IRBs)/EU central ethics committees (ECs)
of related, unexpected SAEs.
In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to 
unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available. If applicable, unblinded data may be 


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made available to quality assurance representatives for the purposes of conducting 
independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
All statistical analyses will be performed using SASVersion 9.1 or higher (SAS Institute, 
,
). 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be 
addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee in this 
study.
9.6
Sample Size Calculation and Power Considerations
The enrollment goal for this study is to randomize at least 66 subjects to ensure 54 subjects 
complete both treatment periods (44 for the crossover sequences, 10 for the active/active 
sequence). This number will be sufficient to address all experimental efficacy and safety 
objectives.
For the primary efficacy endpoint, the NNA, a sample of 44 subjects will provide >90% 
power at an alpha level of 0.025 (1-sided) to detect a difference of 1.0 attacks per month 
between active treatment and placebo assuming a between-subject standard deviation of 2.5. 
This target is supported by the recently completed, dose-ranging, Phase 2 study with CINRYZE
(0624-206).
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR
relative to placebo, 44 subjects will provide >90% power to test the hypothesis H0: proportion 
≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided).
Previous communications have occurred between regulatory authorities and the sponsor 
regarding a Phase 3 study for the SC CINRYZE development program. The regulatory authority 
indicated that the Phase 3 study should be of sufficient size to have a 95% probability for 
detection of safety signals occurring with an incidence of 5% or greater of subjects.
PPD PPD


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With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.
The sample size calculation was conducted using nQuery + nTerim 2.0.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have signed an informed consent and some 
study procedures have begun.
The Randomized Set will consist of all subjects in the Screened Set for whom a 
randomization number has been assigned.
The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The Full Analysis Set will consist of all subjects in the Safety Set who have at least 
1 post-baseline (eg, randomization) primary efficacy assessment.
The Per-protocol Set will consist of all subjects in the Full Analysis Set who complete 
scheduled primary assessments for 6 study weeks and who do not have pre-defined protocol 
deviations that may affect the primary efficacy endpoint. 
The Completer Set will consist of all subjects in the Full Analysis Set who have completed 
the final scheduled primary assessment for the study.
The Pharmacokinetic and Pharmacodynamic Set will consist of all subjects in the Safety 
Set for whom the primary PK and PD data are considered sufficient and interpretable. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the NNA during a treatment period. The NNA is 
expressed as the number of attacks per month (ie, 30.4 days) of exposure:
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period)
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.
The primary efficacy analysis will be conducted for the subjects in the Full Analysis Set 
(Section 9.7) that are randomized to Treatment Sequence 1 (A/B) or 2 (B/A) to evaluate of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection compared 


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to placebo. The null hypothesis to be tested is that the NNA of C1 esterase inhibitor [human] 
liquid for injection is greater than or equal to the NNA of placebo, and the alternative 
hypothesis is that the NNA of C1 esterase inhibitor [human] liquid for injection is less than 
the NNA of placebo as below:
H0: µ C1 INH - µ placebo >0 vs
H1: µ C1 INH - µ placebo <0
The primary efficacy endpoint will be analyzed by using a mixed effect linear model with 
period, sequence, stratification factor (use of prophylactic therapy with C1 INH), and 
treatment as fixed effects, and subject nested within sequence as a random effect. The mean 
treatment difference (µ C1 INH - µ placebo) will be estimated with a 95% CI.
To assess any carryover effect, a sensitivity analysis will exclude from the evaluation of the 
NNA any attacks occurring within the first 2 weeks of Treatment Period 2 for both sequences 
when carryover is suspected to be maximal. Since carryover should occur only with the 
A/B treatment sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] 
liquid for injection efficacy into the placebo treatment period, thereby diluting the efficacy of 
C1 INH and favoring the null hypothesis of the primary efficacy analysis; it is not anticipated 
that any placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection 
within the B/A treatment sequence. The study is powered to demonstrate superior efficacy 
even in the presence of carryover effects. Additional sensitivity analyses may be developed 
and included in the SAP.
Adjustments for multiplicity: To control the overall type 1 error, the primary and key 
secondary endpoints will be tested hierarchically, so that the significance of the key secondary 
endpoint is contingent on whether the primary endpoint is significant. The determination of a 
successful study is based solely on the results of the primary endpoint analysis regardless of 
the results for the key secondary endpoint.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the clinical response to treatment relative to placebo. 
This is defined as achieving a ≥50% reduction in the NNA (PR) during the 2000 IU C1 
esterase inhibitor [human] liquid for injection treatment period relative to the placebo period. 
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion 
PR. The null hypothesis is that PR is less than or equal to 0.2, and the alternative hypothesis is 
that PR is greater than 0.2. The proportion meeting criterion PR will be estimated with an exact 
95% CI. The lower limit of the 95% CI for the proportion will be compared with 0.2. This is 
equivalent to testing the null hypothesis against the alternative hypothesis at a 1-sided alpha 
level of 0.025 using the normal approximation to the binomial distribution.


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9.8.2.2
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints to be evaluated in this study are:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA 
during a treatment period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity 
recorded for each angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every 
day of reported symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day.

Results of the AE-QoL questionnaire.

Determine the response to icatibant when administered as treatment for an acute 
angioedema attack by:

Time to subject-assessed initial symptom improvement (TISI)

Time to subject-assessed complete symptom resolution (TCSR)
Subjects in the Full Analysis Set (Section 9.7) that are randomized to Treatment Sequence 1 
(A/B) or 2 (B/A) will be used to assess the secondary efficacy endpoints in the evaluation of 
the efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection 
compared to placebo. The treatment differences in clinical responder rate, both of which are 
defined within treatments, will be analyzed using McNemar’s test for testing equality of 
proportions of responders within treatments. All other secondary endpoints will be analyzed 
using a linear mixed effect model with period, sequence, stratification factor (use of 
prophylactic therapy with C1 INH), and treatment as fixed effects, and subject nested within 
sequence as a random effect. The results of all secondary efficacy analyses will be 
summarized by the point estimate of within-subject treatment differences or response rates 
and the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75% quartiles, and 
range) will be provided to summarize icatibant-related efficacy endpoints (TISI and TCSR) 
by treatment and icatibant-treated angioedema attack for all subjects in the Full Analysis Set. 
Where appropriate (for subjects ≥12 to <18 years of age), other rescue medications used to 
treat acute angioedema attacks will also be summarized using descriptive statistics. In 
addition, angioedema attacks will be summarized by the maximum symptom severity and 
treatment for all subjects in the Full Analysis Set. 
9.8.3
Exploratory Efficacy Endpoints
There are no exploratory efficacy endpoints in this study.


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9.9
Safety Analyses
Adverse events will be coded using the MedDRA. The number of events, incidence, and 
percentage of TEAEs will be calculated overall, by system organ class, preferred term, and 
treatment. Treatment-emergent AEs will be further summarized by severity and relationship 
to investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG 
findings will be summarized by treatment and visit. Potentially clinically important findings 
will also be summarized or listed.
The incidence and severity (mild, moderate, severe) of SC injection site reactions will be 
summarized by treatment and visit. The overall impact of injection site reactions on daily 
living (yes/no) and duration will be summarized by treatment.
Results of C1 INH antibody testing will be reported for individual subjects.
The tolerability of icatibant therapy for acute angioedema attacks will be summarized.
To assess the influence of any carryover effect on adverse reporting, a sensitivity analysis 
may be conducted by attributing TEAEs that occur during the first 2 weeks of Treatment 
Period 2 to Treatment Period 1 for the A/B (C1 INH to placebo) treatment sequence. In other 
words, C1 esterase inhibitor [human] liquid for injection may account for any TEAEs in the 
first 2 weeks of the placebo treatment, when the carryover effect (if present) is suspected to be 
maximal. 
9.10 Other Analyses
9.10.1
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, C1 INH functional, and complement C4 and C1q for 
individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics (number, geometric mean, coefficient of variation, 
mean, standard deviation, median, minimum, and maximum) for values at each time point.
C1q concentrations will only be assessed at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic parameters will be calculated using observed and baseline-corrected 
concentration-vs-time data using non-compartmental techniques for C1 INH antigen and 
functional activity. The following PK parameters will be calculated using both unadjusted and 
baseline-adjusted concentrations for SC administration: The Cmax, the tmax, the minimum 
observed concentration, and the AUClast. Additional PK parameters will be calculated using 
only baseline-adjusted concentrations, including t1/2, the λz, the AUC0-∞, the VZ/F, and the 
CL/F. Other PK parameters may be calculated as deemed appropriate. Pharmacokinetic 
parameters will be summarized using descriptive statistics.


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Exploratory PK/PD analyses might be performed based on the correlation of plasma 
concentrations of C1 INH antigen, functional C1 INH, and C4 complement in conjunction 
with various safety parameters (eg, selected AEs, clinical laboratory results, antibodies 
generation, frequency, severity, or anatomic location of the angioedema attack, etc.). 
Correlations that will be analyzed will be determined based on observed data.
9.10.2
Health-related Quality of Life Analyses
Results of the EQ-5D-5L health status instrument will be presented in accordance with the 
EQ-5D-5L user guide (version 2.0) by treatment.
Results of the WPAI-GH questionnaire will be summarized by treatment.
Results of the SDS will be summarized by treatment.
9.10.3
Surveys on SC Administration and Self-administration of Investigational 
Product
Results of the surveys for subject acceptability of SC administration and subject experience 
with self-administration of investigational product will be summarized.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. These regulations and 
guidelines also constitute compliance with the ethical principles described in the Declaration 
of Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.


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The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ 
names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the Community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
studies as per guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason. If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 


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demonstrate such qualification. Curriculum vitae for investigators and sub-investigators are 
provided to the study sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The
investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.


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The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective 
national, local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities 
and to have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc).
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).


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10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written 
subject information and received an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent and assent documentation (ie, a complete 
set of subject information sheets and fully executed signature pages) must be given to the 
subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent 
form where applicable) which was reviewed by the IRB/EC and which received their 
favorable opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of
these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible 
for this action. Additionally, if the IRB/EC requires modification of the sample subject 
information and consent document provided by the sponsor, the documentation supporting 
this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, 
or for multicenter studies the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.


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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor, the investigator, or for 
multicenter studies the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market C1 esterase inhibitor [human] liquid for injection; national or local 
regulatory authorities; and the IRBs/ECs which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present 
the study results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire ViroPharma will endeavor to publish the results of all qualifying, applicable, and 
covered studies according to external guidelines in a timely manner regardless of whether the 
outcomes are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma 
adheres to external guidelines (eg, Good Publication Practices 2) when forming a publication 
steering committee, which is done for large, multicenter Phase 2-4 and certain other studies as 
determined by Shire ViroPharma. The purpose of the publication steering committee is to act 
as a non-commercial body that advises or decides on dissemination of scientific study data in 
accordance with the scope of this policy.


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All publications relating to Shire ViroPharma products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma agreement to publish prior 
to release of information. The review is aimed at protecting the sponsor’s proprietary 
information existing either at the commencement of the study or generated during the study. 
To the extent permitted by the publisher and copyright law, the principal investigator will own 
(or share with other authors) the copyright on his/her publications. To the extent that the 
principal investigator has such sole, joint or shared rights, the principal investigator grants the 
sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, the institution and 
principal investigator shall withhold submission of such publication for up to an additional 60 
days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the International Committee of Medical Journal 
Editors current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
Agostoni A, Cicardi M 1992. Hereditary and acquired C1-inhibitor deficiency: biological and 
clinical characteristics in 235 patients. Medicine (Baltimore); 71(4): 206-15.
Aygören-Pürsün E, Bygum A, Beusterien K, et al. 2014. Socioeconomic burden of hereditary 
angioedema: results of the hereditary angioedema burden of illness study in Europe. Orphanet 
J Rare Dis;9:99.
Banerji A 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol; 111(5): 329-36. 
Bernstein
JA 2011. Update on angioedema: evaluation, diagnosis, and treatment. 
Allergy Asthma Proc; 32(6): 408-12.
Bork K, Barnstedt SE, Koch B, Traupe H 2000a. Hereditary angioedema with normal C1-
inhibitor activity in women. Lancet; 356(9225): 213-17.
Bork K, Siedlecki K, Bosch S, Schopf  RE, Kreuz W 2000b. Asphyxiation by laryngeal 
edema in patients with hereditary angioedema. Mayo Clin Proc; 75(4): 349-54. 
Bork K, Gül D, Hardt J, Dewald G 2007. Hereditary angioedema with normal C1 inhibitor: 
clinical symptoms and course. Am J Med; 120(11):987-92.
Bowen T, Cicardi M, Farkas H, et al. 2010. 2010 International consensus algorithm for the 
diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol; 
6(1): 24.
Bygum A, Aygören-Pürsün E, Beusterien K, et al. 2015. Burden of illness in hereditary 
angioedema: a conceptual model. Acta Derm Venereol; [Epub ahead of print].
Caballero T, Aygören-Pürsün E, Bygum A, et al. 2014. The humanistic burden of hereditary 
angioedema: results from the burden of illness study in Europe. Allergy Asthma Proc; 35:47-
53.
Cicardi M, Igarashi T, Rosen FS, Davis AE 3rd 1987. Molecular basis for the deficiency of 
complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest; 79(3): 698-
702.
Cugno M, Nussberger J, Cicardi M, Agostoni A 2003. Bradykinin and the pathophysiology of 
angioedema. Int Immunopharmacol; 3: 311-7.
Cugno M, Nuijens J, Hack E, et al. 1990. Plasma levels of C1 inhibitor complexes and 
cleaved C1 inhibitor in patients with hereditary angioneurotic edema. J Clin Invest; 85:1215-
20.
Farkas H, Harmat G, Füst G, Varga L, Visy B 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol; 13(3): 153-61.
Farkas H, Jakab L, Temesszentandrási G, et al. 2007. Hereditary angioedema: a decade of 
human C1-inhibitor concentrate therapy. J Allergy Clin Immunol; 120(4): 941-7.


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Frank MM, Gelfand JA, Atkinson JP 1976. Hereditary angioedema: the clinical syndrome and 
its management. Ann Intern Med; 84(5): 580-93. 
Georgy MS, Pongracic JA 2012. Chapter 22: Hereditary and acquired angioedema. 
Allergy Asthma Proc; 33(Suppl 1): S73-6. 
Gompels MM, Lock RJ, Abinun M, et al. 2005. C1 inhibitor deficiency: consensus document. 
Clin Exp Immunol; 139(3): 379-94.
Kaplan AP 2010. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role 
of C1 inhibitor therapy. J Allergy Clin Immunol; 126(5): 918-25. 
Kaplan AP, Joseph K 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol; 104(3): 193-204. 
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT 2010. The 
humanistic burden of hereditary angioedema: Impact on health-related quality of life, 
productivity, and depression. Allergy Asthma Proc; 31(5): 407-14.
Ohela K 1977. Hereditary angioneurotic oedema in Finland. Clinical, immunological and 
genealogical studies. Acta Med Scand; 201(5): 415-27.
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65.
Sheehan DV 1983. The Anxiety Disease. New York, NY, USA: Charles Scribner’s Sons.
Weis M 2009. Clinical review of hereditary angioedema: diagnosis and management. 
Postgrad Med; 121(6): 113-20. 
Weller K, Groffik A, Magerl M, et al. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67(10): 1289-98.
Weller K, Groffik A, Magerl M, et al. 2013. Development, validation, and initial results of the 
angioedema activity score. Allergy; 68(9): 1185-92.
Zuraw BL 2003. Diagnosis and management of hereditary angioedema: an American 
approach. Transfus Apher Sci; 29(3): 239-45.
Zuraw BL 2008. Hereditary angioedema: a current state-of-the-art review, IV: short- and 
long-term treatment of hereditary angioedema: out with the old and in with the new? Ann 
Allergy Asthma Immunol; 100(1 Suppl 2): S13-18.
Zuraw BL, Christiansen SC 2009. Pathogenesis and laboratory diagnosis of hereditary 
angioedema. Allergy Asthma Proc; 30(5): 487-92.


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Zuraw BL, Bork K, Binkley KE, et al. 2012. Hereditary angioedema with normal C1 inhibitor 
function: Consensus of an international expert panel. Allergy Asthma Proc; 33(Suppl 1): 
S145-56.


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12.
APPENDICES


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APPENDIX 1 HANDLING OF INVESTIGATIONAL PRODUCT FOR 
SUBCUTANEOUS INJECTION 
The procedures below are provided for the handling of the investigational product. Since 
treatment assignment to C1 esterase inhibitor [human] liquid for injection and placebo 
(Treatments A and B, respectively) is to be blinded, the following instructions apply for all 
SC administrations in Treatment Periods 1 and 2. Always work on a clean surface and wash 
hands before performing the following procedures.
Handling

Prior to administration, investigational product should be protected from light.

No reconstitution or additional dilution of investigational product is required.

A silicone-free syringe is to be used for withdrawal of the product from the vial 
and for administration.

Important Notes: (1) when withdrawing the product from the vial, and during 
administration, the plunger of the syringe should be moved back and forth 
carefully and slowly, avoid introducing any air bubbles, and pulling the plunger 
past the stop on the syringe; (2) there is no need for excessive shaking of either the 
vial or syringe during the preparation for the SC injection.

Investigational product should be inspected carefully for particulate matter or any
discoloration prior to administration, whenever solution and container permit. The 
product should be colorless to slightly blue or colorless to slightly yellow and free 
from visible particles. Do not use if turbid or discolored.

Any vial that has been punctured should be used promptly.

Do not mix investigational product with other materials.

Do not freeze.

Do not use after expiration date.
NOTE: For this protocol, 2 vials of investigational product will be required for each SC 
injection (2x2 mL=4 mL total injection volume).
1. Aseptic technique should be used during handling.
2. Bring vials of investigational product to room temperature.
3. Remove caps from investigational product vials.
4. Cleanse stopper(s) with alcohol swab or germicidal solution, and allow them to dry prior 
to use.
5. Transfer the investigational product to a syringe for administration. Draw up the contents 
of 2 vials of investigational for a total volume of 4 mL.
Be sure to safely dispose of the used needle and syringe.
Retain all used vials of investigational product for drug accountability purposes.


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APPENDIX 2 SUBCUTANEOUS INJECTION SITE SELECTION AND 
PREPARATION
Subcutaneous injections of investigational product will be administered in the abdominal area. 
Injection sites on the abdomen are depicted in the figure below. An abdominal site that is 
approximately at the level of the navel (as allowed by skin condition) and approximately 
15 cm (minimum 10 cm) away from the margin of the navel should be selected. The lateral 
portion of the abdomen is preferred over the midline area. The selected site should include 
fatty tissue. Administer the first injection in the right side (#1 in illustration) and the second 
injection in the left side (#2 in illustration). Keep alternating injection sites to the right side 
and then to the left side for all subsequent injections in Treatment Periods 1 and 2.
Illustration of Injection Sites on the Abdomen
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s 
position: 30-45º) and in a supine position immediately following injection for the evaluation 
of the injection site (ie, laying flat on back).
After the injection site for SC administration has been chosen, the investigational product will 
be administered as a single 4 mL SC injection as described briefly below.

Wipe skin with alcohol to cleanse. Allow to dry.

Gently pinch and lift the skin of the abdomen (ie, “tenting”).

Insert the needle with bevel up close to parallel to the skin or at an angle that is <20°. 
Once the needle is inserted, gently release the pinched and lifted skin (“untent the 
skin”). When the skin is in its normal state, the needle should have a slight upward 
angle of 20-30°. If the subject is obese, a steeper angle for needle insertion can be used 
but it is recommended keeping the angle <45°. In practical terms, the needle 
placement should resemble the angle of an IV needle placement in the arm. The 
purpose of pinching and lifting the skin is to make sure the needle is properly inserted 
in the SC space and is not intradermal.

Release the subcutaneous tissue. The needle will not back out during the injection if 
properly placed.

Care should be taken to avoid inadvertent IV or IM injection.
It may be necessary to adjust the needle by pulling the needle slightly back if there appears to 
be a resistance to flow.
1
2


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APPENDIX 3 WELLS PREDICTION RULE FOR THE DIAGNOSIS OF 
VENOUS THROMBEMBOLISM
Table A.
Wells Prediction Rule for Diagnosing Deep Venous Thrombosis: Clinical 
Evaluation Table for Predicting Pretest Probability of Deep Venous 
Thrombosisa
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months, or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within 12 weeks requiring general anesthesia 
or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Alternative diagnosis at least as likely as deep venous thrombosis
−2
a Clinical probability of deep venous thrombosis: Low= ≤0; Intermediate=1 to 2; High= ≥3. In patients with symptoms in 
both legs, the more symptomatic leg is used.
Data source: Qaseem et al. 2007
Table B.
Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical 
Evaluation Table for Predicting Pretest Probability of Pulmonary 
Embolisma
Clinical Characteristic
Score
Previous pulmonary embolism or deep venous thrombosis
+1.5
Heart rate >100 beats per minute
+1.5
Recent surgery or immobilization
+1.5
Clinical signs of deep venous thrombosis
+3
Alternative diagnosis less likely than pulmonary embolism
+3
Hemoptysis
+1
Cancerb
+1
a Clinical probability of pulmonary embolism: Low=0 to 1; Intermediate=2 to 6; High= ≥7
b For the purposes of this study, cancer will include “treatment ongoing, within previous 6 months, or palliative.”
Data Source: Qaseem et al. 2007
References
Qaseem A, Snow V, Barry P, et al. 2007. Current diagnosis of venous thromboembolism in 
primary care: A clinical practice guideline from the American Academy of Family Physicians 
and the American College of Physicians. Ann Fam Med; 146(6):454-58.


Shire ViroPharma, Inc.
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Page 101 of 106
APPENDIX 4 ALGORITHM FOR SUSPECTED VENOUS
THROMBOEMBOLISM 
References
National Heart, Lung, and Blood Institute. Pulmonary embolism 2011. http://www.nhlbi.nih. 
gov/book/export/html/4865. Accessed May 11, 2015. 
National Heart, Lung, and Blood Institute. Deep vein thrombosis 2011. http://www.nhlbi.nih. 
gov/book/export/html/4871. Accessed May 11, 2015. 
Ozaki A, Bartholomew JR. Venous thromboembolism (deep venous thrombosis & pulmonary 
embolism). In: Carey WD, Rae-Grant A, Rimmerman C, ed. Disease Management Project. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous-
thromboembolism. Accessed May 11, 2015. 


Shire ViroPharma, Inc.
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Protocol SHP616-300
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Page 102 of 106
APPENDIX 5 ALGORITHM FOR SUSPECTED ARTERIAL 
THROMBOEMBOLISM
References
National Library of Medicine. Arterial embolism 2014. http://www.nlm.nih.gov/medlineplus/ 
ency/article/001102.htm. Accessed May 18, 2015.
Lyaker MR, Tulman DB, Dimitrova GT, Pin RH, Papadimos TJ 2013. Arterial embolism. Int 
J Crit Illn Inj Sci; 3(1): 77-87. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665125/ 
?report=printable.


Shire ViroPharma, Inc.
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Protocol SHP616-300
Version 4.0, FINAL
Page 103 of 106
APPENDIX 6 PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
28 May 2015
Global
Protocol Amendment 1
22 Jul 2015
Global
Protocol Amendment 2
03 Sep 2015
Global
Amendment 1 to Protocol SHP616-300 incorporates the following major changes:

Inclusion of final clinical data from Study SHP616-103, which are relevant to patient 
safety and the study rationale.

The baseline angioedema attack rate required for study inclusion has been modified.

Updates were made to some study procedures or requirements (eg, parent/legal 
guardian/caregiver performing and/or assisting an adolescent subject, photographs and 
measurements of injection site reactions, longitudinal follow-up to test for C1 INH 
antibody titers).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 Jul 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the title page to indicate that this will be a multicenter study.
Title page
Changed the baseline attack rate requirement for study entry from a 
history of ≥4 attacks per month average to ≥3 attacks per month average 
for inclusion criterion #3.
Synopsis
Section 4.1
Corrected the secondary efficacy endpoint for the Angioedema Activity 
Score (AAS), to indicate the “98-day AAS” will be calculated in each 
treatment period. 
Synopsis
Section 9.8.2.2
Results from a statistical simulation showed that at least 25% of 
randomized subjects with a baseline attack rate of ≥4 per month average 
need to be included in the efficacy analysis population in order to detect 
a significant reduction (<2) in NNA from baseline. This requirement was 
added to due the revision of the baseline attack rate from ≥4 to ≥3 in 
inclusion criterion #3.
Synopsis
Section 3.1
A parent/legal guardian/caregiver will be allowed to administer 
investigational product to an adolescent subject during Treatment Period 
2, after having received appropriate training and under the supervision of 
study site personnel or a qualified home health professional.
Synopsis
Section 3.1, Section 6.2, Section 6.5, 
Section 7.2.4.5


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 Jul 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
For adolescent subjects, a parent/legal guardian/caregiver is allowed to 
assist the subject in completing the electronic subject diary, including the 
quality of life questionnaires.
Synopsis
Section 3.1
Updated sections to include the final clinical data (safety and 
pharmacokinetics) from Study SHP616-103.
Section 1.2, Section 1.2.1.1, 
Section 1.2.2.2
Modified the presentation of the PK results from Study 0624-206 to 
clarify dose selection.
Section 1.2.2.1
Modified text on dose selection and rationale for the study based on 
results from Study SHP616-103.
Section 1.2.2.3, Section 2.1
Clarified guidelines regarding the treatment of acute angioedema attacks 
with icatibant. 
Section 5.2.1
Updated the details on subject randomization to specify that it will be 
conducted in two phases. 
Section 6.3
Removed the request for subjects to participate in longitudinal follow-up 
for C1 INH antibody titers if they had anti-C1 INH antibodies detected in 
their plasma samples. If warranted, subjects may be requested to 
participate in follow-up of C1 INH antibody titers via a separate study 
protocol.
Section 7.1.5, Section 7.2.4.1
Removed the request for study personnel to obtain a digital photograph 
of severe injection site reactions and clarified that measurements of any 
erythema or swelling should be captured in the CRF.
Section 7.2.3.10
Clarified the collection period for AEs.
Section 8.1
Clarified the population of subjects (ie, those randomized to Treatment 
Sequence 1 [A/B] or 2 [B/A]) to be used in the evaluation of the efficacy 
of SC administration of C1 esterase inhibitor [human] liquid for injection 
compared to placebo.
Section 9.8.1, Section 9.8.2.2


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Page 105 of 106
Amendment 2 to Protocol SHP616-300 incorporates the following major changes:

The inclusion and exclusion criteria regarding the attack rate and baseline prophylactic 
therapy was modified.

A new exclusion criterion was added to prevent any changes of dose in hormonal 
products/therapies prior to study enrollment.

Self-administration is now allowed in both treatment periods (1 and 2), under 
supervision and after receiving adequate training by the site or home health 
professional.

Clarification added for the subjects who continue to have breakthrough attacks on the 
blinded investigational product despite receiving on-demand treatment for the 
management of angioedema attacks during the study.

Added a section to clarify nonpharmacologic treatments and procedures.

Added overall severity and duration assessment for injection site reactions.

Number of subjects randomized in each of the three treatment sequences (A/B, B/A, 
A/A) was modified along with the statistical power calculations. 

Removed “achieving a NNA <2.0” as a secondary efficacy endpoint.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the inclusion criterion # 3 to clarify the baseline prophylactic 
treatment requirement for both adults (≥18 yrs) and adolescents (>12-
<18 yrs).
Synopsis, Section 3.1
Section 4.1
Changed the baseline attack rate requirement for study entry from a 
history of ≥3 attacks per month average to ≥2 attacks per month average 
for inclusion criterion #3.
Synopsis, Section 3.1
Section 4.1
Exclusion criterion #1 was modified to only include adults.
Synopsis
Section 4.2
Added exclusion criterion #2 for adolescents receiving prophylactic 
therapy with C1 INH.
Synopsis
Section 4.2
Added exclusion criterion #5 to prevent females from changing the dose 
of any hormonal contraceptive regimen or hormone replacement therapy 
within 2 months prior to the screening visit.
Synopsis
Section 4.2


Shire ViroPharma, Inc.
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Protocol SHP616-300
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Page 106 of 106
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Authorized self-administration for subjects in both treatment periods, 1 
and 2.
Synopsis, Section 3.1, Section 6.2
Section 6.5,
Section 7.2.4.5
The self-administration survey was added to the assessment schedule for 
Treatment Period 1 for Visit 28a.
Table 1
Section 7.1.2.3
The period required for stabilization of hormonal contraceptives was 
revised from 30 days to 2 months prior to the screening visit.
Section 4.3.1
Added clarification on the management of angioedema attacks for 
subjects who continue to have breakthrough attacks on the blinded 
investigational product despite on-demand therapy.
Section 5.2.1
Added a section to clarify nonpharmacologic treatments and procedures 
and to request that subjects postpone elective procedures during the 
study.
Section 5.2, Section 5.2.3
Added overall assessment of severity and duration for injection site 
reactions, in the CRF.
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3, 
Section 7.2.3.10
SAE reporting timeline was clarified to include 30 days after the last 
dose of investigational product.
Table 3, Section 8.2.4
Updated the new Medical Monitor for the study.
Protocol Signature Page, Emergency 
Contact Information section
Updated the HIV assay test from Western Blot to INNO-LIA.
Table 1, Section 7.2.3.5
Modified number of subjects randomized in each of the 3 treatment 
sequences (A/B, B/A, A/A).
Synopsis, Table 7, Section 6.3
Statistical power calculations were modified based on the change in the 
number of subjects randomized to each treatment sequence.
Section 9.6
Revised the secondary efficacy endpoint defining “clinical response to 
treatment” since one component (achieving a NNA <2.0) is no longer 
clinically meaningful given the study inclusion criterion is now >2 
attacks. The corresponding secondary objective of the study has also 
been revised.
Synopsis, Section 2.2.2, 
Section 9.8.2.2

Prot_002.pdf: 
PROTOCOL: SHP616-300
TITLE:
A 
Phase 
3, 
Randomized, 
Double-blind, 
Placebo-controlled, 
Two-period, Three-sequence, Partial Crossover Study to Evaluate the 
Efficacy and Safety of Subcutaneous Administration of 2000 U of 
C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention 
of Angioedema Attacks in Adolescents and Adults with Hereditary 
Angioedema
DRUG:
SHP616, C1 esterase inhibitor [human] liquid for injection
IND:
16516
EUDRACT NO.:
2015-002478-19
SPONSOR: 
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
INVESTIGATORS: Multicenter
PROTOCOL 
HISTORY:
Amendment 2: 03 Sep 2015
Amendment 1: 22 Jul 2015
Original Protocol: 28 May 2015
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used solely for the 
purposes for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Shire ViroPharma, Inc.


Shire 
Inc. 
Protocol SJPJ>6!6-300 
I have 
this protocol 
CONPillENTlAL 
·version 3 
FThJAL 
Shi.re ViroPharma Study SHP6l6-300_ 
03 Sep 2015 
Page 2 of 103 
A Phase 3, randomized, double-blind, placebo-controlled, two-period, three-sequence, 
partial crossover study to evaluate the efficacy and safety of subcutaneous administration of 
2000 U of Cl esterase inhibitor [human]liquid for injection for the prevention of angioedema 
attacks 
adolescents and adults with hereditary angioedema_ 
I have fully discussed the objective(s) of 
sponsor's representative_ 
study and the contents of this protocol with the 
I understand that the infonnation in this protocol is confidential and should not be disclosed, 
other than to those directly 
the execution or the scientific/ethical review of the 
study, without written authorization from the sponsoL It is, however, permissible to provide 
the infom1ation contained herein to a subject in order to obtain their consent to participate_ 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with Intemational Conference on Hrumonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements_ 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study_ 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing_ Conversely, 
should I decide to 
execution of the study I will communicate my intention 
immediately 
writing to the sponsor, 
Investigator Name and Address: 
(please hand print or type) 
-------- Date: 
PPD
PPD


Shire ViroPharma, Inc.
CONFIDENTIAL
03 Sep 2015
Protocol SHP616-300
Version 3.0, FINAL
Page 3 of 103
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Amendment 2 to Protocol SHP616-300 incorporates the following major changes:

The inclusion and exclusion criteria regarding the attack rate and baseline prophylactic 
therapy was modified.

A new exclusion criterion was added to prevent any changes of dose in hormonal 
products/therapies prior to study enrollment.

Self-administration is now allowed in both treatment periods (1 and 2), under 
supervision and after receiving adequate training by the site or home health 
professional.

Clarification added for the subjects who continue to have breakthrough attacks on the 
blinded investigational product despite receiving on-demand treatment for the 
management of angioedema attacks during the study.

Added a section to clarify nonpharmacologic treatments and procedures.

Added overall severity and duration  assessment for injection site reactions.

Number of subjects randomized in each of the three treatment sequences (A/B, B/A,
A/A) was modified along with the statistical power calculations.

Removed “achieving a NNA <2.0” as a secondary efficacy endpoint.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the inclusion criterion # 3 to clarify the baseline prophylactic 
treatment requirement for both adults (≥18 yrs) and adolescents (>12-
<18 yrs).
Synopsis, Section 3.1
Section 4.1
Changed the baseline attack rate requirement for study entry from a 
history of ≥3 attacks per month average to ≥2 attacks per month average 
for inclusion criterion #3.
Synopsis, Section 3.1
Section 4.1
Exclusion criterion #1 was modified to only include adults.
Synopsis
Section 4.2
Added exclusion criterion #2 for adolescents receiving prophylactic 
therapy with C1 INH.
Synopsis
Section 4.2
Added exclusion criterion #5 to prevent females from changing the dose 
of any hormonal contraceptive regimen or hormone replacement therapy 
within 2 months prior to the screening visit.
Synopsis
Section 4.2


Shire ViroPharma, Inc.
CONFIDENTIAL
03 Sep 2015
Protocol SHP616-300
Version 3.0, FINAL
Page 4 of 103
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Authorized self-administration for subjects in both treatment periods, 1 
and 2.
Synopsis, Section 3.1, Section 6.2
Section 6.5,
Section 7.2.4.5
The self-administration survey was added to the assessment schedule for 
Treatment Period 1 for Visit 28a.
Table 1
Section 7.1.2.3
The period required for stabilization of hormonal contraceptives was 
revised from 30 days to 2 months prior to the screening visit.
Section 4.3.1
Added clarification on the management of angioedema attacks for 
subjects who continue to have breakthrough attacks on the blinded 
investigational product despite on-demand therapy.
Section 5.2.1
Added a section to clarify nonpharmacologic treatments and procedures 
and to request that subjects postpone elective procedures during the 
study.
Section 5.2, Section 5.2.3
Added overall assessment of severity and duration for injection site 
reactions, in the CRF.
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3, 
Section 7.2.3.10
SAE reporting timeline was clarified to include 30 days after the last 
dose of investigational product.
Table 3, Section 8.2.4
Updated the new Medical Monitor for the study.
Protocol Signature Page, Emergency 
Contact Information section
Updated the HIV assay test from Western Blot to INNO-LIA.
Table 1, Section 7.2.3.5
Modified number of subjects randomized in each of the 3 treatment 
sequences (A/B, B/A, A/A).
Synopsis, Table 7, Section 6.3
Statistical power calculations were modified based on the change in the 
number of subjects randomized to each treatment sequence.
Section 9.6
Revised the secondary efficacy endpoint defining “clinical response to 
treatment” since one competent (achieving a NNA <2.0) is no longer 
clinically meaningful given the study inclusion criterion is now >2 
attacks. The corresponding secondary objective of the study has also 
been revised.
Synopsis, Section 2.2.2, 
Section 9.8.2.2
See Appendix 6 for protocol history, including all amendments.


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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover) and are 
provided below. 
US and Canadian Sites
Fax:
Email:
EU/ROW Sites
Fax: 
Email: 
For protocol- or safety-related issues, the investigator must contact the Shire 
ViroPharma Medical Monitor:
, MD,
, Clinical Development 
Office phone: 
Mobile phone: 
Fax:
Email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Shire ViroPharma, Inc.
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Protocol SHP616-300
Version 3.0, FINAL
Page 6 of 103
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire 
ViroPharma product (marketed or investigational) does not meet expectations (eg, inadequate 
or faulty closure, product contamination) or that the product did not meet the specifications 
defined in the application for the product (eg, wrong product such that the label and contents 
are different products). For instructions on reporting AEs related to product complaints, see 
Section 8.
Please report all Product Quality Complaints to:
PPD


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Protocol SHP616-300
Version 3.0, FINAL
Page 7 of 103
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................3
EMERGENCY CONTACT INFORMATION ..........................................................................5
PRODUCT QUALITY COMPLAINTS ....................................................................................6
LIST OF TABLES....................................................................................................................11
LIST OF FIGURES..................................................................................................................12
LIST OF APPENDICES ..........................................................................................................12
ABBREVIATIONS..................................................................................................................13
STUDY SYNOPSIS.................................................................................................................15
STUDY SCHEDULES.............................................................................................................22
1.
BACKGROUND INFORMATION.............................................................................28
1.1
Indication and Current Treatment Options...................................................................28
1.2
Product Background and Clinical Information ............................................................29
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection ...............................31
1.2.1.1
Clinical Safety.............................................................................................32
1.2.1.2
Clinical Efficacy..........................................................................................33
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid 
for Injection............................................................................................................35
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response 
Analysis of CINRYZE ...................................................................................35
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid 
for Injection .................................................................................................39
1.2.2.3
Dose Selection.............................................................................................41
2.
STUDY OBJECTIVES AND PURPOSE....................................................................41
2.1
Rationale for the Study.................................................................................................41
2.2
Study Objectives...........................................................................................................42
2.2.1
Primary Objectives ................................................................................................42
2.2.2
Secondary Objectives ............................................................................................42
3.
STUDY DESIGN.........................................................................................................43


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3.1
Study Design and Flow Chart ......................................................................................43
3.2
Duration and Study Completion Definition .................................................................45
3.3
Sites and Regions .........................................................................................................45
4.
STUDY POPULATION...............................................................................................45
4.1
Inclusion Criteria..........................................................................................................46
4.2
Exclusion Criteria.........................................................................................................47
4.3
Reproductive Potential .................................................................................................47
4.3.1
Female Contraception............................................................................................47
4.3.2
Male Contraception................................................................................................48
4.4
Discontinuation of Subjects..........................................................................................48
4.4.1
Reasons for Discontinuation..................................................................................49
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit ..................................49
4.4.3
Anaphylactic Reaction...........................................................................................49
4.4.4
Thrombotic or Thromboembolic Event.................................................................49
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................50
5.1
Prior Treatment.............................................................................................................50
5.2
Concomitant Treatment and Medical/Surgical Procedures..........................................50
5.2.1
Management of Angioedema Attacks....................................................................51
5.2.2
Prohibited Treatment .............................................................................................52
5.2.3
Nonpharmacologic Treatments and Procedures ....................................................52
6.
INVESTIGATIONAL PRODUCT..............................................................................53
6.1
Identity of Investigational Product...............................................................................53
6.2
Administration of Investigational Product ...................................................................53
6.3
Allocation of Subjects to Treatment Sequence ............................................................53
6.4
Blinding of Treatment ..................................................................................................54
6.4.1
Unblinding the Treatment Assignment..................................................................55
6.5
Treatment Compliance .................................................................................................55
6.6
Packaging and Labeling ...............................................................................................55
6.7
Storage and Accountability ..........................................................................................55
6.8
Investigational Product Retention at Study Site...........................................................56
7.
STUDY PROCEDURES..............................................................................................56
7.1
Study Schedule.............................................................................................................56
7.1.1
Screening Period....................................................................................................57
7.1.2
Treatment Period 1.................................................................................................57
7.1.2.1
Visit 1a (predose) ........................................................................................57


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Page 9 of 103
7.1.2.2
Visit 1a (postdose).......................................................................................58
7.1.2.3
Visit 2a through Visit 28a ...........................................................................58
7.1.3
Treatment Period 2.................................................................................................59
7.1.3.1
Visit 1b (predose) ........................................................................................59
7.1.3.2
Visit 1b (postdose).......................................................................................60
7.1.3.3
Visit 2b through Visit 28b...........................................................................60
7.1.4
Early Discontinuation Visit ...................................................................................61
7.1.5
Follow-up Period ...................................................................................................62
7.2
Study Evaluations and Procedures ...............................................................................63
7.2.1
Demographic and Other Baseline Characteristics .................................................63
7.2.2
Efficacy..................................................................................................................63
7.2.2.1
Definition of an Angioedema Attack ..........................................................63
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary...........63
7.2.2.3
Angioedema Activity Score ........................................................................64
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks .........64
7.2.3
Safety .....................................................................................................................65
7.2.3.1
Medical and Medication History.................................................................65
7.2.3.2
Physical Examination (Including Height and Weight)................................66
7.2.3.3
Adverse Event Collection............................................................................66
7.2.3.4
Vital Signs ...................................................................................................66
7.2.3.5
Clinical Laboratory Evaluations..................................................................66
7.2.3.6
Pregnancy Test ............................................................................................68
7.2.3.7
Electrocardiogram .......................................................................................68
7.2.3.8
Nonpharmacologic Treatments and Procedures..........................................68
7.2.3.9
Thrombotic or Thromboembolic Events.....................................................69
7.2.3.10 Injection Site Reactions...............................................................................70
7.2.4
Others.....................................................................................................................70
7.2.4.1
Clinical Pharmacology Assessments...........................................................70
7.2.4.2
Health-related Quality of Life Assessments................................................71
7.2.4.3
Health Resource Utilization Assessment ....................................................72
7.2.4.4
Survey of Acceptability of SC Administration ...........................................72
7.2.4.5
Self-administration Survey Assessment......................................................72
7.2.5
Volume of Blood to Be Drawn From Each Subject ..............................................73
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................74
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................74
8.1.1
Severity Categorization..........................................................................................74


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Page 10 of 103
8.1.2
Relationship Categorization...................................................................................75
8.1.3
Outcome Categorization ........................................................................................75
8.1.4
Symptoms of the Disease Under Study .................................................................75
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................76
8.1.6
Pregnancy...............................................................................................................76
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................77
8.2
Serious Adverse Event Procedures...............................................................................78
8.2.1
Reference Safety Information................................................................................78
8.2.2
Reporting Procedures.............................................................................................78
8.2.3
Serious Adverse Event Definition .........................................................................78
8.2.4
Serious Adverse Event Collection Time Frame ....................................................79
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................79
8.2.6
Fatal Outcome........................................................................................................79
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................80
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................80
9.1
Data Collection.............................................................................................................80
9.2
Clinical Data Management...........................................................................................80
9.3
Data Handling Considerations......................................................................................80
9.4
Statistical Analysis Process..........................................................................................81
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........81
9.6
Sample Size Calculation and Power Considerations....................................................81
9.7
Study Population ..........................................................................................................82
9.8
Efficacy Analyses.........................................................................................................82
9.8.1
Primary Efficacy Endpoint ....................................................................................82
9.8.2
Secondary Efficacy Endpoints...............................................................................83
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................83
9.8.2.2
Other Secondary Efficacy Endpoints ..........................................................84
9.8.3
Exploratory Efficacy Endpoints.............................................................................84
9.9
Safety Analyses ............................................................................................................85
9.10
Other Analyses .............................................................................................................85
9.10.1 Pharmacokinetic and Pharmacodynamic Analyses ...............................................85
9.10.2 Health-related Quality of Life Analyses................................................................86
9.10.3 Surveys on SC Administration and Self-administration of Investigational 
Product...................................................................................................................86
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................86


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10.1
Sponsor’s Responsibilities ...........................................................................................86
10.1.1 Good Clinical Practice Compliance.......................................................................86
10.1.2 Public Posting of Study Information .....................................................................87
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................87
10.1.4 Study Suspension, Termination, and Completion .................................................87
10.2
Investigator’s Responsibilities .....................................................................................87
10.2.1 Good Clinical Practice Compliance.......................................................................87
10.2.2 Protocol Adherence and Investigator Agreement..................................................88
10.2.3 Documentation and Retention of Records.............................................................88
10.2.3.1 Case Report Forms......................................................................................88
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................89
10.2.3.3 Audit/Inspection..........................................................................................89
10.2.3.4 Financial Disclosure....................................................................................89
10.3
Ethical Considerations..................................................................................................90
10.3.1 Informed Consent ..................................................................................................90
10.3.2 Institutional Review Board or Ethics Committee..................................................90
10.4
Privacy and Confidentiality..........................................................................................91
10.5
Study Results/Publication Policy .................................................................................91
11.
REFERENCE...............................................................................................................93
12.
APPENDICES..............................................................................................................96
LIST OF TABLES
Table 1:
Schedule of Assessments – Treatment Period 1....................................................22
Table 2:
Schedule of Assessments – Treatment Period 2....................................................24
Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits..............................................................................................26
Table 4:
Blood Sample Collection for PK/PD Analyses .....................................................27
Table 5:
Exposure to SC CINRYZE.......................................................................................32
Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)...................................................................................................35
Table 7:
Treatment Sequences.............................................................................................54
Table 8:
Severity Scoring for Injection Site Reactions........................................................70
Table 9:
Approximate Volume of Blood to Be Drawn From Each Subject ........................73


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LIST OF FIGURES
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity .....................................................36
Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)..................................................37
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice-weekly Dose Regimen....................................................................38
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206)...............................................................................................39
Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103) .............40
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)........40
Figure 7:
Study Design Flow Chart.......................................................................................44
LIST OF APPENDICES
Appendix 1 Handling of Investigational Product for Subcutaneous Injection.........................97
Appendix 2 Subcutaneous Injection Site Selection and Preparation........................................98
Appendix 3 Wells Prediction Rule for the Diagnosis of Venous Thrombembolism ...............99
Appendix 4 Algorithm For Suspected Venous Thromboembolism .......................................100
Appendix 5 Algorithm For Suspected Arterial Thromboembolism.......................................101
Appendix 6 Protocol History..................................................................................................102


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ABBREVIATIONS
AE
adverse event
AE-QoL
angioedema quality of life (questionnaire)
AAS
Angioedema Activity Score
ATE
arterial thromboembolism
AUC
area under the curve
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
C1 INH
C1 esterase inhibitor or C1 inhibitor
CI
confidence interval
CL
clearance
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
Cmin
minimum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAE
hereditary angioedema
β-hCG
beta human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRUA
health resource utilization assessment


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ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
λz
first order rate constant associated with the terminal (log-linear) portion of 
the curve
NNA
normalized number of attacks
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDS
Sheehan Disability Scale
t1/2
terminal half-life
T/TE
thrombotic/thromboembolic
TCSR
time-to-subject-assessed-complete-symptom resolution
TEAE
treatment-emergent adverse event
TISI
time-to-subject-assessed-initial-symptom improvement
tmax
time of maximum observed concentration sampled during a dosing 
interval
US
United States
VAS
Visual Analogue Scale
VTE
venous thromboembolism
WPAI-GH
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire)


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STUDY SYNOPSIS
Protocol number: SHP616-300
Drug: C1 esterase inhibitor [human] liquid for injection
Title of the study: A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, 
Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 U of C1 
Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and 
Adults with Hereditary Angioedema.
Number of subjects (total and for each treatment arm):
Approximately 75 subjects will be screened
At least 66 subjects will be enrolled and randomized to ensure that 54 subjects complete both treatment periods
At least 26 subjects will be randomized to the treatment sequence 1 or 2, and at least 14 subjects will be 
randomized to the treatment sequence 3
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites globally (North America and Europe)
Study period (planned):
2015-2017
Clinical phase:
3
Objectives:
Primary:  
To demonstrate the superior efficacy of subcutaneous (SC) administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
normalized number of attacks (NNA) during a treatment period.
Key Secondary:  
To demonstrate the superior efficacy of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection for the prevention of angioedema attacks relative to placebo as measured by the proportion of subjects 
meeting the criterion of at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] 
liquid for injection treatment period relative to the placebo period.
Other Secondary:

To assess the proportion of responders during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo, where the proportion of responders is defined as achieving 
at least a 50% reduction in the NNA during a treatment period relative to the pretreatment assessment (ie, 
the subject’s attack rate without prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of attack-free days during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo

To assess the number of angioedema attacks requiring acute treatment during treatment with 2000 U C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo

To assess the safety and tolerability of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SC administration of 2000 U 


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C1 esterase inhibitor [human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment of acute 
angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS)

To evaluate subject experience with self-administration of SC 2000 U C1 esterase inhibitor [human] liquid 
for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient population
Rationale:
Shire ViroPharma has developed a new, ready-to-use liquid formulation of CINRYZE® for SC administration. 
This product, C1 esterase inhibitor [human] liquid for injection, obviates the need for reconstitution by the 
patient or health care provider and, owing to its higher concentration, affords the opportunity for more rapid 
administration of the drug and may improve tolerability, without an expected change or compromise in efficacy. 
Subcutaneous administration represents a convenient alternative method of administering prophylaxis to 
hereditary angioedema (HAE) patients overall and for whom accessing peripheral veins is difficult or in patients 
where placement of central venous catheters are contraindicated, as well as a means to minimize the potential 
adverse effects of intravenous (IV) administration.
Investigational product, dose, and mode of administration:

C1 esterase inhibitor [human] liquid for injection is supplied in clear glass vials containing 1000 U of 
C1 INH in 2 mL of sterile liquid. The solution also contains the following inactive ingredients: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.

Placebo is supplied in the identical 2 mL presentation as the active investigational product minus the 
C1 INH protein. The inactive ingredients in the 2 mL solution are the same as the active product: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.
Blinded investigational product (Treatments A or B: 2000 U C1 esterase inhibitor [human] liquid for injection 
or placebo) will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate treatment 
periods. Each dose of investigational product will be administered in the subject’s abdomen as a single 4 mL SC 
injection.
Methodology:
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial crossover study. 
This design was chosen as the best way to jointly address the protocol objectives of establishing efficacy 
(relative to placebo) and safety (ie, enrolling an adequate number of subjects for precision of estimation in 
detecting potential safety signals). Additionally, this design maximizes the number of subjects exposed to 
C1 esterase inhibitor [human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have a history (based 
on subject recall and medical records) of ≥2 attacks per month on average per inclusion criterion #3. At least 66 
eligible subjects will be randomized to 1 of 3 treatment sequences prior to the first dose of investigational 
product in Treatment Period 1 using interactive response technology (see table below). Randomization of 
subjects will be stratified by use of prophylactic therapy with C1 INH at the time enrollment.
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 
3 or 4 days) for 14 weeks.
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.


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Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission of a washout 
period is to minimize the duration that subjects will be without active treatment. It is recommended that the 
twice weekly dosing schedule (every 3 or 4 days) be maintained between the last dose of investigational product 
in Treatment Period 1 and the first dose of investigational product in Treatment Period 2.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be blinded to 
treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be administered at the 
investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both treatment periods. Other doses may be 
administered by qualified blinded personnel at the investigational site or at the subject’s home or other agreed 
upon location. During Treatment Periods 1 and 2, after having received appropriate training, subjects will be 
allowed to self-administer the investigational product with direct supervision by study site personnel or a 
qualified home health professional. Alternatively, a parent/legal guardian/caregiver will be allowed to 
administer the investigational product to an adolescent subject, after having received appropriate training and 
under the supervision of study site personnel or a qualified home health professional. Throughout the study, an 
electronic subject diary will be used to record specific information regarding the subject’s symptoms of HAE. 
This will include signs and symptoms of angioedema attacks, location (including whether mucosal or non-
mucosal), triggers for angioedema attacks, medications used for the acute treatment of angioedema attacks, 
elective procedures, and interruptions in activities of daily living due to an angioedema attack. Additionally, 
quality of life questionnaires and surveys on SC administration of the investigational product will be also 
subject evaluated. Note: For adolescent subjects, a parent/legal guardian/caregiver is allowed to assist the 
subject in completing the electronic subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product is administered. In addition, the investigator will report all SAEs that 
occur through 30 days after the last dose of investigational product to Shire Pharmacovigilance and the 
respective Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last dose of 
investigational product in Treatment Period 2 for follow-up safety assessments. In addition, subjects will have 
blood samples collected for PK/PD and C1 INH antibody testing at 1 month (±2 days) after the last dose of 
investigational product. 
If a subject prematurely discontinues investigational product, early discontinuation visit procedures (Table 3) 
are to be performed as completely as possible. Whenever possible, all discontinued subjects should also 
complete the 1-week and 1-month post-treatment visits.  
The schedules of study procedures are provided immediately following the study synopsis:

Table 1: Clinical study assessments – Treatment Period 1 (Visits 1a to 24a).

Table 2: Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Table 3: Clinical study assessments – Early discontinuation visit, 1-week post-treatment and 1-month 
post-treatment visits.

Table 4: Blood sample collection schedule – PK/PD assessments.


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Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 inhibitor (C1 INH) level less than 50% of 
normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in conjunction with the 
subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy with C1 INH, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving prophylactic therapy 
with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) during the 
3 consecutive months prior to the screening visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of attenuated androgens, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any angioedema attacks 
that occur during the study that, in the opinion of the healthcare care provider, requires medical 
intervention. Note: For subjects ≥12 to <18 years of age, standard of care therapy per local protocols 
should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) pregnancy test at 
the screening visit and must have a negative urine pregnancy test prior to the first dose of 
investigational product (Visit 1a), and agree to comply with any applicable contraceptive requirements 
of the protocol.
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, 
barrier control) from the screening visit through 2 months after the last dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide written informed 
consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study 
provide written informed consent for the child to participate in the study before any study-specific 
procedures are performed (with assent from the child when appropriate). Alternatively, certain 
sites/Independent Reviewing Authorities may permit adolescents who are <18 years of age to be 
informed of the nature of the study and provide written informed consent without consent from a 
parent(s)/legal guardian.
Exclusion Criteria:
1.
Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved dosing 
regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with C1 INH.
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose of 
investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention of angioedema 
attacks within 3 calendar days prior to the first dose of investigational product in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or hormone 


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replacement therapy (ie, estrogen/progestin containing products) within 2 months prior to the 
screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism.
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies.
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of 
CINRYZE), or other blood products.
9.
Be pregnant or breastfeeding.
10.
Have received an investigational drug within 30 days prior to the first dose of investigational product in 
Treatment Period 1.
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical or medical 
condition that could interfere with the administration of investigational product or interpretation of 
study results.
Maximum duration of subject involvement in the study:
Individual participation from the screening visit through the 1-month post-treatment visit will be approximately 
9 months.

Planned duration of screening period: Up to 21 days

Planned duration of enrollment period: 6 months

Planned duration of treatment period: Treatment Periods 1 and 2 are 14 weeks each (total 28 weeks) with 
no washout between periods

Planned duration of follow-up: 1 month follow-up in total, with safety assessments at both 1-week and 
1-month post-treatment
Endpoints and statistical analysis:
Primary Efficacy Endpoint: The NNA recorded during each treatment period. The NNA is computed as the 
number of attacks per month (ie, 30.4 days) of exposure (NNA = 30.4 x [number of attacks during treatment 
period]/[days of treatment period]). If a subject discontinues during the treatment period, the denominator of the 
NNA will be the days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation. 
The primary analysis of the primary efficacy endpoint will test against the null hypothesis that the NNA of C1 
esterase inhibitor [human] liquid for injection is greater than or equal to the NNA of placebo 
(H0: µ C1 INH - µ placebo >0; H1: µ C1 INH - µ placebo <0). The primary efficacy endpoint will be analyzed by using a 
mixed effect linear model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH),
and treatment as fixed effects, and subject nested within sequence as a random effect. The mean treatment 
difference (µ C1 INH - µ Placebo) will be estimated with a 95% confidence interval (CI).
To control the overall type 1 error, the primary and key secondary endpoints will be tested hierarchically, so that 
the significance of the key secondary endpoint is contingent on whether the primary endpoint is significant.
Key Secondary Efficacy Endpoint: The clinical response to treatment relative to placebo. This is defined as 
achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion PR. The null 
hypothesis is that PR is less than or equal to 0.2 and the alternative hypothesis is that PR is greater than 0.2. The 
proportion meeting criterion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. 
Other Secondary Efficacy Endpoints:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA during a treatment 


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period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity recorded for each 
angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every day of reported 
symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment during a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS during a treatment 
period, where the daily AAS is the sum of AAS items per day.

Results of the Angioedema Quality of Life (AE-QoL) questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema attack by:
-
Time to subject-assessed initial symptom improvement (TISI).
-
Time to subject-assessed complete symptom resolution (TCSR). 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC administration of C1 
esterase inhibitor [human] liquid for injection. The treatment differences in clinical responder rate, both of 
which are defined within treatments, will be analyzed using McNemar’s test for testing equality of proportions 
of responders within treatments. All other secondary endpoints will be analyzed using a linear mixed effect 
model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH), and treatment as 
fixed effects, and subject nested within sequence as a random effect. The results of all secondary efficacy 
analyses will be summarized by the point estimate of within-subject treatment differences or response rates and 
the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75% quartiles, and range) will be 
provided to summarize icatibant-related efficacy endpoints (TISI and TCSR) by treatment and icatibant-treated 
angioedema attack for all subjects in the Full Analysis Set. Where appropriate (for subjects ≥12 to <18 years of 
age) other rescue medications used to treat acute angioedema attacks will also be summarized using descriptive 
statistics. In addition, angioedema attacks will be summarized by the maximum symptom severity and treatment 
for all subjects in the Full Analysis Set.
Safety Endpoints:

Number of subjects experiencing AEs, including severity and causality. AEs will also be assessed by time 
of onset (eg, during administration of investigational product or within 24 hours after the end of injection of 
investigational product). 

Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings will be 
summarized by treatment and visit. Potentially clinically important findings will also be summarized or 
listed. 

Incidence and severity (mild, moderate, severe) of SC injection site reactions. 

Results of C1 INH antibody testing will be reported for individual subjects and summarized. 

Tolerability of icatibant therapy for acute angioedema attacks will be summarized.
PK/PD Endpoints: Plasma concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
and C1q for individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics for values at each time point. C1q concentrations will only be assessed 
at baseline (ie, pre-injection, Dosing Visit 1a).
PK parameters will be calculated using observed and baseline-corrected concentration-vs-time data using non-
compartmental techniques for C1 INH antigen and functional activity, and results will be summarized using 
descriptive statistics.
Other Endpoints:

Results of the EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) health status instrument will 


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be presented in accordance with the EQ-5D-5L user guide (Version 2.0). 

Results of the Work Productivity and Activity Impairment−General Health (WPAI-GH) questionnaire will 
be summarized. 

Results of the Sheehan Disability Scale (SDS) will be summarized.

Results of the survey of subject acceptability of SC administration of investigational product will be 
summarized.

Results of the survey of subject experience with self-administration of investigational product will be 
summarized. 


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STUDY SCHEDULES
Table 1:
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a 15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a 26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj







j







j







j



j
Acceptability surveyk

Self-administration surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m,
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c,n
c,n
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report 
form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; HRUA=health 
resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; 


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Table 1:
Schedule of Assessments – Treatment Period 1
PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the 
injection.
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
g HIV (single assay antibody/INNO-LIA) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visits 8a, 16a, 24a, and 28a an overall assessment of injection site 
severity (mild, moderate, and severe as defined in Section 8.1.1) and the overall duration of the injection site reactions  will be captured in the CRF.k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack. 
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see Table 4).


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Table 2:
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg







g







g







g



g
Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; 
INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan 
Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site.
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing 
days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.


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Table 2:
Schedule of Assessments – Treatment Period 2
d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visits 8b, 16b, 24b, and 28b an overall assessment of injection site 
severity (mild, moderate, and severe as defined in Section 8.1.1) and the overall duration of the injection site reactions  will be captured in the CRF. h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.


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Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits
Procedures
Early Discontinuation 
Visita
[If Applicable]
1-Week (±1 day)
Post-treatment 
Visit
[All Subjects]
1-Month (±2 days)
Post-treatment
Visit
[All Subjects]
Concomitant medications


Physical examination


Vital signs (BP, pulse)b


Safety labsc


UA with microscopy


Pregnancy testingd


Adverse events/ SAEs g



Angioedema attack monitoringe, f


AASe


Acceptability surveye

Self-administration surveye

AE-QoL questionnairee


EQ-5D-5Le


WPAI-GH and SDSe


HRUA-HAE

Immunogenicity (anti-C1 INH antibodies)



PK/PD



AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; 
BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level 
descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs 
that occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department.
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits. 
b Vital signs will be measured using standard methods at each investigational site. 
c Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer).  
d A urine pregnancy test will be performed for all female subjects of childbearing potential.
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation or at the 
1-week post-treatment visit.
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary.
g  Serious Adverse Events (SAEs) are to be followed until 1 month post-treatment visit.


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Table 4:
Blood Sample Collection for PK/PD Analyses
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Pointsa
C1 INH Antigen, C1 INH Functional, C4
1a / Dose 1b
Predose 1 (within 15 min) 
2a / Dose 2
Predose 2 (within 15 min)
8a / Dose 8
Predose 8 (within 15 min)
16a / Dose 16
Predose 16 (within 15 min) 
24a / Dose 24
Predose 24 (within 15 min)
Either 27a or 28a / Dose 27 or 28c
Predose 27 or 28 (within 15 min) 
48 hours postdose 27 or 28 (±3 hours)
TREATMENT PERIOD 2
1b / Dose 1
Predose 1 (within 15 min)
2b / Dose 2
Predose 2 (within 15 min)
8b / Dose 8
Predose 8 (within 15 min)
16b / Dose 16
Predose 16 (within 15 min)
24b / Dose 24
Predose 24 (within 15 min)
28b / Dose 28
Predose 28 (within 15 min)
24 hours postdose 28 (±3 hours) – optional sampling time point
48 hours postdose 28 (±3 hours) 
72 hours postdose 28 (±6 hours) – optional sampling time point
96 hours postdose 28 (±6 hours)
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT
Early discontinuation
1-week (± 1 day)
1-month (± 2 days)
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for 
guidance is as an approximate value.
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a).
c To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose 
sample to be collected at either Visit 27a or 28a. 


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Hereditary angioedema (HAE) is an autosomal dominant disease caused by a gene mutation 
on chromosome 11 that results in a quantitative or functional deficiency of C1 esterase 
inhibitor (C1 INH) protein (Bernstein 2011). C1 INH is produced mainly by hepatocytes and 
acts as a “suicide inhibitor” by forming complexes with target serine proteases that result in 
their inactivation and the consumption of C1 INH. C1 INH regulates the activity of several 
components of the complement, contact (bradykinin-forming), and fibrinolytic systems 
(Kaplan 2010). Dysregulation of these cascades (particularly the contact system) due to 
C1 INH deficiency causes the uninhibited production of bradykinin, which promotes 
inflammation through increased vascular permeability and excessive accumulation of fluid in 
body tissues (Kaplan and Joseph 2010). Thus, patients with HAE are susceptible to recurrent 
episodes of debilitating swelling throughout the body. During acute angioedema attacks, the 
plasma levels of bradykinin in HAE patients can increase from 2 to 12 times (18.0–90.0 pM) 
the upper limit of normal (0.2-7.1 pM; Cugno et al. 2003). Serum concentrations of C1 INH 
in patients with HAE are 5% to 30% of normal (Cicardi et al. 1987), thus necessitating C1 
INH replacement therapy to prevent manifestations of the disease.
The diagnosis of a C1 INH deficiency is suggested by a history that includes recurrent attacks 
of angioedema, characterized by non-itching swelling of the skin or mucosa. Serum C4, 
C1 INH antigen, and functional C1 INH levels can be measured to assist with the diagnosis of 
HAE. There are 2 main types of HAE: Type I HAE (85% of cases), characterized by a low 
level of C1 INH antigen, and Type II HAE (15% of cases), characterized by “normal” levels 
of functionally deficient C1 INH protein (Frank et al. 1976). There is no clinical difference 
between Type I and Type II HAE. A third form of HAE, where patients have normal C1 INH 
levels, was initially described and referred to as Type III (Bork et al. 2000a). Patients with this 
type of HAE, more frequently women, have normal complement levels (including normal 
C1 INH), but a well-defined history of angioedema in the absence of concurrent urticaria 
(Zuraw and Christiansen 2009; Bernstein 2011). Mutations in the gene for coagulation factor 
XII (F12) have been identified in a minority of affected families (Bork et al. 2007). There are 
subtle phenotypic differences between patients with HAE due to C1 INH deficiency and those 
with normal C1 INH levels, including age at symptom onset, attack location(s), period of 
disease-free intervals, and inheritance pattern (Zuraw et al. 2012). The pathogenesis of HAE 
with normal C1 INH remains to be fully elucidated.  
Hereditary angioedema with C1 INH deficiency can present as early as the first year of life 
(Ohela 1977; Farkas et al. 2002), however, the median age at onset of initial symptoms is 
between 9 and 12 years (Farkas et al. 2007). Nearly all affected individuals experience 
symptoms of the disease; however, the symptoms vary in both their frequency and severity 
throughout a patient’s lifetime (Gompels et al. 2005; Zuraw 2003). Angioedema attacks may 
or may not have a triggering event. Trauma, medical or dental procedures, psychological 
stress, menstruation, infections, oral contraceptive use, and the use of other medications, such 
as angiotensin-converting enzyme inhibitors have been identified as possible triggers (Georgy 


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and Pongracic 2012; Bowen et al. 2010). Angioedema attacks can affect the face, tongue, 
larynx, gastrointestinal tract, genitourinary system, and extremities (Zuraw 2008). Laryngeal 
swelling can occlude the airway and cause death by asphyxiation, and these attacks primarily 
account for the mortality risk associated with C1 INH deficiency (Agostoni and Cicardi 1992; 
Bork et al. 2000b). Gastrointestinal involvement can mimic an acute surgical emergency, and 
misdiagnosis often results in unnecessary procedures to remove normal appendices and 
gallbladders (Weis 2009). Hence, angioedema attacks require prompt treatment, often in an 
emergency room.  
In addition to the impact on physical and mental health, the burden of illness in patients with 
HAE is considerable with respect to missed educational and career opportunities, work 
productivity, and a substantial economic burden for the cost of treatment (Lumry et al. 2010; 
Aygören-Pürsün et al. 2014). Hereditary angioedema not only causes short-term disability 
associated with attacks, but patients endure long-term effects on their daily lifestyle, 
emotional health, family life, and it may also affect caregivers’ quality of life (Bygum et al. 
2015). Effective management of HAE, including optimization of therapy, may reduce the 
clinical burden and have an overall favorable impact on the quality of life for individual HAE 
patients and their families (Banerji 2013; Caballero et al. 2014).
1.2
Product Background and Clinical Information
CINRYZE® (C1 esterase inhibitor [human]) was developed by the sponsor for the management 
of HAE. CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of C1 INH 
produced 
from 
human 
plasma. 
The 
manufacturing 
process 
includes 
3 
virus 
inactivation/removal 
steps: 
polyethylene 
glycol 
precipitation, 
pasteurization, 
and 
nanofiltration. CINRYZE is a normal human plasma protein that is not subject to cytochrome 
P450 metabolism, excretion, or pharmacokinetic (PK) drug-drug interactions exhibited by low 
molecular weight compounds. 
Intravenous administration of 1000 U of CINRYZE every 3 or 4 days is approved for routine 
prevention (prophylaxis) of angioedema attacks in patients with HAE in the United States 
(2008), European Union (2011), Australia (2012), Canada (2012), and Switzerland (2013). In 
several of these countries, CINRYZE is also approved for the acute treatment and preprocedure 
prevention of angioedema attacks.
The clinical efficacy of CINRYZE for the prevention of angioedema attacks in patients with 
HAE was demonstrated in 1
randomized, double-blind, placebo-controlled study 
(LEVP 2005-1/B) and 1 open-label study (LEVP 2006-4). Study LEVP 2005-1/B 
demonstrated that preventive therapy with CINRYZE resulted in both a statistically significant 
and clinically meaningful decrease in the rate, severity, and duration of acute attacks 
compared to placebo/on-demand therapy. Therapy with CINRYZE also increased antigenic 
C1 INH and functional C1 INH levels. These results were supported by Study LEVP 2006-4 
(that provided data for longer periods of preventive therapy across a wider age range of 
subjects), which demonstrated a reduction in the frequency of attacks while on CINRYZE
compared to a historical baseline. The open-label study also demonstrated that the efficacy of 


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CINRYZE for the prevention of angioedema attacks did not diminish over time periods of at 
least 1 year. 
The sponsor initiated a clinical development program for subcutaneous (SC) administration of 
CINRYZE for prevention of angioedema attacks using the same lyophilized formulation as that 
approved for IV injection. The initial program focused on safety, tolerability, and relative 
bioavailability of SC administration of CINRYZE (Studies 0624-100 and 0624-200). 
Preliminary assessments confirmed that CINRYZE can be absorbed after SC administration. 
However, because the exposure profile differed from that following IV administration, it was 
not known whether or to what extent SC administration would confer efficacy for the 
management of HAE.  
Based on results from nonsponsor studies conducted with recombinant human hyaluronidase 
(rHuPH20) and other injectable protein products, it was hypothesized that co-administration 
with rHuPH20 would increase dispersion and absorption of subcutaneously injected CINRYZE. 
Subsequently, 
the 
development 
program 
evaluated 
the 
safety, 
tolerability, 
PK/pharmacodynamics (PD), and efficacy of SC administration of CINRYZE with rHuPH20 
(Studies 0624-101, 0624-102, 0624-204, and 0624-206). However, in August 2013, the FDA 
directed the sponsor to stop administration of rHuPH20 in the ongoing Phase 2 study (0624-
206) of CINRYZE with rHuPH20 due to the development of anti-rHuPH20 antibodies in some 
patients. Dosing was also terminated in an ongoing Phase 1 healthy volunteer study (0624-
102) of CINRYZE with rHuPH20. Because the combination product (CINRYZE with rHuPH20) 
was being studied in these 2 trials, administration of CINRYZE was also discontinued. The 
FDA encouraged the sponsor to further the clinical development of CINRYZE alone 
administered via SC injection. Hence the evolution of the clinical development program with 
the new low volume, ready-to-use liquid formulation (C1 esterase inhibitor [human] liquid for 
injection) for SC administration. 
C1 esterase inhibitor [human] liquid for injection has been evaluated in an in vitro 
hemocompatibilitiy assay using human blood and plasma, a tissue irritation study in New 
Zealand White rabbits, and a 14-day repeat-dose toxicity study in Sprague Dawley rats. 
Incubation with whole blood at a concentration of 225 U/mL C1 esterase inhibitor [human] 
liquid for injection did not elicit hemolysis nor did the same concentration induce 
flocculation, precipitation, or coagulation. In the tissue irritation study in rabbits, microscopic 
examination of the injection sites showed minimal to mild inflammation that was most 
pronounced for perivascular injection route, followed by SC and then IV injection routes. In 
the 14-day repeat-dose study in rats, doses of 0 (sodium phosphate, glycine, and sorbitol), 
200, 400, and 1000 U/kg/day were administered subcutaneously once a day, while a fifth 
group of rats received 1000 U/kg/day intravenously. The only signs of toxicity were related to 
the expected immunogenic response to a human protein. Therefore, the no observed adverse 
effect level is considered to be 1000 U/kg/day of C1 esterase inhibitor [human] liquid for 
injection for both the SC and IV routes of administration. Therefore, the toxicity profile for 
this ready-to-use liquid formulation is generally comparable to the lyophilized product even 
when a higher dose of the new formulation was tested. 


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An initial clinical assessment of the new liquid formulation was conducted in a Phase 1 study 
in healthy volunteers (SHP616-103). This study evaluated the safety, tolerability, and relative 
bioavailability of the SC administration of 1000 U and 2000 U C1 esterase inhibitor [human] 
liquid for injection compared with the marketed formulation of CINRYZE (1000 U IV). This 
single-center, open-label study consisted of a single-dose IV administration of CINRYZE
(lyophilized formulation) in Treatment Period 1 followed by a randomized, open-label, 2x2 
crossover design (Treatment Periods 2 and 3) to evaluate SC C1 esterase inhibitor [human] 
liquid for injection. The safety and pharmacokinetic results from Study SHP616-103 are 
presented in Sections 1.2.1.1 and 1.2.2.2, respectively.
High-level summaries of the clinical experience with SC administration of both CINRYZE
(CINRYZE alone and CINRYZE + rHuPH20) and C1 esterase inhibitor [human] liquid for 
injection are provided below. Always refer to the latest version of the CINRYZE investigator’s 
brochure for the overall risk/benefit assessment and the most accurate and current information 
regarding the drug metabolism, pharmacokinetics, efficacy, and safety of CINRYZE and C1 
esterase inhibitor [human] liquid for injection. 
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection
Studies that evaluated SC administration of CINRYZE alone and CINRYZE with rHuPH20 
provided valuable data that informed key elements of this Phase 3 study of C1 esterase 
inhibitor [human] liquid for injection. Both programs enrolled healthy volunteers and subjects 
with HAE; 86 healthy volunteers (215 doses administered) and 72 subjects with HAE 
(1321 doses administered) have received 1 or more doses of SC CINRYZE in the development 
program to date (Table 5).


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Table 5:
Exposure to SC CINRYZE
Program
Study Number
Total Number of 
Subjects Exposed 
Number of SC Doses Administered
500 U
1000 U
2000 U
Total Doses
Healthy Volunteers
CINRYZE Alone
Study 0624-100a
9
1
0
14
15
Study 0624-102b
37 
0
37
0
37
CINRYZE with rHuPH20
Study 0624-101
24
0
0
47
47
Study 0624-102b
51 
0
116
0
116
Healthy Volunteers Total
86
1
153
61
215
Subjects with HAE
CINRYZE Alone
Study 0624-200
25
0
52
48
100
CINRYZE with rHuPH20
Study 0624-204
12 d
0
24
24
48
Study 0624-206
47
0
578
595
1173
Subjects with HAE Total
72
0
654
667
1321
OVERALL TOTAL
158
1
807
728
1536
HAE=hereditary angioedema; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
a CINRYZE via SC infusion and SC injection.
b A total of 53 subjects were enrolled in Study 0624-102 and received SC CINRYZE either alone (N=37) or co-administered 
with rHuPH20 (N=51).
c These 12 subjects received SC CINRYZE alone in Study 0624-200 and SC CINRYZE with rHuPH20 in Study 0624-204.
1.2.1.1
Clinical Safety 
Across the 2 studies of SC CINRYZE alone (Studies 0624-100 and 0624-200), 9 healthy adults 
and 25 subjects with HAE received CINRYZE doses of 1000 U and/or 2000 U. In healthy adult 
subjects, a single dose of 2000 U CINRYZE administered via the SC route was associated with 
mild injection/infusion site discomfort; however, no subjects were discontinued from study 
drug due to an AE. In HAE subjects, multiple doses of CINRYZE (1000 U or 2000 U) 
administered via the SC route were associated with generally mild to moderate injection site 
reactions, most notably pain, which was commonly characterized as burning or stinging. No 
subjects were discontinued from study drug due to an injection site reaction. No SAEs 
occurred during either SC study, and no subjects experienced a TEAE that was thrombotic or 
thromboembolic in nature. In addition, in both studies of SC CINRYZE, results of clinical 
laboratory evaluations and vital signs measurements were generally unremarkable and did not 
suggest any treatment-emergent abnormalities related to the administration of CINRYZE.
Across the 4 studies of SC CINRYZE + rHuPH20 (Studies 0624-101 0624-102, 0624-204 and 
0624-206), 77 healthy adults and 59 subjects with HAE received CINRYZE doses of 1000 U 


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and/or 2000 U. No SAEs occurred, no subjects were discontinued due to an AE, and no 
subjects experienced a TEAE that was thrombotic or thromboembolic in nature. The most 
commonly reported AEs were mild-moderate injection site reactions (eg, erythema, swelling, 
pain). Other safety parameters (clinical laboratory evaluations and vital signs measurements) 
were generally unremarkable and did not suggest any treatment-emergent abnormalities 
related to the administration of SC CINRYZE + rHuPH20. 
In Study 0624-206, a total of 21 (45%) subjects had detectable anti-rHuPH20 antibodies 
during the study, with 15 (32%) of the 21 subjects having a post-baseline titer of >1:20. All 
samples from these subjects were determined to be negative for rHuPH20-neutralizing 
activity. As requested by the FDA, the sponsor followed subjects who had treatment-emergent 
titers of ≥1:20 for 1 year post-treatment. There were no clinical sequelae observed in any 
subject and all titers declined during longitudinal follow-up. Three subjects in Study 0624-102 
had reportable anti-rHuPH20 antibodies at a titer ≥1:20; however, in all 3 cases, subjects had 
antibodies to rHuPH20 present at baseline (prior to the first dose of study drug). Subjects 
were not asked to participate in longitudinal follow-up, as anti-rHuPH20 antibody titers 
remained at or below the baseline level for each subject by the end of the study. 
In Study SHP616-103, a total of 26 healthy volunteers were enrolled in the study. Twenty-
three (23) subjects received a single SC dose of both 1000 and 2000 U, and 1 subject only 
received a single SC dose of the 1000 U C1 esterase inhibitor [human] liquid for injection. 
Therefore 24 unique subjects have been exposed to 47 doses of C1 esterase inhibitor [human] 
liquid for injection.
Subcutaneous administration of 1000 U and 2000 U C1 esterase inhibitor [human] liquid for 
injection was generally well tolerated and the clinical safety data were consistent with 
previous CINRYZE IV or SC studies. Overall 19 (73.1%) of the 26 subjects reported at least 1 
TEAE in the study: 62% (16/26), 29% (7/24), and 44% (10/23) of subjects administered 
1000 U IV CINRYZE, 1000 U and 2000 U of SC C1 esterase inhibitor [human] liquid for 
injection, respectively.
With regard to the local tolerability of SC administration of 1000 U and 2000 U C1 esterase 
inhibitor [human] liquid for injection, there was no clear difference in the overall incidence of 
injection site reactions with respect to dose (1000 U versus 2000 U). Twenty-three of 24 
(95.8%) subjects reported injection site reactions, all were mild (58.3%) to moderate (37.5%) 
in severity, and the majority resolved within 2 hours postdose. The majority of reported 
reactions were erythema (mild or moderate) and a warm sensation (all mild).
1.2.1.2
Clinical Efficacy
The Phase 2 dose-ranging, crossover Study 0624-206 was designed to determine if there was 
a difference in efficacy between 2 SC doses of CINRYZE (1000 U and 2000 U co-administered 
with rHuPH20). The study was terminated before enrollment was complete (at the request of 
FDA due to the detection of anti-rHuPH20 antibodies in some subjects). Of the 47 subjects 
enrolled, 22 completed both treatment periods. Thus, due to the early termination of the study, 
the final sample size of the intent-to-treat efficacy population was smaller than planned 


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(22/47, 47%). Regardless, the statistical advantage of a crossover study is that patients serve 
as their own control and the relative effect of the experimental treatments can be determined 
most efficiently with respect to within-patient differences.
The experimental results favored twice weekly SC administration of CINRYZE 2000 U + 
48,000 U rHuPH20 compared with CINRYZE 1000 U + 24,000 U rHuPH20 for the primary 
and all secondary efficacy endpoints during treatment, most notably in the within-subject 
treatment comparison.
An analysis of primary and secondary efficacy endpoints during treatment was performed for 
the mean difference between treatments (2000 U – 1000 U SC CINRYZE), within subjects in a 
treatment sequence and overall, as shown below in Table 6.
For the primary endpoint of normalized number of angioedema attacks during treatment, a 
treatment effect favoring the 2000 U compared with the 1000 U SC CINRYZE dose was 
observed for the within-subject treatment comparison; the overall mean difference (95% 
confidence interval [CI]) between treatments was -0.61 (-1.23, 0.01) and achieved borderline 
significance (p=0.0523).
With regard to secondary efficacy endpoints, statistically significant (p<0.05) treatment 
effects favoring the 2000 U compared with the 1000 U SC CINRYZE dose were observed for 
the within-subject treatment comparisons for both cumulative attack severity and for the 
number of attacks requiring acute treatment, with overall mean differences between 
treatments of -1.33 (p=0.0277) and -0.56 (p=0.0315), respectively.
No sequence effect was observed for the mean difference between the 2000 U and 1000 U SC 
CINRYZE doses within subjects in Sequences A/B or B/A for the primary or for any secondary 
endpoint (p-value for sequence effect across endpoints: ≥0.6290).
These findings indicated that CINRYZE at a dose of 2000 U SC was superior to a dose of 
1000 U in terms of clinical efficacy improvement. The results are more compelling in light of 
their arising from truncated enrollment and consequently, an underpowered study.


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Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)
Endpoints (Normalized)
Sequence A/B
Difference: B-A
N=12
Sequence B/A
Difference: B-A
N=10
Overall
Difference: B-A
N=22
Treatment
Comparison
p-valuea
Primary
Number of angioedema attacks
-0.72
(-1.71, 0.27)
-0.48
(-1.36, 0.40)
-0.61
(-1.23, 0.01)
0.0523
Secondary
Cumulative attack severity
-1.53
(-3.41, 0.35)
-1.09
(-2.74, 0.57)
-1.33
(-2.49, -0.16)
0.0277
Cumulative daily severity
-1.53
(-4.42, 1.36)
-2.19
(-6.06, 1.69)
-1.83
(-3.98, 0.32)
0.0912
Cumulative symptomatic days
-0.95
(-2.64, 0.74)
-0.87
(-3.35, 1.62)
-0.91
(-2.23, 0.41)
0.1660
Number of attacks requiring acute 
treatment
-0.67
(-1.20, -0.14)
-0.43
(-1.47, 0.62)
-0.56
(-1.06, -0.05)
0.0315
CI=confidence interval; ITT-E=intent-to-treat efficacy; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
Note: Data are presented as the mean (95% CI). Treatment A=1000 U SC CINRYZE + 24,000 U rHuPH20; 
Treatment B=2000 U SC CINRYZE + 48,000 U rHuPH20. Subjects who were dosed but did not have any attacks in the 
period were assigned a value of zero for each of the efficacy parameters.
a p-value for paired t-test.
b Only subjects who completed both treatment periods are included in the ITT-E population.
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid for 
Injection
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis of CINRYZE
Population PK and PK/PD modeling of C1 INH and C4 were developed based on data 
collected in 10 clinical studies with healthy volunteers and HAE patients who received IV or 
SC administrations of CINRYZE. Exposure-response analyses were performed based on 
2 studies for the use of CINRYZE for the prophylactic treatment to prevent HAE. 
The final population PK model of C1 INH was a 1-compartment model with endogenous 
C1 INH levels. The absorption of CINRYZE following SC dosing was characterized with a 
first-order rate and relative absorption fraction (Frel). Based on the population PK model, the 
relative bioavailability of CINRYZE following SC dosing without rHuPH20 was 38.8%. 
Typical CL of C1 INH was 0.0864 L/h (1.44 mL/min) in HAE patients with a typical body 
weight of 70 kg. The t1/2 of C1 INH in a typical 18.0, 36.6, and 80.0-year-old patient weighing 
70 kg were 32.0, 29.0, and 26.0 hours, respectively.
The effect of rHuPH20 on the rate and extent of absorption of C1 INH was included in the 
model. The use of rHuPH20 with SC administration appears to have little to no improvement 
on C1 INH exposure. This was illustrated in the Phase 1 study with healthy volunteers 


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(Study 0624-102) where CINRYZE 1000 U SC administered with 200, 2000, or 20,000 U 
rHuPH20 was not statistically different in Cmax and AUClast compared with CINRYZE alone. In 
addition, the population PK model estimated only a 10% increase in bioavailability with 
rHuPH20, which reached saturation with increasing rHuPH20 concentrations as presented in 
Figure 1.
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity
C1 INH=C1 esterase inhibitor; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
The population PK model was used to support the assessment of the exposure-response 
relationship of CINRYZE during prophylactic treatment of angioedema attacks for C1 INH and 
C4. The response criterion originally used in Study 0624-400 was used to define responder 
status, whereby a response was defined as ≤1 angioedema attack/month, since this criterion 
has been deemed clinically meaningful by both expert clinicians and patients with HAE. A 
logistic regression model was used to link Cmin values of C1 INH (continuous) with the 
probability of response (binary) following IV dosing of 1000 U of CINRYZE in studies LEVP 
2005-1/B and LEVP 2006-4 (Section 1.2). The exposure-response relationship of Cmin values 
of C1 INH following IV dosing of CINRYZE is presented in Figure 2.


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Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)
C1 INH=C1 esterase inhibitor; ROC=receiver-operating characteristic
Higher Cmin values of C1 INH were associated with a higher probability of response in 
patients with HAE (p<0.001). The above exposure-response relationship was to be used to 
predict the probability of response for any Cmin values of C1 INH in subjects with HAE. For 
example, typical Cmin values of 0.207, 0.289, 0.380, and 0.556 U/mL (corresponding to first, 
second, third, and fourth quartiles of Cmin of C1 INH, respectively) would be expected to 
result in response probabilities of 54.4%, 61.5%, 68.8%, and 80.5%, respectively. Typical C1 
INH plasma functional activity levels in HAE patients range from 5–30% of normal 
(0.05-0.3 U/mL) (Cugno et al. 1990).
Receiver-operating characteristic analysis was used to identify an optimal Cmin cutoff of C1 
INH that would optimize the probability of avoiding an angioedema attack. Based on data 
from study LEVP 2006-4 with IV administration of 1000 U CINRYZE approximately twice 
weekly, the optimal Cmin cutoff was 0.479 U/mL. When considering a 2-week period of delay, 
the optimal Cmin cutoff was 0.433 U/mL. Based on the above ROC analyses, a targeted C1 
INH Cmin value of 0.45 U/mL was used to determine the expected response following SC 
dosing of 2000 U of CINRYZE. Based on the exposure-response model, a C1 INH Cmin value 
of >0.45 U/mL would achieve at least a 70% probability of success (≤1 angioedema 
attack/month).


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No statistically significant relationship was observed between minimum C4 concentrations 
and the probability of response.
The combination of the population PK model and exposure-response relationship model was 
used to simulate C1 INH Cmin following SC dosing of CINRYZE to support the dosing rationale 
and improve the likelihood of success at achieving an efficacious dose in patients with HAE 
(Figure 3).
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice-weekly Dose Regimen
C1 INH=C1 esterase inhibitor; HAE=hereditary angioedema
From these simulations, results show that a dose of 2000 U would maintain mean (blue line) 
functional C1 INH Cmin values above the targeted level of 0.45 U/mL (red horizontal line).
In studies LEVP 2005-1/B and LEVP 2006-4, in which subjects with HAE received IV doses 
of 1000 U CINRYZE approximately twice weekly, mean pre-infusion functional C1 INH 
concentrations ranged from 0.38-0.41 U/mL and 0.37-0.52 U/mL, respectively, during the 
treatment period. 
In the recent Phase 2 clinical study 0624-206, in which subjects with HAE received twice 
weekly SC doses of 1000 U CINRYZE with 24,000 U rHuPH20 or 2000 U CINRYZE with 
48,000 U rHuPH20 in two 8-week crossover periods, higher exposure with the 2000 U 
CINRYZE dose was observed (Figure 4). The mean baseline-corrected Cmax and AUC0-168 of 


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antigenic C1 INH for 2000 U SC CINRYZE + 48,000 U rHuPH20 were 1.8- and 2.3-fold 
higher, respectively, compared to those observed for 1000 U SC CINRYZE + 24,000 U 
rHuPH20. The mean baseline-corrected Cmax and AUC0-168 of functional C1 INH activity for 
2000 U SC CINRYZE + 48,000 U rHuPH20 were 2.0- and 2.6 fold higher, respectively, 
compared to their respective means for 1000 U SC CINRYZE + 24,000 U rHuPH20. The 
observed mean minimum concentration (Cmin) of functional C1 INH activity at steady-state 
for the 2000 U dose of SC CINRYZE with rHuPH20 was above the physiologically relevant 
level of 0.4 U/mL compared with 1000 U dose of SC CINRYZE with rHuPH20 (0.408 and 
0.319 U/mL, respectively). 
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206)
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid for Injection
In Study SHP616-103, new bioanalytical assays were developed and validated for the 
quantitative determination of C1 INH protein and functional binding of C1 INH in human 
plasma. These assays differed from those used in previous CINRYZE SC studies to determine 
plasma concentrations of C1 INH antigen and functional C1 INH activity. 
Following SC administration of 1000 U and 2000 U C1 esterase inhibitor [human] liquid for 
injection, injected C1 INH was slowly absorbed with median tmax ranging from 36–48 hours 
for both C1 INH antigen and functional C1 INH binding. Mean baseline-corrected Cmax and 


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AUClast PK parameters for both C1 INH antigen and functional C1 INH binding after IV and 
SC administration are shown in Figure 5 and Figure 6, respectively.
Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Subcutaneous administration of C1 esterase inhibitor [human] liquid for injection was less 
than dose proportional, with a 2-fold increase in dose resulting in 1.76- and 1.58-fold increase 
in Cmax and AUClast respectively for C1 INH antigen, and 0.99- and 1.09-fold increase in Cmax
and AUClast respectively for functional C1 INH binding. 
The baseline-corrected point estimates of the AUClast ratios and 90% confidence intervals for 
C1 INH antigen and functional C1 INH binding was used to determine the relative 
bioavailability of 1000 and 2000 U C1 esterase inhibitor [human] liquid for injection with 
1000 U IV CINRYZE. The relative bioavailabilities for the 1000 U and 2000 U SC dose of C1 
esterase inhibitor [human] liquid for injection were approximately 69% (44–110%) and 60% 
(38–95%) respectively for C1 INH antigen, and 67% (34–130%) and 39% (20–77%) 
respectively for C1 INH functional binding (in non-HAE subjects).


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1.2.2.3
Dose Selection
The approach for preventative therapy in HAE patients is to provide enough CINRYZE to 
achieve or exceed a threshold C1 INH functional activity concentration in plasma that has a 
>70% likelihood of preventing an angioedema attack. The combined data from prior SC 
CINRYZE studies (including the evaluation of bioavailability) along with the demonstration of 
similar bioavailability achieved in the completed Phase 1 single dose study of C1 esterase 
inhibitor [human] liquid for injection, support dose selection of 2000 U C1 esterase inhibitor 
[human] liquid for injection for further evaluation in a Phase 3 study. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The sponsor has developed a new, ready-to-use liquid formulation of CINRYZE (C1 esterase 
inhibitor [human]). The CINRYZE liquid product (C1 esterase inhibitor [human] liquid for 
injection) is intended for the same indication as the licensed, lyophilized powder formulation 
of CINRYZE: routine prophylaxis against angioedema attacks in adolescent and adult patients 
with HAE. The route of administration will be SC injection, and the dosing regimen will be 
2000 U every 3 or 4 days. Shire ViroPharma anticipates that patients will benefit from the 
inherent advantages of SC administration, as well as the ready-to-use liquid, lower volume 
product compared with one requiring reconstitution. In addition, the CINRYZE liquid product 
is more concentrated than the licensed CINRYZE product (500 vs 100 U/mL), which should 
enable more rapid administration of the drug and may improve tolerability, without an 
expected change or compromise in efficacy.
The sponsor has selected 2000 U of C1 esterase inhibitor [human] liquid for injection as the 
appropriate active dose for this Phase 3 study. This dose is based on the results of a recently 
completed Phase 2, randomized, double-blind, dose-ranging, crossover study that evaluated 
SC administration of CINRYZE with rHuPH20 (a dispersing agent) for the prevention of 
angioedema attacks in adolescents and adults with HAE (Study 0624-206). Results revealed 
greater clinical benefit with 2000 U of CINRYZE compared with 1000 U. In addition, the 
2000 U dose is supported by PK results from Study 0624-206, by the results of population PK 
and exposure-response modeling, and by PK data from a Phase 1 study (0624-102) that 
demonstrated the minimal influence of rHuPH20 on functional C1 INH activity when co-
administered with CINRYZE (Section 1.2.2.1). Finally, the 2000 U dose is further supported by 
the PK and bioavailability data from the Phase 1 study of C1 esterase inhibitor [human] liquid 
for injection (Protocol SHP616-103).
The study design was chosen as the best way to jointly address the protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, adequate numbers of subjects for 
precision of estimation in detecting potential safety signals). Additionally, this design 
maximizes the number of patients exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes patient exposure to placebo while having adequate patient exposure 
to placebo to assess efficacy. Thus, the proposed study is described as a “partial” crossover 
because 2 treatment sequences involve crossing over to the other experimental agent and the 


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third sequence does not. All subjects will receive active treatment during this study and will 
have an overall two-thirds probability to be randomized to active drug in any treatment 
period.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to demonstrate superior efficacy of SC administration 
of 2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo based on the normalized number of attacks (NNA) during a 
treatment period.
2.2.2
Secondary Objectives
The key secondary objective is to demonstrate the superior efficacy of SC administration of 
2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by the proportion of subjects meeting the criterion of 
at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
Other secondary objectives are:

To assess the proportion of responders during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo, where the 
proportion of responders is defined as achieving at least a 50% reduction in the NNA 
during a treatment period relative to the pretreatment assessment (ie, the subject’s 
attack rate without prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of attack-free days during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of angioedema attacks requiring acute treatment during treatment 
with 2000 U C1 esterase inhibitor [human] liquid for injection relative to treatment 
with placebo 

To assess the safety and tolerability of SC administration of 2000 U C1 esterase 
inhibitor [human] liquid for injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection 

To characterize the PK and PD of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection


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
To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the 
treatment of acute angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS) 

To evaluate subject experience with self-administration of SC 2000 U C1 esterase 
inhibitor [human] liquid for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient 
population
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial 
crossover study. The design was chosen to optimally address the joint protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, enrolling an adequate number of 
subjects to have precision of estimation to detect or rule out safety signals). Additionally, this 
design maximizes the number of subjects exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes subject exposure to placebo, while having adequate subject exposure 
to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have 
a history (based on subject recall and medical records) of ≥2 attacks per month on average per 
inclusion criterion #3. At least 66 eligible subjects will be randomized to 1 of 3 treatment 
sequences prior to the first dose of investigational product in Treatment Period 1 (ie, Dosing 
Day 1a) using interactive response technology (IRT). Randomization of subjects will be 
stratified by use of prophylactic therapy with C1 INH at the time enrollment. 


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Figure 7:
Study Design Flow Chart
Each treatment period will be 14 weeks, without a washout between the 2 periods. The 
omission of a washout period is to minimize the duration that subjects will be without active 
treatment. It is recommended that the twice weekly dosing schedule (every 3 or 4 days) be 
maintained between the last dose of investigational product in Treatment Period 1 and the first
dose of investigational product in Treatment Period 2.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be 
blinded to treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be 
administered at the investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both 
treatment periods. Other doses may be administered by qualified blinded personnel at the 
investigational site or at the subject’s home or other agreed upon location. During Treatment 
Periods 1 and 2, after having received appropriate training, subjects will be allowed to 
self-administer the investigational product with direct supervision by the study site personnel 
or a qualified home health professional. Alternatively, a parent/legal guardian/caregiver will 
be allowed to administer the investigational product to an adolescent subject, after having 
received appropriate training and under the supervision of study site personnel or a qualified 
home health professional.
Throughout the study, an electronic subject diary will be used to record specific information 
regarding the subject’s symptoms of HAE. This will include signs and symptoms of 
angioedema attacks, triggers for angioedema attacks, location (including whether mucosal or 
non-mucosal), medications used for acute treatment of angioedema attacks, elective 
procedures, and interruptions in activities of daily living due to an angioedema attack. 


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Additionally, quality of life questionnaires and surveys on SC administration of the 
investigational product will be also subject evaluated. Note: For adolescent subjects, a 
parent/legal guardian/caregiver is allowed to assist the subject in completing the electronic 
subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days 
after the last dose of investigational product. This includes events occurring during the 
screening phase of the study, regardless of whether or not the investigational product is 
administered. In addition, the investigator will report all SAEs that occur through 30 days 
after the last dose of investigational product to Shire Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of the investigational product in Treatment Period 2 for follow-up safety assessments. In 
addition, subjects will have blood samples collected for PK/PD and C1 INH antibody testing 
at 1 month (±2) days after the last dose of the investigational product.
If a subject prematurely discontinues investigational product, regardless of the reason, the 
early discontinuation visit safety procedures listed in Table 3 are to be performed as 
completely as possible. Whenever possible, all discontinued subjects should also complete the 
1-week and 1-month post-treatment visits. 
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 9 months. 
The study will be completed in approximately 15 months. 
The Study Completion Date is defined as the date the final subject, across all sites, completes
their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. The Study Completion Date is used to ascertain timing for study
results posting and reporting.
3.3
Sites and Regions
Approximately 40 sites globally (North America and Europe) are expected to participate in 
this study.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.


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4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria
below.
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 INH level less than 50% 
of normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in 
conjunction with the subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy 
with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) 
during the 3 consecutive months prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving 
prophylactic therapy with C1 INH, have a history of ≥2.0 angioedema attacks 
per month (average) during the 3 consecutive months prior to the screening 
visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of 
attenuated androgens, have a history of ≥2.0 angioedema attacks per month 
(average) during the 3 consecutive months prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any 
angioedema attacks that occur during the study that, in the opinion of the healthcare 
care provider, require medical intervention. Note: For subjects ≥12 to <18 years of 
age, standard of care therapy per local protocols should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) 
pregnancy test at the screening visit and must have a negative urine pregnancy test 
prior to the first dose of investigational product (Visit 1a), and agree to comply with 
any applicable contraceptive requirements of the protocol. 
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control 
(eg, abstinence, barrier control) from the screening visit through 2 months after the last 
dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide 
written informed consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the 
nature of the study provide written informed consent for the child to participate in the 
study before any study-specific procedures are performed (with assent from the child 
when appropriate). Alternatively, certain sites/Independent Reviewing Authorities 


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may permit adolescents who are <18 years of age to be informed of the nature of the 
study and provide written informed consent without consent from a parent(s)/legal 
guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1.
Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved 
dosing regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with 
C1 INH.
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first 
dose of the investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or 
hormone replacement therapy (ie, estrogen/progestin containing products) within 
2 months prior to the screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition 
for thromboembolism. 
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH 
antibodies. 
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), or other blood products. 
9.
Be pregnant or breastfeeding. 
10.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following 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 


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sexually active must agree to use acceptable contraception, as defined below, if they become 
sexually active during the period of the study and 30 days following the last dose of 
investigational product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and aged 
51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
Screening Visit and a negative urine pregnancy test prior to randomization (predose at 
Visit 1a). Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception 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 2 months prior to the Screening Visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to a hormonal contraceptive for 30 days.
4.3.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 2 months after the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Early Discontinuation Visit are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also complete the 1-week and 1-month Post-
treatment visits. Comments (spontaneous or elicited) or complaints made by the subject must 
be recorded in the source documents. The reason for termination, date of stopping 


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investigational product, and the total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow up

Lack of efficacy

Other (specify) 
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.4.3
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, investigational product will be discontinued, 
and the subject will follow the schedule of assessments for early discontinuation (Table 3). 
Subjects already enrolled will continue with study drug administration and procedures. 
4.4.4
Thrombotic or Thromboembolic Event
If a thrombotic/thromboembolic (T/TE) event occurs in any subject, no further enrollment 
will occur pending a complete review of all available data. Already enrolled subjects will 
continue with investigational product administration and study procedures. Following a safety 
review of the T/TE event, study enrollment may be restarted if the medical monitor 
determines that the event was unrelated or unlikely to be related to investigational product or 
other C1 inhibitors, which may have been administered for an angioedema attack. Unblinding 
of the randomization code for that subject may be required (see below).


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If a T/TE event occurs in any subject, investigational product administration for that subject 
will be interrupted; however, other study procedures will continue, as clinically appropriate. 
Diagnosis and management of all suspected T/TE events should be per local standard of care; 
Appendix 4 and Appendix 5 present a suggested medical algorithm for diagnosis and 
management of such conditions. Investigators must also comply with all reporting and/or 
concerning procedures for AEs/SAEs as indicated in the suggested algorithm. Following a 
complete medical review by the sponsor in conjunction with the investigator, and if 
determined safe to do so, dosing with investigational product may be resumed to complete a 
total of 28 doses in the treatment period that was interrupted. Study procedures, including 
PK/PD testing, will resume relative to dosing. If investigational product cannot be restarted 
within 30 days of the temporary interruption, the subject will be discontinued from treatment 
and will follow the schedule of assessments for early discontinuation (Table 3). If unblinding 
is required, a physician external to the study will review relevant safety information, including 
the subject’s assigned treatment. The unblinded physician will relay his or her findings and 
recommendations to the medical monitor, exercising caution not to reveal the subject’s 
randomization to anyone associated with the conduct of the study.
5.
PRIOR AND CONCOMITANT TREATMENT
Prior and concomitant medications that will be recorded on the appropriate CRF page include 
prescription medications, blood products (eg, albumin, packed red blood cells, whole blood, 
fresh frozen plasma, platelets), dietary supplements/vitamins, electrolyte supplementation, 
and over-the-counter medications. Topical medications (non-prescription) will be recorded 
only if used as treatment for an AE.
5.1
Prior Treatment
Any therapy received during the 12 months prior to randomization for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and 
the HAE indication (ie, acute treatment, long-term prevention, short-term [preprocedural] 
prevention).  
In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the CRF.
5.2
Concomitant Treatment and Medical/Surgical Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the 1-week post-treatment visit, inclusive. All prescription and 
over-the-counter medications being taken by subjects during this time period are regarded as 
concomitant treatments. For any medication that is administered, the investigator will 
document the drug name, amount, route of administration, frequency, and duration 
administered, as well as the reason for administering the medication on the appropriate CRF 
page.


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Elective procedures should be postponed, where possible. Medical/surgical procedures 
performed during the study will be recorded on the CRF, along with the date, time, and reason 
for the procedure. Pre-procedure prophylaxis may be provided (and documented as outlined 
above) if medically indicated and according to local standard of care.
5.2.1
Management of Angioedema Attacks 
If a subject (≥18 years of age) experiences an acute angioedema attack at any time during the 
study that in the opinion of the investigator requires medical intervention, icatibant should be 
administered to treat the attack. Icatibant is supplied in a single-dose pre-filled glass syringe 
delivering 3 mL of solution containing 30 mg icatibant. Icatibant is to be administered by the 
SC route in the abdominal area. The entire volume in the syringe should be administered and 
the injection should occur over at least 30 seconds. If response is inadequate or symptoms 
recur, additional injections of 30 mg may be administered at intervals of at least 6 hours. Do 
not administer more than 3 injections in 24 hours. The subject will be allowed to self-
administer icatibant if already trained by a health care provider or after receiving instructions 
on the use and appropriate training by study site personnel or a qualified home health 
professional. If it is the opinion of the investigator that the subject still needs medication for 
his/her acute angioedema attack after icatibant administration, then other standard of care 
therapy (eg, C1 INH, ecallantide) may be provided per locally approved product information. 
For subjects ≥12 to <18 years of age standard of care therapy per local protocols should be 
provided, such as (where approved for adolescents) C1 esterase inhibitor (human), C1 
esterase inhibitor (recombinant), and ecallantide. The determination of the necessity for 
therapy to alleviate subject symptoms will be at the discretion of the investigator. 
Administration of investigational product and study procedures will continue without 
alteration to the protocol schedule, even if a subject receives any treatment for an angioedema
attack.
For all medications (including fluids, anti-emetics, analgesics) associated with management of 
acute angioedema attacks, study personnel will record start/stop dates, time of administration, 
dose, unit, frequency, and route of administration in the subject’s CRF page. Adverse events 
associated with medications used in the treatment of acute angioedema attacks will be 
captured on the AE CRF and attributed to the concomitant medication administered. 
Adult subjects receiving long-term prophylaxis with C1 INH prior to randomization may be 
randomized to treatment sequences that contain a placebo treatment period (ie, A/B or B/A); 
such subjects remain eligible for on-demand therapy as outlined above.  If, after receipt of at 
least 3 weeks of investigational product, the subject’s quality of life significantly deteriorates
and interferes with daily living routines, and the subject experiences a 2-fold increase in 
attack frequency with greater severity (relative to the subject’s baseline without  prophylaxis), 
following discussion of the investigator with the sponsor, subject may be discontinued from 
the treatment.  
The investigator
will be responsible for entering information about the subjects 
discontinuation from study drug in the CRF and where applicable, perform study related 


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procedures as outlined in Table 3.  The investigator will also ensure the subject receives 
appropriate treatment based on the subjects past HAE treatment and according to local 
standard of care.  Angioedema attacks will not be considered AEs; however, events satisfying 
the serious criteria should be recorded as a SAE and reported to Shire Pharmacovigilance 
(Section 8.1.4). Data on angioedema attacks will be collected separately from general reports 
of AEs and will be used in the evaluation of efficacy (Section 7.2.2). In addition, if applicable, 
subjects will record their response to icatibant therapy when used for treating an angioedema 
attack, as well as any associated side effects or tolerability issues. This information will be 
recorded in the electronic subject diary (Section 7.2.2.4).
5.2.2
Prohibited Treatment
Use of C1 INH therapy (other than investigational product) for prophylaxis against 
angioedema attacks is prohibited during this study (from the first dose of investigational 
product through the 1-month post-treatment visit). 
The initiation of androgen therapy is prohibited during the study (from the first dose of 
investigational product through the 1-month post-treatment visit). 
5.2.3
Nonpharmacologic Treatments and Procedures
To the extent possible, subjects will postpone elective procedures (eg, dental work) while 
participating in the study. In the event a procedure cannot be postponed, the subject will 
record this information in the subject diary and notify the site. Pre-procedure prophylaxis may 
be provided if medically indicated and according to local standard of care. 
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
during the treatment periods, as well as any medications associated with the procedure, will 
be recorded in the eCRF (see Section 5.2).


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is C1 esterase inhibitor [human] liquid for injection, which is supplied in 
clear glass vials containing 1000 U of C1 INH in 2 mL of sterile liquid. The solution also 
contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection.
The reference product is placebo, which is supplied in an identical 2 mL presentation as the 
active investigational product minus the C1 INH protein. The inactive ingredients in the 
solution are the same as the active drug product: sodium phosphate, sorbitol, glycine, and 
water for injection.
No reconstitution or dilution is required for the test or reference product. Vials must be stored 
at 2–8oC (36–46oF) and protected from light.
Instructions for handling of investigational product and for SC injection site selection and 
preparation are provided in Appendix 1 and Appendix 2, respectively.
6.2
Administration of Investigational Product
Blinded investigational product (C1 esterase inhibitor [human] liquid for injection or placebo) 
will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate 
treatment periods. The contents of 2 vials of investigational products (a total volume of 4 mL) 
will be drawn into a silicone-free syringe for each SC injection. Following appropriate SC 
injection site selection and preparation (Appendix 2), the needle will be inserted in the 
subject’s abdominal area in order to administer the SC injection as quickly as tolerated by the 
subject. 
Investigational product will be administered at the investigational site for Dosing Visits 1, 8, 
16, 24, and 28 during both treatment periods. Other doses may be administered by qualified 
blinded personnel at the investigational site or at the subject’s home or other agreed upon 
location. During Treatment Periods 1 and 2, after having received appropriate training, 
subjects will be allowed to self-administer the investigational product with direct supervision 
by study site personnel or a qualified home health professional. Alternatively, a parent/legal 
guardian/caregiver will be allowed to administer the investigational product to an adolescent 
subject, after having received appropriate training and under the supervision of study site 
personnel or a qualified healthcare professional.
6.3
Allocation of Subjects to Treatment Sequence
This is a double-blind, placebo-controlled, two-period, 3-sequence, partial crossover study. At 
least 66 eligible subjects will be randomized to 1 of 3 treatment sequences (Table 7) prior to 
the first dose of investigational product in Treatment Period 1. The actual treatment sequence 
given to individual subjects is determined by a randomization schedule automatically assigned 
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Table 7:
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects 
Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC 
twice weekly (every 3 or 4 days) for 14 weeks. 
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each level of use of prophylactic therapy with C1 INH across sites, the subject number is 
assigned to subjects according to the sequence of presentation for study participation. Subject 
number is unique within a protocol.
The randomization number represents a unique number corresponding to treatment sequence 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IRT at the baseline visit (predose Visit 1a) after subject eligibility has been 
confirmed using the randomization criteria. The randomization schedule will be stratified for 
use of prophylactic therapy with C1 INH at the time of enrollment versus no prophylactic 
therapy with C1 INH at the time of enrollment. Subjects will be randomized to the treatment 
sequence 1 (A/B), 2 (B/A), or 3 (A/A) in the randomization ratio of 2:2:1.
The subject’s treatment sequence will be held in strict confidence. The treatment sequence for 
an individual subject may be broken in cases of emergency or for reasons of subject safety, as 
described in Section 6.4.1.
6.4
Blinding of Treatment
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence. 
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo will have 
an identical presentation, including its packaging and labeling, such that the contents of the 
glass vials within the prepackaged study kits will be indistinguishable from each other. As 
described in Section 6.6, investigational product will be identified only by a unique study 
drug kit number. Each prepackaged study kit will contain 2x2 mL vials of investigational 
product (a total volume of 4 mL), which will be required to be drawn into a silicone-free 
syringe for each SC injection. If possible, a different individual should draw up the 
investigational product into the syringe than the individual administering the SC injection to 
the study subject. 


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Knowledge of the PK/PD data would compromise the study blind. As such, the independent 
external laboratory performing the PK/PD analyses will keep the results in strict confidence 
until the study is unblinded.
Additionally, a limited number of representatives of the sponsor responsible for the IRT and 
product labeling will be unblinded to treatment assignment in order to review drug 
accountability on an ongoing basis throughout the study (Section 6.7).
6.4.1
Unblinding the Treatment Assignment
The randomization code for an individual subject may only be broken by the investigator or 
the sponsor for reasons of subject safety or in an emergency when knowledge of the product 
administered would be important for the treatment of the subject. If the blind is broken by the 
investigator, he/she must notify the Shire ViroPharma Medical Monitor immediately and must 
document the date, time, and reason for the code break in a note to file.
6.5
Treatment Compliance
Investigational product will be administered either by study site personnel or a qualified home 
health professional or will occur under their direct supervision for subjects (or parent/legal 
guardian/caregiver) who elect to self-administer during Treatment Periods 1 and 2 
(Section 6.2). Therefore, full subject compliance with treatment is expected in this study. 
6.6
Packaging and Labeling
C1 esterase inhibitor [human] liquid for injection and placebo will be packaged and labeled 
such that the products will be indistinguishable from each other by the investigator, study site 
personnel, home health professionals, and subjects.
Investigational product will be supplied in a prepackaged study kit. Each study kit will 
contain 2 vials of investigational product (C1 esterase inhibitor [human] liquid for injection or 
placebo). Both the vials and carton (kit) will be appropriately labeled according to local 
regulations and bear the unique study drug kit number.  
The investigative site will also be provided with ancillary supplies including silicone-free 
syringes and needles. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection.
Refer to the Pharmacy Manual for additional details on the investigational product and its 
administration.
6.7
Storage and Accountability
Investigational product will shipped refrigerated to the study site at 2–8oC. Vials of 
investigational product must be stored at 2–8oC (36–46oF) and protected from light. Do not 
freeze investigational product.


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The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log. The date and time of administration of the investigational product must be documented 
on the appropriate CRF.
The principal investigator, study site personnel, or qualified home health professional must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.
6.8
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an investigational product 
returns process/policy, the sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the site regulatory binder.
If the investigational product is to be destroyed by the sites, sites must follow their own 
process/policy that describes such activities. Sites must retain copies of these documents 
within the site regulatory binder. Sites must ensure that the clinical trial material 
accountability and destruction log is complete, accurate, and ready for review and/or audit at 
each monitoring visit.
All manifests documenting shipments of investigational product must be retained, as well as 
copies of any investigational product return forms.
Refer to the Pharmacy Manual for additional details.
7.
STUDY PROCEDURES
Subjects may be enrolled in the study after the nature and purpose of the protocol has been 
explained, written informed consent to participate has been voluntarily granted, and the 
eligibility criteria listed in Sections 4.1 and 4.2 have been met.
7.1
Study Schedule
Table 1 (Treatment Period 1), Table 2 (Treatment Period 2), Table 3 (early discontinuation 
visit, 1-week and 1-month post-treatment follow-up visits), and Table 4 (blood sample 
collection for PK/PD Analyses) provide the timing of all study procedures and assessments. 


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7.1.1
Screening Period
Informed consent must be obtained before any study-specific procedures are performed. Note 
that AEs will be collected from the time of informed consent through 7 days after the last dose 
of investigational product.
Subjects will have all screening procedures completed with 21 days prior to the first dose of 
investigational product (Visit 1a=Dosing Day 1) according to Table 1. The following 
procedures will occur:
•
Informed consent/assent
•
Adverse events (collection begins from the time of informed consent through 7 days after 
the last dose of investigational product)
•
Inclusion/exclusion criteria
•
Medical history (includes HAE history with the documentation of attack rate for study 
entry criteria)
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Virology screening 
•
Vital signs
•
ECG
•
Height and weight
•
Serum pregnancy test (in females of childbearing potential)
•
Recording of prior and concomitant medications
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 
7.1.2
Treatment Period 1
7.1.2.1
Visit 1a (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Randomization


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•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications (needed for confirmation of subject eligibility)
•
PK (C1 INH antigen, C1 INH functional, [includes measurement of C1q]) and PD (C4) 
sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody)
•
Angioedema quality of life (AE-QoL) questionnaire, EuroQol 5-dimensional 5-level 
descriptive system (EQ-5D-5L), Work Productivity and Activity Impairment-General 
Health (WPAI-GH) questionnaire, and Sheehan Disability Scare (SDS) assessments 
recorded in the electronic subject diary
•
Health resource utilization assessment (HRUA)-HAE
7.1.2.2
Visit 1a (postdose)
The following procedures will be performed after the administration of the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack (and the subject diary is to be updated daily; Section 7.2.2.2).
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.2.3
Visit 2a through Visit 28a
The following procedures will be performed throughout Treatment Period 1 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2a-28a)
•
Recording in the electronic subject diary daily any symptoms or occurrences of an 
angioedema attack (Visits 2a-28a)


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•
Recording the daily AAS in the electronic subject diary (Visits 2a-28a)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2a, 3a, 4a, 8a, 16a, 24a, 28a)
•
Physical examination (Visits 8a, 16a, 24a, 28a)
•
Investigational product will be administered at each visit (2a-28a); Visits 8a, 16a, 24a, and 
28a must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2a-28a). At Visits 8a, 16a, 24a, and 
28a an overall assessment of injection site severity and duration will be performed.
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8a, 16a, 24a, 
and 28a
•
Urinalysis testing with microscopy at Visit 28a
•
Acceptability and self-administration survey assessment (recorded in the electronic 
subject diary) at Visit 28a
•
Quality of life assessments recorded in the electronic subject diary: AE-QoL (Visits 9a, 
17a, 25a), EQ-5D-5L (Visit 24a and on each day that a subject experiences signs or 
symptoms of an angioedema attack), and WPAI-GH and SDS (Visits 3a, 5a, 7a, 9a, 11a, 
13a, 15a, 17a, 19a, 21a, 23a, 25a, 27a)
•
HRUA-HAE (Visits 8a, 16a, 24a)
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8a, 16a, 24a, 27a or 28a)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2a, 8a, 
16a, 24a, 27a or 28a [within ≈15 min], and 48 h postdose Visits 27a or 28a [±3 hours])
7.1.3
Treatment Period 2
7.1.3.1
Visit 1b (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product in Treatment Period 2 at Visit 1b:
•
Collection of AEs
•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)


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•
Recording of concomitant medications 
•
PK (C1 INH antigen, C1 INH functional) and PD (C4) sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody) blood sample collection
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS assessments recorded in the electronic subject 
diary
•
HRUA-HAE
7.1.3.2
Visit 1b (postdose)
The following procedures will be performed after the administration of investigational 
product at Visit 1b:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.3.3
Visit 2b through Visit 28b
The following procedures will be performed throughout Treatment Period 2 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2b-28b)
•
Recording in the subject diary daily any symptoms or occurrences of an angioedema 
attack (Visits 2b-28b)
•
Recording the daily AAS in the subject diary (Visits 2b-28b)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2b, 3b, 4b, 8b, 16b, 24b, 28b)
•
Physical examination (Visits 8b, 16b, 24b, 28b)
•
Investigational product will be administered at each visit (2b-28b); Visits 8b, 16b, 24b, 
and 28b must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2b-28b). At Visits 8b, 16b, 24b, and 
28a an overall assessment of injection site severity and duration will be performed.


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•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8b, 16b, 24b, 
and 28b
•
Urinalysis testing with microscopy at Visit 28b
•
Quality of life assessments: AE-QoL (Visits 9b, 17b, 25b), EQ-5D-5L (Visit 24b and on 
each day that a subject experiences signs or symptoms of an angioedema attack), and 
WPAI-GH and SDS (Visits 3b, 5b, 7b, 9b, 11b, 13b, 15b, 17b, 19b, 21b, 23b, 25b, 27b) 
recorded in the electronic subject diary
•
HRUA-HAE (Visits 8b, 16b, 24b)
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments at Visit 28b
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8b, 16b, 24b, 28b)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2b, 8b, 
16b, 24b, and 28b [within ≈15 min], and 24 hours (±3 hours) (optional time point), 
48 hours (±3 hours), 72 h (±6 hours) (optional time point), and 96 hours (±6 hours) 
postdose Visit 28b) 
7.1.4
Early Discontinuation Visit
If a subject prematurely discontinues from investigational product, the following procedures 
are to be performed as completely as possible:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments


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•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
7.1.5
Follow-up Period
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of investigational product for follow-up safety assessments (Table 3). The following 
procedures will occur:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
A second post-treatment visit will occur at the investigative site 1 month (±2 days) after the 
last dose of investigational product. The following procedures will be performed at this visit:
•
HRUA-HAE
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to the Shire Pharmacovigilance Department.


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7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic details, medical history (including HAE history), prior and concomitant 
medication data, vital signs, height, weight, physical examination, 12-lead ECG, 
biochemistry, hematology, coagulation, virology screening, and serum β-hCG pregnancy test 
will be collected at the time of enrollment at the Screening Visit. 
7.2.2
Efficacy
Analyses of the efficacy endpoints in this study require documentation of specific information 
regarding the subject’s symptoms of any angioedema attacks they may experience during the 
study. 
7.2.2.1
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported indication of swelling or pain at 
any location following a report of no swelling or pain on the previous day (ie, there must be a 
full symptom-free calendar day preceding the onset of symptoms for an attack to be 
considered a new attack). Therefore, 

Attacks that progress from 1 site to another will be considered a single attack 

Attacks that begin to regress and then worsen before complete resolution will be 
considered 1 attack 

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar 
day reported after the appearance of resolution will also be considered 1 attack 
Note: An angioedema attack does not include swelling due to trauma, arthritis, or symmetrical 
nonpainful swelling of the lower extremities.
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary
During the study, subjects will use an electronic subject diary each day to record any 
symptoms or occurrences of an angioedema attack. The investigator will complete a separate 
angioedema attack CRF for each attack based upon their review of the data in the subject 
diary. Information will include the following:

Date and time of onset of angioedema attack symptoms

Characterization of whether swelling or pain is (indicate all that apply):

Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)

Non-mucosal (truncal, extremity, facial)


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
Location (site) of the swelling or pain (indicate all that apply):

Upper airway (includes laryngeal or pharyngeal)
Note: Pharyngeal or oral swelling that results in airway compromise will be 
classified as a laryngeal attack.
Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)

Genitourinary (including scrotum or vulva)

Cutaneous (facial)
Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, 
trunk])

Severity (intensity) of the sign/symptom at each location listed:

Absent
Mild: the angioedema attack sign/symptom(s) is noticeable but is easily 
tolerated by the subject and does not interfere with routine activities.
Moderate: the angioedema attack sign/symptom(s) interferes with the subject’s 
ability to attend work/school or participate in family life and social/recreational 
activities.
Severe: the angioedema attack sign/symptom(s) significantly limits the 
subject’s ability to attend work/school or participate in family life and 
social/recreational activities.

Visual Analogue Scale (VAS) pain measurement score

Angioedema attack trigger(s)

Answer to the question, “Was treatment administered for the attack?” If yes, record the 
date, time, and name of treatment administered.
7.2.2.3
Angioedema Activity Score
Subject self-assessment of disease activity will be assessed daily by the AAS. Subjects will 
respond to questions in the electronic subject diary about any swelling episode that has 
occurred within the previous 24 hours. Each AAS item (or question) is scored between 0 and 
3 points, with the minimum and maximum daily AAS ranging between 0 and 15 points 
(Weller et al. 2013).
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks
Efficacy endpoints are based on subject-assessed symptom improvement as a measure of 
response to icatibant therapy. When a subject receives treatment with icatibant for an acute 
angioedema attack, they will record the date and time of administration of the SC injection in 
the electronic subject diary and will monitor the following events:


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Initial Symptom Improvement

Report date and time when you feel that your symptoms start to improve.
Complete Symptom Resolution

Report date and time when you feel that your symptoms have completely resolved.
Tolerability

Report any side effects associated with administration of icatibant therapy.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical and Medication History
A medical history will be taken at the screening visit. All medical history findings that have 
been present/active within the 5 years prior to enrollment will be entered into the CRF 
regardless of clinical relevance or presence at study start. Medical history findings that have 
not been present within the 5 years prior to enrollment will be recorded if deemed clinically 
relevant by the investigator to the conduct of the study. The medical history should include 
any history of allergic reactions to drugs. 
HAE History
The following information associated with HAE history will be recorded in the CRF at the 
screening visit (Note: the attack rate may be estimated based on subject or parent/caregiver 
recall as well as the subject’s medical records):  

HAE type (I or II)

Estimated date of last angioedema (swelling) attack prior to the screening visit

Any therapy received during the last 12 months for management of HAE (Section 5.1)

Total number, typical locations and average overall duration (days), and average overall 
severity of angioedema attacks experienced:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.

Typical score, estimated on a scale from 0-100, for the subject’s angioedema attack 
pain:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)


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
during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.
7.2.3.2
Physical Examination (Including Height and Weight)
The investigator or designee will perform physical examinations at the time points specified 
in Table 1, Table 2, and Table 3. General physical examinations will be performed in 
accordance with standard practices at the study site. Physical examination abnormalities 
observed prior to the screening visit will be entered into the medical history section of the 
CRF. Any new or worsening of pre-existing abnormalities noted at post-screening 
examinations should be captured as an AE on the AE CRF page, per investigator’s judgment. 
Body weight and height will be measured at the time points specified in Table 1 and Table 2. 
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed (Section 8.1).
7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse and will be measured at the time points specified 
in Table 1, Table 2, and Table 3. During the study, additional vital signs measurements will 
be performed if clinically indicated. Vital signs performed on a dosing day should be obtained 
immediately (≤30 minutes) before the start of the injection of investigational product, 
immediately after completion of the injection of investigational product (≤10 minutes), and 
then between 30 minutes and 1 hour after completion of the injection of investigational 
product. Every effort should be made to measure vital signs prior to any blood sample 
collection. Blood pressure should be determined by cuff (using the same method, the same 
arm, and in the same position throughout the study). Any clinically significant deviations 
from Baseline (predose Visit 1a) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. Reference ranges are to be supplied by the laboratory and will be used to assess 
the clinical laboratory data for clinical significance and out-of-range pathological changes. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.


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The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 6 mL) for biochemistry will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Aspartate aminotransferase (AST)
Albumin
Alanine aminotransferase (ALT)
Total protein
Alkaline phosphatase (ALP)
Glucose
Creatine phosphokinase (CPK)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Chloride
Carbon dioxide
Phosphorus
Hematology
Blood samples (approximately 2 mL) for hematology will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Hemoglobin
Red blood cell count
Hematocrit
Platelet count
White blood cell count – total and differential
Coagulation
Blood samples (approximately 3 mL) for coagulation will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
International normalized ratio (INR)
Prothrombin time (PT)
D-dimer a
Activated partial thromboplastin time (aPTT)
a In addition, D-dimer should be evaluated in any subject who presents with signs and symptoms consistent with 
suspected venous thromboembolism.


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Virology
Blood samples (approximately 6 mL) will be taken according to Table 1. The following 
parameters will be assessed:
Human immunodeficiency virus (HIV; single 
assay/INNO-LIA)
Hepatitis (hepatitis B surface antigen and 
hepatitis C antibody)
Urinalysis with microscopy
Urine samples (approximately 10 mL) will be taken according to Table 1, Table 2, and Table 
3. The following parameters will be assessed:
pH
Specific gravity
Dipstick (protein, glucose, ketones, 
hemoglobin)
Microscopic evaluation (red blood cells, 
white blood cells, crystals, casts, bacteria)
7.2.3.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all females of childbearing potential at the 
screening visit and a urine pregnancy test is performed thereafter according to the time points 
specified in Table 1, Table 2, and Table 3. Pregnancy test results must be confirmed as 
negative before subjects proceed in the study. 
7.2.3.7
Electrocardiogram 
Subjects will have a 12-lead ECG recorded at the screening visit, as specified in Table 1. 
During the study, additional ECGs will be performed if clinically indicated. The following 
ECG data will be entered into the CRF: heart rate, PR interval, QRS duration, and QT 
interval. The PQ interval may be used if the PR interval is not reported on the 12-lead ECG. 
The investigator will be responsible for providing the interpretation of all ECGs (clinically 
significant/not clinically significant). The subject’s ECG(s) should be consistently recorded in 
the same position (supine).
7.2.3.8
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
from the first dose of investigational product through the 1-week post-treatment visit will be 
recorded in the CRF (Section 5.2).


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7.2.3.9
Thrombotic or Thromboembolic Events
Monitoring for Venous Thromboembolism or Arterial Thromboembolism
Study personnel will actively monitor subjects for possible venous thromboembolism (VTE), 
encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), and 
arterial thromboembolism (ATE) with medical history, physical examinations, review of AEs, 
routine coagulation laboratory testing, and/or other diagnostic tests as applicable per local 
standard of care at the time points specified in Table 1, Table 2, and Table 3. 
Subjects will also receive instruction on how to recognize symptoms associated with potential 
thrombotic events and to seek medical attention for these symptoms in addition to informing 
their investigator. Treatment procedures, when applicable, will be provided per local standard 
of care.
Suspected Venous Thromboembolism or Arterial Thromboembolism
In subjects who present with signs and symptoms that are suspicious of a possible VTE (DVT 
or PE) based on clinical history and physical examination, the Wells Prediction Rules 
(Appendix 3) in conjunction with D-dimer assessment and/or other diagnostic tests, as 
applicable per local standard of care, are suggested to help guide the physician. Diagnostic 
and/or treatment procedures, when applicable, will be provided per local standard of care.
Based on the Wells Prediction Rule scores, the following procedures are recommended:

If the Wells Prediction DVT risk score is ≥1, coagulation studies and an imaging 
study (eg, lower extremity ultrasound or contrast venography) may be performed 
as described below. 

If the Wells Prediction PE risk score is ≥2, coagulation studies and 1 or more 
imaging studies (eg, ventilation-perfusion scan, multidetector helical computed 
axial tomography, or pulmonary angiography) may be performed as described 
below. 
In the setting of suspected VTE events, site personnel will the complete the Wells Prediction 
Rule CRF.
Diagnosis and management of all suspected VTE and ATE events should be per local 
standard of care; Appendix 4 and Appendix 5 also presents a suggested medical algorithm for 
diagnosis and management of such conditions. Investigators must also comply with all 
reporting and/or concerning procedures for AEs/SAEs as indicated in the suggested 
algorithm. Confirmed diagnoses of T/TE events will be reported as SAEs (Section 8.2). 
However, superficial thrombophlebitis and catheter-related thrombosis will be reported as 
either a nonserious AE or an SAE based on investigator assessment and standard AE/SAE 
definitions.


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7.2.3.10 Injection Site Reactions
Investigational product SC injection site reactions will be captured in the local tolerability 
CRF. Injection site reactions that do not meet the criteria of a SAE will not need to be 
reported as an AE.
Subcutaneous injection site reactions will be assessed at the following post-injection time 
points in each treatment period: 15 minutes, 30 minutes, and 1 hour post-injection. Study 
personnel will examine injection sites for erythema or swelling and will question the subject 
to collect information on cutaneous pain, burning sensation, itching/pruritus, and warm 
sensation. The diameter of any erythema or swelling should be measured to obtain the 
severity grading. The injection site reactions will be graded as absent, mild, moderate, or 
severe using the scoring criteria shown in Table 8. Both the severity score and the 
measurement of any erythema or swelling is to be captured in  the CRF. In addition, an 
overall  assessment of injection site reaction severity (mild, moderate, or severe as defined per 
Section 8.1.1) and the overall duration assessment of the injection site reactions will be 
carried out every 2-4 weeks by the study personnel as noted within schedule of assessments in 
Table 1 and Table 2, and will be captured in the CRF.
Table 8:
Severity Scoring for Injection Site Reactions
Reaction
Severity
Mild
Moderate
Severe
Erythema
>0 to 5 cm
>5 to 10 cm
>10 cm
Swelling
>0 to 5 cm
>5 to 10 cm
>10 cm
Cutaneous pain
Mild discomfort to touch
Discomfort with movement
Significant discomfort at rest
Burning sensation
Mild burning sensation, 
which is easily tolerated
Moderate burning sensation, 
causing some discomfort
Severe burning sensation, 
causing significant discomfort
Itching/pruritus
Mild itching/pruritus, 
which is easily tolerated
Moderate itching/pruritus, 
causing some discomfort
Severe itching/pruritus, causing 
significant discomfort
Warm sensation
Mild warmth to touch
Moderate warmth to touch
Significant warmth to touch
The injection site reaction data will be recorded on the local tolerability page of the CRF. Site 
personnel will distinguish between injection site reactions related to the procedure (eg, will 
check for redness after needle is inserted and prior to investigational product administration) 
vs the actual investigational product.
7.2.4
Others
7.2.4.1
Clinical Pharmacology Assessments
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Subjects will have blood samples (7 mL) collected for the determination of plasma 
concentrations of C1 INH antigen, functional C1 INH, complement C4, and C1q at time 
points specified in Table 4. Serum samples (5 mL) will be collected prior to the first dose of 


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investigational product on Visit 1a (Dose 1 of Treatment Period 1), Visit 1b (Dose 1 of 
Treatment Period 2), and throughout both treatment periods for the analysis of anti-C1 INH 
antibodies (Table 1 and Table 2). Additional blood samples for PK/PD and C1 INH antibody 
testing will be collected at the early discontinuation visit (if applicable) and the 1-week and 
1-month post treatment visits (Table 3). 
The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH activity, complement C4 and C1q 
concentrations, and serum samples for the evaluation of anti-C1 INH antibodies will be 
analyzed using validated methods. All PK/PD and immunogenicity samples will be processed 
according to the procedure outlined in the laboratory manual.
Selected samples may be analyzed to investigate incurred sample reproducibility of the 
bioanalytical methods. These analyses are only to investigate the reproducibility of the 
bioanalytical methods used to determine C1 INH antigen and functional C1 INH 
concentrations in study samples. All incurred sample reproducibility results will be reported 
in a separate table in the bioanalytical report. Details of disposal will be documented and 
maintained with the study file at the analytical laboratory.
7.2.4.2
Health-related Quality of Life Assessments
Angioedema Quality of Life Questionnaire
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema (Weller et al. 2012). It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and food. Subjects will be asked how often 
they were restricted by—as well as the difficulties and problems that could be associated 
with—recurrent swellings (angioedema) during the previous 4 weeks. The AE-QoL will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3. Details about the use of the AE-QoL instrument are provided in a separate study 
manual. 
Health-related Quality of Life Questionnaire
The EQ-5D-5L1 is a descriptive system of health-related quality of life states consisting of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
of which can take 1 of 5 responses. The responses record 5 levels of severity within a 
particular dimension. The EQ-5D-5L will be completed in the electronic subject diary at the 
time points specified in Table 1, Table 2, and Table 3, as well as on each day that a subject 
experiences signs or symptoms of an angioedema attack. Details about the use and 
administration of the EQ-5D-5L instrument are provided in a separate study manual. 
Work Productivity and Activity Impairment-General Health Questionnaire
The WPAI-GH questionnaire includes 6 questions about work and activity impairment due to 
health problems during the past 7 days (Reilly et al. 1993). Outcomes are expressed as 
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.


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impairment percentages, with higher numbers indicating greater impairment and less work or 
productivity. The WPAI-GH will be completed in the electronic subject diary at the time 
points specified in Table 1, Table 2, and Table 3. Details about the use of the WPAI-GH 
instrument are provided in a separate study manual.
Sheehan Disability Scale
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a 
subject’s disability due to an illness or health problem interferes with work/school, social 
life/leisure activities, and family life/home responsibilities (Sheehan 1983). The SDS will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3.
7.2.4.3
Health Resource Utilization Assessment
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. The Health Resource Utilization 
Assessment (HRUA-HAE) will be completed at the time points specified in Table 1, Table 2, 
and Table 3. Study personnel will enter the survey responses into the appropriate CRF.
7.2.4.4
Survey of Acceptability of SC Administration
Study personnel will ask subjects to rate their overall experience in receiving twice weekly 
SC injections of investigational product at the time points specified in Table 1, Table 2, and 
Table 3. For subjects who have previously received C1 INH products via IV administration, 
they will be asked to indicate the preferred route for medication administration. Study 
personnel will enter the subject’s survey responses into the electronic subject diary.
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) 
on the route to administer medications to prevent angioedema attacks. 
7.2.4.5
Self-administration Survey Assessment
After receiving appropriate training, subjects are allowed to self-administer investigational 
product during Treatment Periods 1 and 2 under the supervision of study site personnel or a 
qualified home health professional. Alternatively, a parent/legal guardian/caregiver will be 
allowed to administer the investigational product to an adolescent subject, after having 
received appropriate training, and under the supervision of study site personnel or a qualified 
healthcare professional. For those subjects who choose to self-administer or have a 
parent/legal guardian/caregiver administer the investigational product, study personnel will 
ask specific questions about their experience with self-administration of SC medication (Table 
2 and Table 3). Study personnel will enter the subject’s survey responses into the electronic 
subject diary.


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7.2.5
Volume of Blood to Be Drawn From Each Subject
Table 9:
Approximate Volume of Blood to Be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
PK/PD 
7
20b
140
Immunogenicity (anti-C1 INH antibodies)
5
13
65
Safety
Biochemistry and -HCGa
6
13
78
Hematology
2
13
26
Coagulation
3
13
39
Virology
6
1
6
All assessments (mL)
354
Β-hCG=beta human chorionic gonadotrophin; C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a -hCG testing for females of childbearing potential at the Visit 1a (predose) only.
a Two of the 20 samples are optional as indicated in Table 4.
During this study, it is expected that maximum volume of blood to be drawn from all subjects 
will be 354 mL.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of 
blood drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 354 mL. When more than 1 blood assessment is done at 
the same time point/period, if they require the same type of tube, the assessments may be 
combined. 


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until 7 days after the last 
dose of investigational product. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE 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:
A type of AE that is usually alleviated with 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 subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product 
for each AE. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related.” The causality 
assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (angioedema attacks) should not be captured as AEs as 
long as they are within the normal day-to-day fluctuation or expected progression of the 
disease and are part of the efficacy data to be collected in the study; however, events 


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satisfying the serious criteria should be recorded as a SAE and reported to Shire 
Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range (either 
while continuing treatment or after the end of treatment with the investigational product), and 
the range of variation of the respective parameter within its reference range must be taken into 
consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department 
using the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Shire ViroPharma 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 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire 
Clinical Trial Serious Adverse Event Form. Note: An elective abortion is not considered an 
SAE.


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In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event 
Form as well as the Shire Investigational and Marketed Products Pregnancy Report Form. The 
test date of the first positive serum/urine -hCG test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: This includes a situation where the investigational product is not used 
as directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
higher than the protocol-specified dose.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Medication errors should be collected and reported to the sponsor for all products under 
investigation. The following should be considered as examples of reportable medication 
errors:

The administration and/or use of the unassigned treatment

The administration and/or use of an expired investigational product

Violation of storage or refrigeration requirements for the investigational product
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
All investigational products administered to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, 
or medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 
Trial Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to 
the contract research organization/Shire ViroPharma Medical Monitor using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as an SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 


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definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be 
reported to the Shire Pharmacovigilance Department and  Medical Monitor within 24 hours of 
the first awareness of the event until 30 days after the last dose of investigational product. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).


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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical contract research organization (CRO) are responsible for 
notifying the relevant regulatory authorities/US central Institutional Review Boards 
(IRBs)/EU central ethics committees (ECs) of related, unexpected SAEs.
In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to 
unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available. If applicable, unblinded data may be 


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made available to quality assurance representatives for the purposes of conducting 
independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
All statistical analyses will be performed using SASVersion 9.1 or higher (SAS Institute, 
,
). 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be 
addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee in this 
study.
9.6
Sample Size Calculation and Power Considerations
The enrollment goal for this study is to randomize at least 66 subjects to ensure 54 subjects 
complete both treatment periods (44 for the crossover sequences, 10 for the active/active 
sequence). This number will be sufficient to address all experimental efficacy and safety 
objectives.
For the primary efficacy endpoint, the NNA, a sample of 44 subjects will provide >90% 
power at an alpha level of 0.025 (1-sided) to detect a difference of 1.0 attacks per month 
between active treatment and placebo assuming a between-subject standard deviation of 2.5. 
This target is supported by the recently completed, dose-ranging, Phase 2 study with CINRYZE
(0624-206).
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR
relative to placebo, 44 subjects will provide >90% power to test the hypothesis H0: proportion 
≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided).
Previous communications have occurred between regulatory authorities and the sponsor 
regarding a Phase 3 study for the SC CINRYZE development program. The regulatory authority 
indicated that the Phase 3 study should be of sufficient size to have a 95% probability for 
detection of safety signals occurring with an incidence of 5% or greater of subjects.
PPD PPD


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With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.
The sample size calculation was conducted using nQuery + nTerim 2.0.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have signed an informed consent and some 
study procedures have begun.
The Randomized Set will consist of all subjects in the Screened Set for whom a 
randomization number has been assigned.
The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The Full Analysis Set will consist of all subjects in the Safety Set who have at least 
1 post-baseline (eg, randomization) primary efficacy assessment.
The Per-protocol Set will consist of all subjects in the Full Analysis Set who complete 
scheduled primary assessments for 6 study weeks and who do not have pre-defined protocol 
deviations that may affect the primary efficacy endpoint. 
The Completer Set will consist of all subjects in the Full Analysis Set who have completed 
the final scheduled primary assessment for the study.
The Pharmacokinetic and Pharmacodynamic Set will consist of all subjects in the Safety 
Set for whom the primary PK and PD data are considered sufficient and interpretable. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the NNA during a treatment period. The NNA is 
expressed as the number of attacks per month (ie, 30.4 days) of exposure:
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period)
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.
The primary efficacy analysis will be conducted for the subjects in the Full Analysis Set 
(Section 9.7) that are randomized to Treatment Sequence 1 (A/B) or 2 (B/A) to evaluate of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection compared 


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to placebo. The null hypothesis to be tested is that the NNA of C1 esterase inhibitor [human] 
liquid for injection is greater than or equal to the NNA of placebo, and the alternative 
hypothesis is that the NNA of C1 esterase inhibitor [human] liquid for injection is less than 
the NNA of placebo as below:
H0: µ C1 INH - µ placebo >0 vs
H1: µ C1 INH - µ placebo <0
The primary efficacy endpoint will be analyzed by using a mixed effect linear model with 
period, sequence, stratification factor (use of prophylactic therapy with C1 INH), and 
treatment as fixed effects, and subject nested within sequence as a random effect. The mean 
treatment difference (µ C1 INH - µ placebo) will be estimated with a 95% CI.
To assess any carryover effect, a sensitivity analysis will exclude from the evaluation of the 
NNA any attacks occurring within the first 2 weeks of Treatment Period 2 for both sequences 
when carryover is suspected to be maximal. Since carryover should occur only with the 
A/B treatment sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] 
liquid for injection efficacy into the placebo treatment period, thereby diluting the efficacy of 
C1 INH and favoring the null hypothesis of the primary efficacy analysis; it is not anticipated 
that any placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection 
within the B/A treatment sequence. The study is powered to demonstrate superior efficacy 
even in the presence of carryover effects. Additional sensitivity analyses may be developed 
and included in the SAP.
Adjustments for multiplicity: To control the overall type 1 error, the primary and key 
secondary endpoints will be tested hierarchically, so that the significance of the key secondary 
endpoint is contingent on whether the primary endpoint is significant. The determination of a 
successful study is based solely on the results of the primary endpoint analysis regardless of 
the results for the key secondary endpoint.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the clinical response to treatment relative to placebo. 
This is defined as achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase 
inhibitor [human] liquid for injection treatment period relative to the placebo period.
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion 
PR. The null hypothesis is that PR is less than or equal to 0.2, and the alternative hypothesis is 
that PR is greater than 0.2. The proportion meeting criterion PR will be estimated with an exact 
95% CI. The lower limit of the 95% CI for the proportion will be compared with 0.2. This is 
equivalent to testing the null hypothesis against the alternative hypothesis at a 1-sided alpha 
level of 0.025 using the normal approximation to the binomial distribution.


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9.8.2.2
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints to be evaluated in this study are:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA 
during a treatment period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity 
recorded for each angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every 
day of reported symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day.

Results of the AE-QoL questionnaire.

Determine the response to icatibant when administered as treatment for an acute 
angioedema attack by:

Time to subject-assessed initial symptom improvement (TISI) 

Time to subject-assessed complete symptom resolution (TCSR) 
Subjects in the Full Analysis Set (Section 9.7) that are randomized to Treatment Sequence 1 
(A/B) or 2 (B/A) will be used to assess the secondary efficacy endpoints in the evaluation of 
the efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection 
compared to placebo. The treatment differences in clinical responder rate, both of which are 
defined within treatments, will be analyzed using McNemar’s test for testing equality of 
proportions of responders within treatments. All other secondary endpoints will be analyzed 
using a linear mixed effect model with period, sequence, stratification factor (use of 
prophylactic therapy with C1 INH), and treatment as fixed effects, and subject nested within 
sequence as a random effect. The results of all secondary efficacy analyses will be 
summarized by the point estimate of within-subject treatment differences or response rates 
and the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75% quartiles, and 
range) will be provided to summarize icatibant-related efficacy endpoints (TISI and TCSR) 
by treatment and icatibant-treated angioedema attack for all subjects in the Full Analysis Set. 
Where appropriate (for subjects ≥12 to <18 years of age), other rescue medications used to 
treat acute angioedema attacks will also be summarized using descriptive statistics. In 
addition, angioedema attacks will be summarized by the maximum symptom severity and 
treatment for all subjects in the Full Analysis Set. 
9.8.3
Exploratory Efficacy Endpoints
There are no exploratory efficacy endpoints in this study.


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9.9
Safety Analyses
Adverse events will be coded using the MedDRA. The number of events, incidence, and 
percentage of TEAEs will be calculated overall, by system organ class, preferred term, and 
treatment. Treatment-emergent AEs will be further summarized by severity and relationship 
to investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG 
findings will be summarized by treatment and visit. Potentially clinically important findings 
will also be summarized or listed.
The incidence and severity (mild, moderate, severe) of SC injection site reactions will be 
summarized by treatment and visit. 
Results of C1 INH antibody testing will be reported for individual subjects.
The tolerability of icatibant therapy for acute angioedema attacks will be summarized.
To assess the influence of any carryover effect on adverse reporting, a sensitivity analysis 
may be conducted by attributing TEAEs that occur during the first 2 weeks of Treatment 
Period 2 to Treatment Period 1 for the A/B (C1 INH to placebo) treatment sequence. In other 
words, C1 esterase inhibitor [human] liquid for injection may account for any TEAEs in the 
first 2 weeks of the placebo treatment, when the carryover effect (if present) is suspected to be 
maximal. 
9.10 Other Analyses
9.10.1
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, C1 INH functional, and complement C4 and C1q for 
individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics (number, geometric mean, coefficient of variation, 
mean, standard deviation, median, minimum, and maximum) for values at each time point.
C1q concentrations will only be assessed at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic parameters will be calculated using observed and baseline-corrected 
concentration-vs-time data using non-compartmental techniques for C1 INH antigen and 
functional activity. The following PK parameters will be calculated using both unadjusted and 
baseline-adjusted concentrations for SC administration: The Cmax, the tmax, the minimum 
observed concentration, and the AUClast. Additional PK parameters will be calculated using 
only baseline-adjusted concentrations, including t1/2, the λz, the AUC0-∞, the VZ/F, and the 
CL/F. Other PK parameters may be calculated as deemed appropriate. Pharmacokinetic 
parameters will be summarized using descriptive statistics.
Exploratory PK/PD analyses might be performed based on the correlation of plasma 
concentrations of C1 INH antigen, functional C1 INH, and C4 complement in conjunction 


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with various safety parameters (eg, selected AEs, clinical laboratory results, antibodies 
generation, frequency, severity, or anatomic location of the angioedema attack, etc.). 
Correlations that will be analyzed will be determined based on observed data.
9.10.2
Health-related Quality of Life Analyses
Results of the EQ-5D-5L health status instrument will be presented in accordance with the 
EQ-5D-5L user guide (version 2.0) by treatment.
Results of the WPAI-GH questionnaire will be summarized by treatment.
Results of the SDS will be summarized by treatment.
9.10.3
Surveys on SC Administration and Self-administration of Investigational 
Product
Results of the surveys for subject acceptability of SC administration and subject experience 
with self-administration of investigational product will be summarized.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. These regulations and 
guidelines also constitute compliance with the ethical principles described in the Declaration 
of Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 


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submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ 
names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the Community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
studies as per guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason. If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification. Curriculum vitae for investigators and sub-investigators are 
provided to the study sponsor (or designee) before starting the study.


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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The
investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.


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10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective 
national, local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities 
and to have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc).
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).


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10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written 
subject information and received an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent and assent documentation (ie, a complete 
set of subject information sheets and fully executed signature pages) must be given to the 
subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent 
form where applicable) which was reviewed by the IRB/EC and which received their 
favorable opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of
these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible 
for this action. Additionally, if the IRB/EC requires modification of the sample subject 
information and consent document provided by the sponsor, the documentation supporting 
this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, 
or for multicenter studies the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.


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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor, the investigator, or for 
multicenter studies the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market C1 esterase inhibitor [human] liquid for injection; national or local 
regulatory authorities; and the IRBs/ECs which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present 
the study results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire ViroPharma will endeavor to publish the results of all qualifying, applicable, and 
covered studies according to external guidelines in a timely manner regardless of whether the 
outcomes are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma 
adheres to external guidelines (eg, Good Publication Practices 2) when forming a publication 
steering committee, which is done for large, multicenter Phase 2-4 and certain other studies as 
determined by Shire ViroPharma. The purpose of the publication steering committee is to act 
as a non-commercial body that advises or decides on dissemination of scientific study data in 
accordance with the scope of this policy.


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All publications relating to Shire ViroPharma products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma agreement to publish prior 
to release of information. The review is aimed at protecting the sponsor’s proprietary 
information existing either at the commencement of the study or generated during the study. 
To the extent permitted by the publisher and copyright law, the principal investigator will own 
(or share with other authors) the copyright on his/her publications. To the extent that the 
principal investigator has such sole, joint or shared rights, the principal investigator grants the 
sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, the institution and 
principal investigator shall withhold submission of such publication for up to an additional 60 
days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the International Committee of Medical Journal 
Editors (ICMJE) current standards. Participation as an investigator does not confer any rights 
to authorship of publications.


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Zuraw BL, Bork K, Binkley KE, et al. 2012. Hereditary angioedema with normal C1 inhibitor 
function: Consensus of an international expert panel. Allergy Asthma Proc; 33(Suppl 1): 
S145-56.


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12.
APPENDICES


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APPENDIX 1 HANDLING OF INVESTIGATIONAL PRODUCT FOR 
SUBCUTANEOUS INJECTION 
The procedures below are provided for the handling of the investigational product. Since 
treatment assignment to C1 esterase inhibitor [human] liquid for injection and placebo 
(Treatments A and B, respectively) is to be blinded, the following instructions apply for all 
SC administrations in Treatment Periods 1 and 2. Always work on a clean surface and wash 
hands before performing the following procedures.
Handling

Prior to administration, investigational product should be protected from light.

No reconstitution or additional dilution of investigational product is required.

A silicone-free syringe is to be used for withdrawal of the product from the vial 
and for administration.

Important Notes: (1) when withdrawing the product from the vial, and during 
administration, the plunger of the syringe should be moved back and forth 
carefully and slowly, avoid introducing any air bubbles, and pulling the plunger 
past the stop on the syringe; (2) there is no need for excessive shaking of either the 
vial or syringe during the preparation for the SC injection.

Investigational product should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. The 
product should be colorless and free from visible particles. Do not use if turbid or 
discolored.

Any vial that has been punctured should be used promptly.

Do not mix investigational product with other materials.

Do not freeze.

Do not use after expiration date.
NOTE: For this protocol, 2 vials of investigational product will be required for each SC 
injection (2x2 mL=4 mL total injection volume).
1. Aseptic technique should be used during handling.
2. Bring vials of investigational product to room temperature.
3. Remove caps from investigational product vials.
4. Cleanse stopper(s) with alcohol swab or germicidal solution, and allow them to dry prior 
to use.
5. Transfer the investigational product to a syringe for administration. Draw up the contents 
of 2 vials of investigational for a total volume of 4 mL.
Be sure to safely dispose of the used needle and syringe.
Retain all used vials of investigational product for drug accountability purposes.


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APPENDIX 2 SUBCUTANEOUS INJECTION SITE SELECTION AND 
PREPARATION
Subcutaneous injections of investigational product will be administered in the abdominal area. 
Injection sites on the abdomen are depicted in the figure below. An abdominal site that is 
approximately at the level of the navel (as allowed by skin condition) and approximately 
15 cm (minimum 10 cm) away from the margin of the navel should be selected. The lateral 
portion of the abdomen is preferred over the midline area. The selected site should include 
fatty tissue. Administer the first injection in the right side (#1 in illustration) and the second 
injection in the left side (#2 in illustration). Keep alternating injection sites to the right side 
and then to the left side for all subsequent injections in Treatment Periods 1 and 2.
Illustration of Injection Sites on the Abdomen
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s 
position: 30-45º) and in a supine position immediately following injection for the evaluation 
of the injection site (ie, laying flat on back).
After the injection site for SC administration has been chosen, the investigational product will 
be administered as a single 4 mL SC injection as described briefly below.

Wipe skin with alcohol to cleanse. Allow to dry.

Gently pinch and lift the skin of the abdomen (ie, “tenting”).

Insert the needle with bevel up close to parallel to the skin or at an angle that is <20°. 
Once the needle is inserted, gently release the pinched and lifted skin (“untent the 
skin”). When the skin is in its normal state, the needle should have a slight upward 
angle of 20-30°. If the subject is obese, a steeper angle for needle insertion can be used 
but it is recommended keeping the angle <45°. In practical terms, the needle 
placement should resemble the angle of an IV needle placement in the arm. The 
purpose of pinching and lifting the skin is to make sure the needle is properly inserted 
in the SC space and is not intradermal.

Release the subcutaneous tissue. The needle will not back out during the injection if 
properly placed.

Care should be taken to avoid inadvertent IV or IM injection.
It may be necessary to adjust the needle by pulling the needle slightly back if there appears to 
be a resistance to flow.
1
2


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APPENDIX 3 WELLS PREDICTION RULE FOR THE DIAGNOSIS OF 
VENOUS THROMBEMBOLISM
Table A.
Wells Prediction Rule for Diagnosing Deep Venous Thrombosis: Clinical 
Evaluation Table for Predicting Pretest Probability of Deep Venous 
Thrombosisa
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months, or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within 12 weeks requiring general anesthesia 
or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Alternative diagnosis at least as likely as deep venous thrombosis
−2
a Clinical probability of deep venous thrombosis: Low= ≤0; Intermediate=1 to 2; High= ≥3. In patients with symptoms in 
both legs, the more symptomatic leg is used.
Data source: Qaseem et al. 2007
Table B.
Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical 
Evaluation Table for Predicting Pretest Probability of Pulmonary 
Embolisma
Clinical Characteristic
Score
Previous pulmonary embolism or deep venous thrombosis
+1.5
Heart rate >100 beats per minute
+1.5
Recent surgery or immobilization
+1.5
Clinical signs of deep venous thrombosis
+3
Alternative diagnosis less likely than pulmonary embolism
+3
Hemoptysis
+1
Cancerb
+1
a Clinical probability of pulmonary embolism: Low=0 to 1; Intermediate=2 to 6; High= ≥7
b For the purposes of this study, cancer will include “treatment ongoing, within previous 6 months, or palliative.”
Data Source: Qaseem et al. 2007
References
Qaseem A, Snow V, Barry P, et al. 2007. Current diagnosis of venous thromboembolism in 
primary care: A clinical practice guideline from the American Academy of Family Physicians 
and the American College of Physicians. Ann Fam Med; 146(6):454-58.


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APPENDIX 4 ALGORITHM FOR SUSPECTED VENOUS 
THROMBOEMBOLISM 
References
National Heart, Lung, and Blood Institute. Pulmonary embolism 2011. http://www.nhlbi.nih.
gov/book/export/html/4865. Accessed May 11, 2015. 
National Heart, Lung, and Blood Institute. Deep vein thrombosis 2011. http://www.nhlbi.nih.
gov/book/export/html/4871. Accessed May 11, 2015. 
Ozaki A, Bartholomew JR. Venous thromboembolism (deep venous thrombosis & pulmonary 
embolism). In: Carey WD, Rae-Grant A, Rimmerman C, ed. Disease Management Project. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous-
thromboembolism. Accessed May 11, 2015. 


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APPENDIX 5 ALGORITHM FOR SUSPECTED ARTERIAL 
THROMBOEMBOLISM
References
National Library of Medicine. Arterial embolism 2014. http://www.nlm.nih.gov/medlineplus/
ency/article/001102.htm. Accessed May 18, 2015.
Lyaker MR, Tulman DB, Dimitrova GT, Pin RH, Papadimos TJ 2013. Arterial embolism. Int 
J Crit Illn Inj Sci; 3(1): 77-87. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665125/
?report=printable.


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APPENDIX 6 PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
28 May 2015
Global
Protocol Amendment 1
22 Jul 2015
Global
Amendment 1 to Protocol SHP616-300 incorporates the following major changes:

Inclusion of final clinical data from Study SHP616-103, which are relevant to patient 
safety and the study rationale.

The baseline angioedema attack rate required for study inclusion has been modified.

Updates were made to some study procedures or requirements (eg, parent/legal 
guardian/caregiver performing and/or assisting an adolescent subject, photographs and 
measurements of injection site reactions, longitudinal follow-up to test for C1 INH 
antibody titers).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 July 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the title page to indicate that this will be a multicenter study.
Title page
Changed the baseline attack rate requirement for study entry from a 
history of ≥4 attacks per month average to ≥3 attacks per month average 
for inclusion criterion #3.
Synopsis
Section 4.1
Corrected the secondary efficacy endpoint for the Angioedema Activity 
Score (AAS), to indicate the “98-day AAS” will be calculated in each 
treatment period. 
Synopsis
Section 9.8.2.2
Results from a statistical simulation showed that at least 25% of 
randomized subjects with a baseline attack rate of ≥4 per month average 
need to be included in the efficacy analysis population in order to detect 
a significant reduction (<2) in NNA from baseline. This requirement was 
added to due the revision of the baseline attack rate from ≥4 to ≥3 in 
inclusion criterion #3.
Synopsis
Section 3.1
A parent/legal guardian/caregiver will be allowed to administer 
investigational product to an adolescent subject during Treatment Period 
2, after having received appropriate training and under the supervision of 
study site personnel or a qualified home health professional.
Synopsis
Section 3.1, Section 6.2, Section 6.5, 
Section 7.2.4.5


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 July 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
For adolescent subjects, a parent/legal guardian/caregiver is allowed to 
assist the subject in completing the electronic subject diary, including the 
quality of life questionnaires.
Synopsis
Section 3.1
Updated sections to include the final clinical data (safety and 
pharmacokinetics) from Study SHP616-103.
Section 1.2, Section 1.2.1.1, 
Section 1.2.2.2
Modified the presentation of the PK results from Study 0624-206 to 
clarify dose selection.
Section 1.2.2.1
Modified text on dose selection and rationale for the study based on 
results from Study SHP616-103.
Section 1.2.2.3, Section 2.1
Clarified guidelines regarding the treatment of acute angioedema attacks 
with icatibant. 
Section 5.2.1
Updated the details on subject randomization to specify that it will be 
conducted in two phases. 
Section 6.3
Removed the request for subjects to participate in longitudinal follow-up 
for C1 INH antibody titers if they had anti-C1 INH antibodies detected in 
their plasma samples. If warranted, subjects may be requested to 
participate in follow-up of C1 INH antibody titers via a separate study 
protocol.
Section 7.1.5, Section 7.2.4.1
Removed the request for study personnel to obtain a digital photograph 
of severe injection site reactions and clarified that measurements of any 
erythema or swelling should be captured in the CRF.
Section 7.2.3.10
Clarified the collection period for AEs.
Section 8.1
Clarified the population of subjects (ie, those randomized to Treatment 
Sequence 1 [A/B] or 2 [B/A]) to be used in the evaluation of the efficacy 
of SC administration of C1 esterase inhibitor [human] liquid for injection 
compared to placebo.
Section 9.8.1, Section 9.8.2.2

Prot_004.pdf: 
PROTOCOL: SHP616-300
TITLE:
A Phase 3, Randomized, Double-blind, Placebo-controlled, 
Two-period, Three-sequence, Partial Crossover Study to Evaluate the 
Efficacy and Safety of Subcutaneous Administration of 2000 IU of 
C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention 
of Angioedema Attacks in Adolescents and Adults with Hereditary 
Angioedema
DRUG:
SHP616, C1 esterase inhibitor [human] liquid for injection
IND:
16516
EUDRACT NO.:
2015-002478-19
SPONSOR: 
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
INVESTIGATORS: Multicenter
PROTOCOL 
HISTORY:
Amendment 4: 08 Feb 2017
Amendment 3: 11 Jan 2016
Amendment 2: 03 Sep 2015
Amendment 1: 22 Jul 2015
Original Protocol: 28 May 2015
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used solely for the 
purposes for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Shire ViroPharma, Inc.


Shire ViroPharma, Inc. 
Protocol Amendment 4 
SHP616-300
CONFIDENTIAL 
 
Page 2 
 
08 Feb 2017
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire ViroPhanna, Inc.) Approval 
Signature: 
 MD, PhD 
Investigator's Acknovvledgement 
Date: 
I have read this protocol for Shire ViroPbarma Study SHP616-300. 
Title: A Phase 3, randomized, double-blind. placebo-controlled, two-period, three-sequence, 
partial crossover study to evaluate the efficacy and safety of subcutanecms aclnuni:;tration of 
2000 IU of Cl esterase inhibitor [human] liquid for injection fc)r the prevention of 
angioedema 
in adolescents and adults with herediLary angioedema. 
I have fully discus:;ed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, howeveL pem1issible to provide 
the inf(Jm1ation contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol :wd to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with Intemational Conference on I-lam1onisation guiclel ines on Good Climcal 
Practice and with the applicable regulatory reqltirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
tennination of my partkipation as an investigator for this study 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should l decide to withdraw from execution of the study I 'Y\rill communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Adch·ess: 
(please hand print or 
Signature: 
Date: 
PPD
PPD
PPD


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CONFIDENTIAL
Page 3
Protocol Amendment 4
SHP616-300
08 Feb 2017
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Amendment 4 to Protocol SHP616-300 incorporates the following major changes:

Added 2 key secondary efficacy endpoints to assess efficacy excluding the first 2 weeks of
each treatment period. The primary and existing key secondary endpoints are not affected. 
The new key secondary endpoints provide additional efficacy assessments while allowing the 
investigational product to attain steady-state levels and reducing potential carryover effects.
Corresponding updates were made to the key secondary study objectives. In addition, revised 
description of multiplicity adjustments to account for the 2 new key secondary efficacy 
endpoints.

Harmonized country-specific protocol requirements into this global amendment.

Updates were made to some study procedures (eg, reporting period for all angioedema 
attacks and concomitant medications is now through 1-month post-treatment, blood samples 
collected from subjects for PD assessments may also be used for exploratory HAE biomarker 
assays).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency, clarity, or format) are not reflected in the summary 
of changes.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
08 Feb 2017
Global/Country/Site Specific
Global
Description of Change and Rationale
Section(s) Affected by Change
The Sponsor’s Medical Monitor has changed to
 MD, PhD.
Protocol Signature Page, Emergency 
Contact Information
Clarified that at least 75 subjects will be screened and at least 66 subjects 
will be enrolled and randomized to support all efficacy and safety 
objectives. 
Synopsis
Added 2 key secondary efficacy endpoints to assess efficacy excluding 
the first 2 weeks of each treatment period, to allow the investigational 
product to attain steady-state levels and reduce potential carryover 
effects. Corresponding updates were made to the key secondary study 
objectives. In addition, revised description of multiplicity adjustments to 
account for the 2 new key secondary efficacy endpoints.
Synopsis, Section 2.2.2, 
Sections 9.8.1 and 9.8.2.1
Revised inclusion criteria to only allow enrollment of adult (≥18 years) 
HAE patients in Germany and Israel.
Synopsis, Section 4.1
Added “not applicable to Germany and Israel” to the exclusion criterion
for adolescent subjects and rescue medications allowed in adolescent
subjects.
Synopsis, Section 4.2, Section 5.2.1
Revised exclusion criteria to exclude subjects positive for hepatitis B, 
hepatitis C, or HIV infection; alcohol, drug, or medication abuse within 
1 year before screening; or mental condition rendering the subject or 
Synopsis, Section 4.2
PPD


Shire ViroPharma, Inc.
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Protocol Amendment 4
SHP616-300
08 Feb 2017
parent(s)/legal guardian unable to understand the nature, scope of the 
study, and possible consequences of the study. Also excluding subjects 
with a relationship to study staff or sponsor (including people 
accommodated in an institution as well as people who are dependent on 
the sponsor, CRO, site or the investigator).
Added that blood samples collected from subjects for PD assessments
may also be used for exploratory HAE biomarker assays.
Synopsis, Table 4, Section 7.2.4.1, 
Section 9.10.1
Revised to clarify that the reporting period for all angioedema attacks 
and concomitant medications is from the first dose of investigational 
product through to the 1-month post-treatment visit and to indicate the 
subject diary should be completed on the day of discontinuation and/or at 
the 1-week and 1-month post-treatment visits, as applicable.
Table 3, Section 5.2, Sections 7.1.4
and 7.1.5
Noted that double-barrier methods are not an acceptable form of female 
contraception in Germany.
Section 4.3.1
Added that mandatory discontinuation of investigational product would 
occur if the sponsor became aware of conditions that were unexpected, 
were significant, or posed an unacceptable risk to patients.
Section 4.4
Added that in Germany, if a subject discontinues investigational product 
for a mandatory reason, this must be specified in the subject’s CRF.
Section 4.4.1
Added that for subjects participating in Germany, if a 
thrombotic/thromboembolic event occurs in any subject, investigational 
product administration for that subject will be discontinued.
Section 4.4.4, Appendix 4, 
Appendix 5
Added that for subjects who experience a laryngeal attack, they should 
inject icatibant and proceed immediately to the nearest medical care 
facility.
Section 5.2.1
Revised to include the date and time of complete resolution of 
angioedema attack symptoms should be recorded for each attack.
Section 7.2.2.2
Added a section to define adverse events of special interest for CINRYZE. 
Adverse events of special interest will be summarized as a part of the 
safety analyses.
Section 8.1.8, Section 9.9
Removed paragraph describing the study’s enrollment goal as it was not 
needed in this section for the sample size calculation and power 
considerations. Corrected typographical errors.
Section 9.6
Editorial revisions to clarify planned pharmacokinetic/pharmacodynamic 
analyses.
Synopsis, Section 9.10.1
Clarified that the sponsor may suspend or terminate the study if 
conditions arise which indicate that the clinical investigation should be 
halted due to an unacceptable patient risk.
Section 10.1.4
See Appendix 6 for protocol history, including all amendments.


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Protocol Amendment 4
SHP616-300
08 Feb 2017
EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover) and are 
provided below. 
US and Canadian Sites
Fax: 
Email: 
EU/ROW Sites
Fax: 
Email: 
For protocol- or safety-related issues, the investigator must contact the Shire ViroPharma 
Medical Monitor:
, MD, PhD, Clinical Development 
Office phone: 
Mobile phone: 
Fax: 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Protocol Amendment 4
SHP616-300
08 Feb 2017
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire ViroPharma 
product (marketed or investigational) does not meet expectations (eg, inadequate or faulty 
closure, product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please report all Product Quality Complaints to:
PPD


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULES..................................................................................................................22
1.
BACKGROUND INFORMATION.......................................................................................28
1.1
Indication and Current Treatment Options...............................................................28
1.2
Product Background and Clinical Information ........................................................29
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and with 
SC C1 Esterase Inhibitor [Human] Liquid for Injection........................................31
1.2.1.1
Clinical Safety........................................................................................32
1.2.1.2
Clinical Efficacy.....................................................................................33
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid 
for Injection............................................................................................................34
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response 
Analysis of CINRYZE ..............................................................................34
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid 
for Injection............................................................................................38
1.2.2.3
Dose Selection........................................................................................39
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................40
2.1
Rationale for the Study.............................................................................................40
2.2
Study Objectives ......................................................................................................41
2.2.1
Primary Objectives.................................................................................................41
2.2.2
Secondary Objectives.............................................................................................41
3.
STUDY DESIGN ...................................................................................................................42
3.1
Study Design and Flow Chart ..................................................................................42
3.2
Duration and Study Completion Definition .............................................................44
3.3
Sites and Regions .....................................................................................................44
4.
STUDY POPULATION.........................................................................................................44
4.1
Inclusion Criteria......................................................................................................44
4.2
Exclusion Criteria.....................................................................................................45
4.3
Reproductive Potential .............................................................................................46


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4.3.1
Female Contraception............................................................................................46
4.3.2
Male Contraception................................................................................................47
4.4
Discontinuation of Subjects .....................................................................................47
4.4.1
Reasons for Discontinuation..................................................................................47
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit ..................................47
4.4.3
Anaphylactic Reaction...........................................................................................48
4.4.4
Thrombotic or Thromboembolic Event .................................................................48
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................48
5.1
Prior Treatment ........................................................................................................49
5.2
Concomitant Treatment and Medical/Surgical Procedures......................................49
5.2.1
Management of Angioedema Attacks....................................................................49
5.2.2
Prohibited Treatment .............................................................................................50
5.2.3
Nonpharmacologic Treatments and Procedures ....................................................50
6.
INVESTIGATIONAL PRODUCT ........................................................................................51
6.1
Identity of Investigational Product...........................................................................51
6.2
Administration of Investigational Product ...............................................................51
6.3
Allocation of Subjects to Treatment Sequence ........................................................52
6.4
Blinding of Treatment ..............................................................................................52
6.4.1
Unblinding the Treatment Assignment..................................................................53
6.5
Treatment Compliance .............................................................................................53
6.5.1
Self-Administration................................................................................................53
6.6
Packaging and Labeling ...........................................................................................54
6.7
Storage and Accountability ......................................................................................54
6.8
Investigational Product Retention at Study Site.......................................................55
7.
STUDY PROCEDURES........................................................................................................55
7.1
Study Schedule.........................................................................................................55
7.1.1
Screening Period....................................................................................................55
7.1.2
Treatment Period 1.................................................................................................56
7.1.2.1
Visit 1a (predose) ...................................................................................56
7.1.2.2
Visit 1a (postdose)..................................................................................57
7.1.2.3
Visit 2a through Visit 28a ......................................................................57
7.1.3
Treatment Period 2.................................................................................................58
7.1.3.1
Visit 1b (predose)...................................................................................58
7.1.3.2
Visit 1b (postdose) .................................................................................58
7.1.3.3
Visit 2b through Visit 28b......................................................................59
7.1.4
Early Discontinuation Visit....................................................................................60
7.1.5
Follow-up Period ...................................................................................................60
7.2
Study Evaluations and Procedures ...........................................................................61


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7.2.1
Demographic and Other Baseline Characteristics .................................................61
7.2.2
Efficacy..................................................................................................................61
7.2.2.1
Definition of an Angioedema Attack .....................................................61
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary......62
7.2.2.3
Angioedema Activity Score ...................................................................63
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks ....63
7.2.3
Safety .....................................................................................................................63
7.2.3.1
Medical and Medication History............................................................63
7.2.3.2
Physical Examination (Including Height and Weight) ..........................64
7.2.3.3
Adverse Event Collection.......................................................................64
7.2.3.4
Vital Signs..............................................................................................65
7.2.3.5
Clinical Laboratory Evaluations.............................................................65
7.2.3.6
Pregnancy Test .......................................................................................67
7.2.3.7
Electrocardiogram ..................................................................................67
7.2.3.8
Nonpharmacologic Treatments and Procedures.....................................67
7.2.3.9
Thrombotic or Thromboembolic Events................................................67
7.2.3.10
Injection Site Reactions..........................................................................68
7.2.4
Others.....................................................................................................................69
7.2.4.1
Clinical Pharmacology Assessments......................................................69
7.2.4.2
Health-related Quality of Life Assessments...........................................70
7.2.4.3
Health Resource Utilization Assessment ...............................................70
7.2.4.4
Survey of Acceptability of SC Administration ......................................71
7.2.4.5
Self-administration Survey Assessment.................................................71
7.2.5
Volume of Blood to Be Drawn From Each Subject ..............................................71
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................72
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................72
8.1.1
Severity Categorization..........................................................................................72
8.1.2
Relationship Categorization...................................................................................73
8.1.3
Outcome Categorization ........................................................................................73
8.1.4
Symptoms of the Disease Under Study .................................................................74
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................74
8.1.6
Pregnancy...............................................................................................................74
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................75
8.1.8
Adverse Events of Special Interest ........................................................................75
8.2
Serious Adverse Event Procedures ..........................................................................76
8.2.1
Reference Safety Information................................................................................76
8.2.2
Reporting Procedures.............................................................................................76


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8.2.3
Serious Adverse Event Definition .........................................................................76
8.2.4
Serious Adverse Event Collection Time Frame.....................................................77
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................77
8.2.6
Fatal Outcome........................................................................................................77
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................77
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................78
9.1
Data Collection.........................................................................................................78
9.2
Clinical Data Management.......................................................................................78
9.3
Data Handling Considerations..................................................................................78
9.4
Statistical Analysis Process......................................................................................78
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......79
9.6
Sample Size Calculation and Power Considerations................................................79
9.7
Study Population ......................................................................................................79
9.8
Efficacy Analyses.....................................................................................................80
9.8.1
Primary Efficacy Endpoint ....................................................................................80
9.8.2
Secondary Efficacy Endpoints...............................................................................81
9.8.2.1
Key Secondary Efficacy Endpoints........................................................81
9.8.2.2
Other Secondary Efficacy Endpoints .....................................................81
9.8.3
Exploratory Efficacy Endpoints.............................................................................82
9.9
Safety Analyses........................................................................................................82
9.10
Other Analyses .........................................................................................................83
9.10.1 Pharmacokinetic and Pharmacodynamic Analyses ...............................................83
9.10.2 Health-related Quality of Life Analyses................................................................84
9.10.3 Surveys on SC Administration and Self-administration of Investigational 
Product...................................................................................................................84
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................84
10.1
Sponsor’s Responsibilities .......................................................................................84
10.1.1 Good Clinical Practice Compliance.......................................................................84
10.1.2 Public Posting of Study Information......................................................................85
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................85
10.1.4 Study Suspension, Termination, and Completion..................................................85
10.2
Investigator’s Responsibilities .................................................................................85
10.2.1 Good Clinical Practice Compliance.......................................................................85
10.2.2 Protocol Adherence and Investigator Agreement..................................................86
10.2.3 Documentation and Retention of Records.............................................................86
10.2.3.1
Case Report Forms.................................................................................86


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................86
10.2.3.3
Audit/Inspection.....................................................................................87
10.2.3.4
Financial Disclosure...............................................................................87
10.3
Ethical Considerations..............................................................................................87
10.3.1 Informed Consent...................................................................................................87
10.3.2 Institutional Review Board or Ethics Committee..................................................88
10.4
Privacy and Confidentiality......................................................................................88
10.5
Study Results/Publication Policy .............................................................................89
11. REFERENCES .......................................................................................................................91
12. APPENDICES ........................................................................................................................94
LIST OF TABLES
Table 1
Schedule of Assessments – Treatment Period 1.................................................22
Table 2
Schedule of Assessments – Treatment Period 2.................................................24
Table 3
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits ..........................................................................................26
Table 4
Blood Sample Collection for PK/PD Analyses..................................................27
Table 5
Exposure to SC CINRYZE....................................................................................31
Table 6
Primary and Secondary Efficacy Endpoints During Treatment by 
Sequence (Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)................................................................................................34
Table 7
Treatment Sequences..........................................................................................52
Table 8
Severity Scoring for Injection Site Reactions ....................................................69
Table 9
Approximate Volume of Blood to Be Drawn From Each Subject.....................71
LIST OF FIGURES
Figure 1
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity..................................................35
Figure 2
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)..............................................36
Figure 3
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice-weekly Dose Regimen ................................................................37
Figure 4
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206) ...........................................................................................38


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Figure 5
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-
103).....................................................................................................................39
Figure 6
Individual and Mean (±SD) Baseline-corrected AUClast Across 
Treatments for C1 INH Antigen and Functional C1 INH Binding (Study 
SHP616-103)......................................................................................................39
Figure 7
Study Design Flow Chart ...................................................................................42
LIST OF APPENDICES
Appendix 1 Handling of Investigational Product for Subcutaneous Injection ........................95
Appendix 2 Subcutaneous Injection Site Selection and Preparation.......................................96
Appendix 3 Wells Prediction Rule for the Diagnosis of Venous Thrombembolism...............97
Appendix 4 Algorithm For Suspected Venous Thromboembolism ........................................98
Appendix 5 Algorithm For Suspected Arterial Thromboembolism ........................................99
Appendix 6 Protocol History .................................................................................................100


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ABBREVIATIONS
AAS
Angioedema Activity Score
AE
adverse event
AE-QoL
angioedema quality of life (questionnaire)
ATE
arterial thromboembolism
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
C1 INH
C1 esterase inhibitor or C1 inhibitor
CI
confidence interval
CL
clearance
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
Cmin
minimum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAE
hereditary angioedema
β-hCG
beta human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRUA
health resource utilization assessment
ICH
International Conference on Harmonisation


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IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
λz
first order rate constant associated with the terminal (log-linear) portion of 
the curve
NNA
normalized number of attacks
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDS
Sheehan Disability Scale
t1/2
terminal half-life
T/TE
thrombotic/thromboembolic
TCSR
time-to-subject-assessed-complete-symptom resolution
TEAE
treatment-emergent adverse event
TISI
time-to-subject-assessed-initial-symptom improvement
tmax
time of maximum observed concentration sampled during a dosing 
interval
UK
United Kingdom
US
United States
VAS
Visual Analogue Scale
VTE
venous thromboembolism
WPAI-GH
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire)


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STUDY SYNOPSIS
Protocol number: SHP616-300
Drug: C1 esterase inhibitor [human] liquid for injection
Title of the study: A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, 
Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 
Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and 
Adults with Hereditary Angioedema.
Number of subjects (total and for each treatment arm):
At least 75 subjects will be screened
At least 66 subjects will be enrolled and randomized to support all efficacy and safety objectives
At least 26 subjects will be randomized to the treatment sequence 1 or 2, and at least 14 subjects will be 
randomized to the treatment sequence 3 
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites globally (North America and Europe)
Study period (planned):
2015-2017
Clinical phase:
3
Objectives:
Primary:  
To demonstrate the superior efficacy of subcutaneous (SC) administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
normalized number of attacks (NNA) during a treatment period.
Key Secondaries:  
To demonstrate the superior efficacy of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for 
injection for the prevention of angioedema attacks relative to placebo as measured by:
1.
The proportion of subjects meeting the criterion of at least 50% reduction in the NNA during the 2000 IU 
C1 esterase inhibitor [human] liquid for injection treatment period relative to the placebo period.
2.
The NNA during each treatment period excluding the first 2 weeks.
3.
The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA for the 2000 IU C1 
esterase inhibitor [human] liquid for injection treatment period relative to the placebo period excluding the 
first 2 weeks of each treatment period.
Other Secondary:

To assess the proportion of responders during treatment with 2000 IU C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo, where the proportion of responders is defined as achieving 
at least a 50% reduction in the NNA during a treatment period relative to the pretreatment assessment (ie, 
the subject’s attack rate without prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 IU C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of attack-free days during treatment with 2000 IU C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of angioedema attacks requiring acute treatment during treatment with 2000 IU C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo

To assess the safety and tolerability of SC administration of 2000 IU C1 esterase inhibitor [human] liquid 


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for injection

To assess the immunogenicity of SC administration of 2000 IU C1 esterase inhibitor [human] liquid for 
injection

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SC administration of 2000 IU 
C1 esterase inhibitor [human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment of acute 
angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS)

To evaluate subject experience with self-administration of SC 2000 IU C1 esterase inhibitor [human] liquid 
for injection

To evaluate the impact of treatment on health status (quality of life) in this patient population
Rationale:
Shire ViroPharma has developed a new, ready-to-use liquid formulation of CINRYZE® for SC administration. 
This product, C1 esterase inhibitor [human] liquid for injection, obviates the need for reconstitution by the 
patient or health care provider and, owing to its higher concentration, affords the opportunity for more rapid 
administration of the drug and may improve tolerability, without an expected change or compromise in efficacy. 
Subcutaneous administration represents a convenient alternative method of administering prophylaxis to 
hereditary angioedema (HAE) patients overall and for whom accessing peripheral veins is difficult or in patients 
where placement of central venous catheters are contraindicated, as well as a means to minimize the potential 
adverse effects of intravenous (IV) administration.                                                                                                     
Investigational product, dose, and mode of administration:

C1 esterase inhibitor [human] liquid for injection is supplied in clear glass vials containing 1000 IU of 
C1 INH in 2 mL of sterile liquid. Two (2) vials, a total 4 mL, are required per 2000 IU dose. The solution 
also contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection. No reconstitution or dilution is required. Vials must be stored at 2–8oC (36–46oF) and protected 
from light.

Placebo is supplied in the identical 2 mL presentation as the active investigational product minus the 
C1 INH protein. Two (2) vials, a total 4 mL, are required per dose. The inactive ingredients in the 2 mL 
solution are the same as the active product: sodium phosphate, sorbitol, glycine, and water for injection. 
No reconstitution or dilution is required. Vials must be stored at 2–8oC (36–46oF) and protected from light.
Blinded investigational product (Treatments A or B: 2000 IU C1 esterase inhibitor [human] liquid for injection 
or placebo) will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate treatment 
periods. Each dose of investigational product will be administered in the subject’s abdomen as a single 4 mL SC 
injection.
Commercial icatibant labeled for clinical trial use will be supplied as rescue medication for the treatment of 
acute angioedema attacks.


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Methodology:
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial crossover study. 
This design was chosen as the best way to jointly address the protocol objectives of establishing efficacy 
(relative to placebo) and safety (ie, enrolling an adequate number of subjects for precision of estimation in 
detecting potential safety signals). Additionally, this design maximizes the number of subjects exposed to 
C1 esterase inhibitor [human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have a history (based 
on subject recall and medical records) of ≥2 attacks per month on average per inclusion criterion #3. At least 66 
eligible subjects will be randomized to 1 of 3 treatment sequences prior to the first dose of investigational 
product in Treatment Period 1 using interactive response technology (see table below). Randomization of 
subjects will be stratified by use of prophylactic therapy with C1 INH at the time enrollment.
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 
3 or 4 days) for 14 weeks.
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission of a washout 
period is to minimize the duration that subjects will be without active treatment. It is recommended that the 
twice weekly dosing schedule (every 3 or 4 days) be maintained between the last dose of investigational product 
in Treatment Period 1 and the first dose of investigational product in Treatment Period 2. Every effort should be 
made to complete scheduled dosing and to avoid situations where investigational product is not received. In
order to prevent a missed dose, a less than 3-day interval may occur, with the recommendation of allowing at 
least 24 hours between doses.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be blinded to 
treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be administered at the 
investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both treatment periods. Other doses may be 
administered by qualified blinded personnel at the investigational site or at the subject’s home or other agreed 
upon location or self-administered by the subject (adolescent or adult) with or without supervision (qualified 
home health professional and/or study site personnel), after receiving appropriate training by the investigator or 
designee. Adolescent subjects self-administering the investigational product will be supervised by a parent/legal 
guardian/caregiver (if home health professional and/or study site personnel is not present). Alternatively, a 
parent/legal guardian/caregiver after receiving appropriate training, will be allowed to administer the 
investigational product to an adolescent subject with or without supervision. 
Throughout the study, an electronic subject diary will be used to record specific information regarding the 
subject’s symptoms of HAE and details on self-administration. This will include signs and symptoms of 
angioedema attacks, location (including whether mucosal or non-mucosal), triggers for angioedema attacks, 
medications used for the acute treatment of angioedema attacks, elective procedures, and interruptions in 
activities of daily living due to an angioedema attack. Additionally, quality of life questionnaires and surveys on 
SC administration of the investigational product will be also subject evaluated. Note: For adolescent subjects, a 
parent/legal guardian/caregiver is allowed to assist the subject in completing the electronic subject diary, 
including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product is administered. In addition, the investigator will report all SAEs that 
occur through 30 days after the last dose of investigational product to Shire Pharmacovigilance and the 
respective Independent Reviewing Authority according to local reporting requirements.


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A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last dose of 
investigational product in Treatment Period 2 for follow-up safety assessments. In addition, subjects will have 
blood samples collected for PK/PD and C1 INH antibody testing at 1 month (±2 days) after the last dose of 
investigational product. 
If a subject prematurely discontinues investigational product, early discontinuation visit procedures (Table 3) 
are to be performed as completely as possible. Whenever possible, all discontinued subjects should also 
complete the 1-week and 1-month post-treatment visits.  
The schedules of study procedures are provided immediately following the study synopsis:

Table 1: Clinical study assessments – Treatment Period 1 (Visits 1a to 24a).

Table 2: Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Table 3: Clinical study assessments – Early discontinuation visit, 1-week post-treatment and 1-month 
post-treatment visits.

Table 4: Blood sample collection schedule – PK/PD assessments.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Be ≥12 years of age, or in Germany and Israel, be ≥ 18 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 inhibitor (C1 INH) level less than 50% of 
normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in conjunction with the 
subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy with C1 INH, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving prophylactic therapy 
with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) during the 
3 consecutive months prior to the screening visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of attenuated androgens, 
have a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any angioedema attacks 
that occur during the study that, in the opinion of the healthcare care provider, requires medical 
intervention. Note: For subjects ≥12 to <18 years of age, standard of care therapy per local protocols 
should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) pregnancy test at 
the screening visit and must have a negative urine pregnancy test prior to the first dose of 
investigational product (Visit 1a), and agree to comply with any applicable contraceptive requirements 
of the protocol.
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, 
barrier control) from the screening visit through 2 months after the last dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide written informed 
consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study 
provide written informed consent for the child to participate in the study before any study-specific 


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procedures are performed (with assent from the child when appropriate). Alternatively, certain 
sites/Independent Reviewing Authorities may permit adolescents who are <18 years of age to be 
informed of the nature of the study and provide written informed consent without consent from a 
parent(s)/legal guardian.
Exclusion Criteria:
1.
Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved dosing 
regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with C1 INH (not 
applicable to Germany and Israel).
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose of 
investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention of angioedema 
attacks within 3 calendar days prior to the first dose of investigational product in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or hormone 
replacement therapy (ie, estrogen/progestin containing products) within 2 months prior to the 
screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism.
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies.
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of 
CINRYZE), or other blood products, or Firazyr (icatibant).
9.
Be pregnant or breastfeeding.
10.
Have received an investigational drug within 30 days prior to the first dose of investigational product in 
Treatment Period 1.
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical or medical 
condition (including positive for hepatitis B, hepatitis C, or HIV infection; alcohol, drug, or medication 
abuse within 1 year before screening; or mental condition rendering the subject or parent(s)/legal 
guardian unable to understand the nature, scope of the study, and possible consequences of the study), 
or relationship to study staff or sponsor (including people accommodated in an institution as well as 
people who are dependent on the sponsor, CRO, site or the investigator) that could interfere with the 
administration of investigational product or interpretation of study results.
Maximum duration of subject involvement in the study:
Individual participation from the screening visit through the 1-month post-treatment visit will be approximately 
9 months.

Planned duration of screening period: Up to 21 days

Planned duration of enrollment period: 6 months

Planned duration of treatment period: Treatment Periods 1 and 2 are 14 weeks each (total 28 weeks) with 
no washout between periods

Planned duration of follow-up: 1 month follow-up in total, with safety assessments at both 1-week and 
1-month post-treatment
Endpoints and statistical analysis:
Primary Efficacy Endpoint: The NNA recorded during each treatment period. The NNA is computed as the 
number of attacks per month (ie, 30.4 days) of exposure (NNA = 30.4 x [number of attacks during treatment 
period]/[days of treatment period]). If a subject discontinues during the treatment period, the denominator of the 
NNA will be the days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation. 


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The primary analysis of the primary efficacy endpoint will test against the null hypothesis that the NNA of C1 
esterase inhibitor [human] liquid for injection is greater than or equal to the NNA of placebo 
(H0: µ C1 INH - µ placebo >0; H1: µ C1 INH - µ placebo <0). The primary efficacy endpoint will be analyzed by using a 
linear mixed effect model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH),
and treatment as fixed effects, and subject nested within sequence as a random effect. The mean treatment 
difference (µ C1 INH - µ Placebo) will be estimated with a 95% confidence interval (CI).
To control the overall type 1 error, the primary and key secondary endpoints will be tested at the 0.05 
significance level in the pre-specified order of the primary endpoint, key secondary endpoint 1, key secondary 
endpoint 2, and key secondary endpoint 3. Once one hypothesis test is not significant, the significance of all 
subsequent tests will not be assessed.
Key Secondary Efficacy Endpoints:
1.
The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA during the 2000 IU 
C1 esterase inhibitor [human] liquid for injection treatment period relative to the placebo period.
2.
The NNA excluding the first 2 weeks of each treatment period.
3.
The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA for the 2000 IU C1 
esterase inhibitor [human] liquid for injection treatment period relative to the placebo period excluding the 
first 2 weeks of each treatment period.
Key secondary endpoints 1 and 3 are defined as achieving a ≥50% reduction in the NNA (PR) during the 2000 
IU C1 esterase inhibitor [human] liquid for injection treatment period relative to the placebo period. Key 
secondary endpoints 1 and 3 will be analyzed as the proportion of subjects meeting criterion PR. The null 
hypothesis is that PR is less than or equal to 0.2 and the alternative hypothesis is that PR is greater than 0.2. The 
proportion meeting criterion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. 
Analysis of key secondary endpoint 2 will follow the same method (ie, the linear mixed effect model) used for 
the primary efficacy endpoint.
Other Secondary Efficacy Endpoints:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA during a treatment 
period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity recorded for each 
angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every day of reported 
symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment during a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS during a treatment 
period, where the daily AAS is the sum of AAS items per day.

Results of the Angioedema Quality of Life (AE-QoL) questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema attack by:
-
Time to subject-assessed initial symptom improvement (TISI).
-
Time to subject-assessed complete symptom resolution (TCSR). 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC administration of C1 
esterase inhibitor [human] liquid for injection. The treatment differences in clinical responder rate, both of 
which are defined within treatments, will be analyzed using McNemar’s test for testing equality of proportions 
of responders within treatments. All other secondary endpoints will be analyzed using a linear mixed effect 
model with period, sequence, stratification factor (use of prophylactic therapy with C1 INH), and treatment as 
fixed effects, and subject nested within sequence as a random effect. The results of all secondary efficacy 


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analyses will be summarized by the point estimate of within-subject treatment differences or response rates and 
the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75% quartiles, and range) will be 
provided to summarize icatibant-related efficacy endpoints (TISI and TCSR) by treatment and icatibant-treated 
angioedema attack for all subjects in the Full Analysis Set. Where appropriate (for subjects ≥12 to <18 years of 
age) other rescue medications used to treat acute angioedema attacks will also be summarized using descriptive 
statistics. In addition, angioedema attacks will be summarized by the maximum symptom severity and treatment 
for all subjects in the Full Analysis Set.
Safety Endpoints:

Number of subjects experiencing AEs, including severity and causality. AEs will also be assessed by time 
of onset (eg, during administration of investigational product or within 24 hours after the end of injection of 
investigational product). 

Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings will be 
summarized by treatment and visit. Potentially clinically important findings will also be summarized or 
listed. 

Incidence, severity (mild, moderate, severe), overall impact on daily living, and duration of SC injection 
site reactions. 

Results of C1 INH antibody testing will be reported for individual subjects and summarized. 

Tolerability of icatibant therapy for acute angioedema attacks will be summarized.
PK/PD Endpoints: Plasma concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
and C1q for individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics for values at each time point. C1q concentrations will only be assessed 
at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic/pharmacodynamic 
(PK/PD)
parameters 
will 
be 
calculated 
using 
observed 
and 
baseline-corrected concentration-vs-time data using non-compartmental analysis for C1 INH antigen, functional 
activity, and C4 levels (as appropriate), and results will be summarized using descriptive statistics. The PK/PD 
properties of SC C1 esterase inhibitor [human] liquid for injection will be characterized by population PK/PD 
modeling, and exposure-response will be explored.
Blood samples collected from subjects for PD assessments may also be used for exploratory HAE biomarker 
assays.
Other Endpoints:

Results of the EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) health status instrument will 
be presented in accordance with the EQ-5D-5L user guide (Version 2.0). 

Results of the Work Productivity and Activity Impairment−General Health (WPAI-GH) questionnaire will 
be summarized. 

Results of the Sheehan Disability Scale (SDS) will be summarized.

Results of the survey of subject acceptability of SC administration of investigational product will be 
summarized.

Results of the survey of subject experience with self-administration of investigational product will be 
summarized. 


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STUDY SCHEDULES
Table 1
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a 13a
14a
15a
16a
17a
18a
19a 20a
21a
22a
23a
24a
25a
26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion 
criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj




j
Acceptability surveyk

Self-administration 
surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c, 
n
c, n
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4


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Table 1
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a 13a
14a
15a
16a
17a
18a
19a 20a
21a
22a
23a
24a
25a
26a
27a
28a
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; 
HRUA=health resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; 
PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health 
Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of 
the injection. Note: Vital sign measurements are not required at Visits 2a, 3a, and 4a for subjects self-administering investigational product without supervision (ie, assessment may 
not be possible).
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
g HIV (single assay antibody/INNO-LIA) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28a the overall impact on daily living (yes/no) and the 
duration of injection site reactions will be assessed for each subject.
k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack. 
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see 
Table 4).


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Table 2
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b 23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg




g
Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; 
INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan 
Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing 
days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.
Note: Vital sign measurements are not required at Visits 2b, 3b, and 4b for subjects self-administering investigational product without supervision (ie, assessment may not be 
possible).
d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28b, the overall impact on daily living (yes/no) and the duration 


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Table 2
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b 23b
24b
25b
26b
27b
28b
of injection site reactions will be assessed for each subject. 
h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site.


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Table 3
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits
Procedures
Early Discontinuation 
Visita
[If Applicable]
1-Week (±1 day)
Post-treatment 
Visit
[All Subjects]
1-Month (±2 days)
Post-treatment
Visit
[All Subjects]
Concomitant medications



Physical examination


Vital signs (BP, pulse)b


Safety labsc


UA with microscopy


Pregnancy testingd


Adverse events/ SAEs g



Angioedema attack monitoringe, f



AASe


Acceptability surveye

Self-administration surveye

AE-QoL questionnairee


EQ-5D-5Le


WPAI-GH and SDSe


HRUA-HAE

Immunogenicity (anti-C1 INH antibodies)



PK/PD



AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood 
pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level descriptive system; 
HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international normalized ratio; 
PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work 
Productivity and Activity Impairment-General Health Questionnaire
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits. 
b Vital signs will be measured using standard methods at each investigational site. 
c Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer).  
d A urine pregnancy test will be performed for all female subjects of childbearing potential.
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation and/or at 
the 1-week and 1-month post-treatment visits, as applicable.
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary.
g Serious Adverse Events (SAEs) are to be followed until 1-month post-treatment visit.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs that 
occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department.


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Table 4
Blood Sample Collection for PK/PD Analyses
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Pointsa
C1 INH Antigen, C1 INH Functional, C4
1a / Dose 1b
Predose 1 (within 15 min) 
2a / Dose 2c
Predose 2 (within 15 min)
8a / Dose 8
Predose 8 (within 15 min)
16a / Dose 16
Predose 16 (within 15 min) 
24a / Dose 24
Predose 24 (within 15 min)
Either 27a or 28a / Dose 27 or 28d
Predose 27 or 28 (within 15 min) 
48 hours postdose 27 or 28 (±3 hours)
TREATMENT PERIOD 2
1b / Dose 1
Predose 1 (within 15 min)
2b / Dose 2c
Predose 2 (within 15 min)
8b / Dose 8
Predose 8 (within 15 min)
16b / Dose 16
Predose 16 (within 15 min)
24b / Dose 24
Predose 24 (within 15 min)
28b / Dose 28
Predose 28 (within 15 min)
24 hours postdose 28 (±3 hours) – optional sampling time point
48 hours postdose 28 (±3 hours) 
72 hours postdose 28 (±6 hours) – optional sampling time point
96 hours postdose 28 (±6 hours)
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT
Early discontinuation
1-week (± 1 day)
1-month (± 2 days)
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for guidance 
is as an approximate value.
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a).
c Subjects who self-administer investigational product without supervision are not required to have a blood sample collected at 
Visit 2a or 2b.
d To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose 
sample to be collected at either Visit 27a or 28a.
Note: Blood samples collected from subjects for PD assessments may also be used for exploratory HAE biomarker assays.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Hereditary angioedema (HAE) is an autosomal dominant disease caused by a gene mutation on 
chromosome 11 that results in a quantitative or functional deficiency of C1 esterase inhibitor (C1 
INH) protein (Bernstein 2011). C1 INH is produced mainly by hepatocytes and acts as a “suicide 
inhibitor” by forming complexes with target serine proteases that result in their inactivation and 
the consumption of C1 INH. C1 INH regulates the activity of several components of the 
complement, contact (bradykinin-forming), and fibrinolytic systems (Kaplan 2010). 
Dysregulation of these cascades (particularly the contact system) due to C1 INH deficiency 
causes the uninhibited production of bradykinin, which promotes inflammation through 
increased vascular permeability and excessive accumulation of fluid in body tissues (Kaplan and 
Joseph 2010). Thus, patients with HAE are susceptible to recurrent episodes of debilitating 
swelling throughout the body. During acute angioedema attacks, the plasma levels of bradykinin 
in HAE patients can increase from 2 to 12 times (18.0–90.0 pM) the upper limit of normal (0.2-
7.1 pM; Cugno et al. 2003). Serum concentrations of C1 INH in patients with HAE are 5% to 
30% of normal (Cicardi et al. 1987), thus necessitating C1 INH replacement therapy to prevent 
manifestations of the disease.
The diagnosis of a C1 INH deficiency is suggested by a history that includes recurrent attacks of 
angioedema, characterized by non-itching swelling of the skin or mucosa. Serum C4, C1 INH
antigen, and functional C1 INH levels can be measured to assist with the diagnosis of HAE. 
There are 2 main types of HAE: Type I HAE (85% of cases), characterized by a low level of C1 
INH antigen, and Type II HAE (15% of cases), characterized by “normal” levels of functionally 
deficient C1 INH protein (Frank et al. 1976). There is no clinical difference between Type I and 
Type II HAE. A third form of HAE, where patients have normal C1 INH levels, was initially 
described and referred to as Type III (Bork et al. 2000a). Patients with this type of HAE, more 
frequently women, have normal complement levels (including normal C1 INH), but a well-
defined history of angioedema in the absence of concurrent urticaria (Zuraw and Christiansen 
2009; Bernstein 2011). Mutations in the gene for coagulation factor XII (F12) have been 
identified in a minority of affected families (Bork et al. 2007). There are subtle phenotypic 
differences between patients with HAE due to C1 INH deficiency and those with normal C1 INH 
levels, including age at symptom onset, attack location(s), period of disease-free intervals, and 
inheritance pattern (Zuraw et al. 2012). The pathogenesis of HAE with normal C1 INH remains 
to be fully elucidated.  
Hereditary angioedema with C1 INH deficiency can present as early as the first year of life 
(Ohela 1977; Farkas et al. 2002), however, the median age at onset of initial symptoms is 
between 9 and 12 years (Farkas et al. 2007). Nearly all affected individuals experience symptoms 
of the disease; however, the symptoms vary in both their frequency and severity throughout a 
patient’s lifetime (Gompels et al. 2005; Zuraw 2003). Angioedema attacks may or may not have 
a triggering event. Trauma, medical or dental procedures, psychological stress, menstruation, 
infections, oral contraceptive use, and the use of other medications, such as 
angiotensin-converting enzyme inhibitors have been identified as possible triggers (Georgy and 
Pongracic 2012; Bowen et al. 2010). Angioedema attacks can affect the face, tongue, larynx, 


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gastrointestinal tract, genitourinary system, and extremities (Zuraw 2008). Laryngeal swelling 
can occlude the airway and cause death by asphyxiation, and these attacks primarily account for 
the mortality risk associated with C1 INH deficiency (Agostoni and Cicardi 1992; Bork et al. 
2000b). Gastrointestinal involvement can mimic an acute surgical emergency, and misdiagnosis 
often results in unnecessary procedures to remove normal appendices and gallbladders (Weis 
2009). Hence, angioedema attacks require prompt treatment, often in an emergency room.  
In addition to the impact on physical and mental health, the burden of illness in patients with 
HAE is considerable with respect to missed educational and career opportunities, work 
productivity, and a substantial economic burden for the cost of treatment (Lumry et al. 2010; 
Aygören-Pürsün et al. 2014). Hereditary angioedema not only causes short-term disability 
associated with attacks, but patients endure long-term effects on their daily lifestyle, emotional 
health, family life, and it may also affect caregivers’ quality of life (Bygum et al. 2015). 
Effective management of HAE, including optimization of therapy, may reduce the clinical 
burden and have an overall favorable impact on the quality of life for individual HAE patients 
and their families (Banerji 2013; Caballero et al. 2014).
1.2
Product Background and Clinical Information
CINRYZE® (C1 esterase inhibitor [human]) was developed by the sponsor for the management of 
HAE. CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of C1 INH 
produced from human plasma. The manufacturing process includes 3 virus inactivation/removal 
steps: polyethylene glycol precipitation, pasteurization, and nanofiltration. CINRYZE is a normal 
human plasma protein that is not subject to cytochrome P450 metabolism, excretion, or 
pharmacokinetic (PK) drug-drug interactions exhibited by low molecular weight compounds. 
Intravenous (IV) administration of 1000 U of CINRYZE every 3 or 4 days is approved for routine 
prevention (prophylaxis) of angioedema attacks in patients with HAE in the United States 
(2008), European Union (2011), Australia (2012), Canada (2012), and Switzerland (2013). In 
several of these countries, CINRYZE is also approved for the acute treatment and preprocedure 
prevention of angioedema attacks.
The clinical efficacy of CINRYZE for the prevention of angioedema attacks in patients with HAE 
was demonstrated in 1 randomized, double-blind, placebo-controlled study (LEVP 2005-1/B) 
and 1 open-label study (LEVP 2006-4). Study LEVP 2005-1/B demonstrated that preventive 
therapy with CINRYZE resulted in both a statistically significant and clinically meaningful 
decrease in the rate, severity, and duration of acute attacks compared to placebo/on-demand 
therapy. Therapy with CINRYZE also increased antigenic C1 INH and functional C1 INH levels. 
These results were supported by Study LEVP 2006-4 (that provided data for longer periods of 
preventive therapy across a wider age range of subjects), which demonstrated a reduction in the 
frequency of attacks while on CINRYZE compared to a historical baseline. The open-label study 
also demonstrated that the efficacy of CINRYZE for the prevention of angioedema attacks did not 
diminish over time periods of at least 1 year. 
The sponsor initiated a clinical development program for subcutaneous (SC) administration of 
CINRYZE for prevention of angioedema attacks using the same lyophilized formulation as that 
approved for IV injection. The initial program focused on safety, tolerability, and relative 


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bioavailability of SC administration of CINRYZE (Studies 0624-100 and 0624-200). Preliminary 
assessments confirmed that CINRYZE can be absorbed after SC administration. However, because 
the exposure profile differed from that following IV administration, it was not known whether or 
to what extent SC administration would confer efficacy for the management of HAE.  
Based on results from nonsponsor studies conducted with recombinant human hyaluronidase 
(rHuPH20) and other injectable protein products, it was hypothesized that co-administration with 
rHuPH20 would increase dispersion and absorption of subcutaneously injected CINRYZE. 
Subsequently, the development program evaluated the safety, tolerability, 
PK/pharmacodynamics (PD), and efficacy of SC administration of CINRYZE with rHuPH20 
(Studies 0624-101, 0624-102, 0624-204, and 0624-206). However, in August 2013, the FDA 
directed the sponsor to stop administration of rHuPH20 in the ongoing Phase 2 study (0624-206) 
of CINRYZE with rHuPH20 due to the development of anti-rHuPH20 antibodies in some patients. 
Dosing was also terminated in an ongoing Phase 1 healthy volunteer study (0624-102) of 
CINRYZE with rHuPH20. Because the combination product (CINRYZE with rHuPH20) was being 
studied in these 2 trials, administration of CINRYZE was also discontinued. The FDA encouraged 
the sponsor to further the clinical development of CINRYZE alone administered via SC injection. 
Hence the evolution of the clinical development program with the new low volume, ready-to-use 
liquid formulation (C1 esterase inhibitor [human] liquid for injection) for SC administration. 
C1 esterase inhibitor [human] liquid for injection has been evaluated in an in vitro 
hemocompatibility assay using human blood and plasma, a tissue irritation study in New Zealand 
White rabbits, and a 14-day repeat-dose toxicity study in Sprague Dawley rats. Incubation with 
whole blood at a concentration of 225 IU/mL C1 esterase inhibitor [human] liquid for injection 
did not elicit hemolysis nor did the same concentration induce flocculation, precipitation, or 
coagulation. In the tissue irritation study in rabbits, microscopic examination of the injection 
sites showed minimal to mild inflammation that was most pronounced for perivascular injection 
route, followed by SC and then IV injection routes. In the 14-day repeat-dose study in rats, doses 
of 0 (sodium phosphate, glycine, and sorbitol), 200, 400, and 1000 IU/kg/day were administered 
subcutaneously once a day, while a fifth group of rats received 1000 IU/kg/day intravenously. 
The only signs of toxicity were related to the expected immunogenic response to a human 
protein. Therefore, the no observed adverse effect level is considered to be 1000 IU/kg/day of C1 
esterase inhibitor [human] liquid for injection for both the SC and IV routes of administration. 
Therefore, the toxicity profile for this ready-to-use liquid formulation is generally comparable to
the lyophilized product even when a higher dose of the new formulation was tested. 
An initial clinical assessment of the new liquid formulation was conducted in a Phase 1 study in 
healthy volunteers (SHP616-103). This study evaluated the safety, tolerability, and relative 
bioavailability of the SC administration of 1000 IU and 2000 IU C1 esterase inhibitor [human] 
liquid for injection compared with the marketed formulation of CINRYZE (1000 U IV). This 
single-center, open-label study consisted of a single-dose IV administration of CINRYZE
(lyophilized formulation) in Treatment Period 1 followed by a randomized, open-label, 2x2 
crossover design (Treatment Periods 2 and 3) to evaluate SC C1 esterase inhibitor [human] liquid 
for injection. The safety and pharmacokinetic results from Study SHP616-103 are presented in 
Sections 1.2.1.1 and 1.2.2.2, respectively.


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High-level summaries of the clinical experience with SC administration of both CINRYZE
(CINRYZE alone and CINRYZE + rHuPH20) and C1 esterase inhibitor [human] liquid for injection 
are provided below. Always refer to the latest version of the CINRYZE investigator’s brochure for 
the overall risk/benefit assessment and the most accurate and current information regarding the 
drug metabolism, pharmacokinetics, efficacy, and safety of CINRYZE and C1 esterase inhibitor 
[human] liquid for injection. 
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and with 
SC C1 Esterase Inhibitor [Human] Liquid for Injection
Studies that evaluated SC administration of CINRYZE alone and CINRYZE with rHuPH20 
provided valuable data that informed key elements of this Phase 3 study of C1 esterase inhibitor 
[human] liquid for injection. Both programs enrolled healthy volunteers and subjects with HAE; 
86 healthy volunteers (215 doses administered) and 72 subjects with HAE (1321 doses 
administered) have received 1 or more doses of SC CINRYZE in the development program to date 
(Table 5).
Table 5
Exposure to SC CINRYZE
Program
Study Number
Total Number of 
Subjects Exposed 
Number of SC Doses Administered
500 U
1000 U
2000 U
Total Doses
Healthy Volunteers
CINRYZE Alone
Study 0624-100a
9
1
0
14
15
Study 0624-102b
37 
0
37
0
37
CINRYZE with rHuPH20
Study 0624-101
24
0
0
47
47
Study 0624-102b
51 
0
116
0
116
Healthy Volunteers Total
86
1
153
61
215
Subjects with HAE
CINRYZE Alone
Study 0624-200
25
0
52
48
100
CINRYZE with rHuPH20
Study 0624-204
12 c
0
24
24
48
Study 0624-206
47
0
578
595
1173
Subjects with HAE Total
72
0
654
667
1321
OVERALL TOTAL
158
1
807
728
1536
HAE=hereditary angioedema; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
a CINRYZE via SC infusion and SC injection.
b A total of 53 subjects were enrolled in Study 0624-102 and received SC CINRYZE either alone (N=37) or co-administered with 
rHuPH20 (N=51).
c These 12 subjects received SC CINRYZE alone in Study 0624-200 and SC CINRYZE with rHuPH20 in Study 0624-204.


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1.2.1.1
Clinical Safety 
Across the 2 studies of SC CINRYZE alone (Studies 0624-100 and 0624-200), 9 healthy adults 
and 25 subjects with HAE received CINRYZE doses of 1000 U and/or 2000 U. In healthy adult 
subjects, a single dose of 2000 U CINRYZE administered via the SC route was associated with 
mild injection/infusion site discomfort; however, no subjects were discontinued from study drug 
due to an AE. In HAE subjects, multiple doses of CINRYZE (1000 U or 2000 U) administered via 
the SC route were associated with generally mild to moderate injection site reactions, most 
notably pain, which was commonly characterized as burning or stinging. No subjects were 
discontinued from study drug due to an injection site reaction. No SAEs occurred during either 
SC study, and no subjects experienced a TEAE that was thrombotic or thromboembolic in 
nature. In addition, in both studies of SC CINRYZE, results of clinical laboratory evaluations and 
vital signs measurements were generally unremarkable and did not suggest any treatment-
emergent abnormalities related to the administration of CINRYZE.
Across the 4 studies of SC CINRYZE + rHuPH20 (Studies 0624-101 0624-102, 0624-204 and 
0624-206), 77 healthy adults and 59 subjects with HAE received CINRYZE doses of 1000 U 
and/or 2000 U. No SAEs occurred, no subjects were discontinued due to an AE, and no subjects 
experienced a TEAE that was thrombotic or thromboembolic in nature. The most commonly 
reported AEs were mild-moderate injection site reactions (eg, erythema, swelling, pain). Other 
safety parameters (clinical laboratory evaluations and vital signs measurements) were generally 
unremarkable and did not suggest any treatment-emergent abnormalities related to the 
administration of SC CINRYZE + rHuPH20. 
In Study 0624-206, a total of 21 (45%) subjects had detectable anti-rHuPH20 antibodies during 
the study, with 15 (32%) of the 21 subjects having a post-baseline titer of >1:20. All samples 
from these subjects were determined to be negative for rHuPH20-neutralizing activity. As 
requested by the FDA, the sponsor followed subjects who had treatment-emergent titers of ≥1:20 
for 1 year post-treatment. There were no clinical sequelae observed in any subject and all titers 
declined during longitudinal follow-up. Three subjects in Study 0624-102 had reportable anti-
rHuPH20 antibodies at a titer ≥1:20; however, in all 3 cases, subjects had antibodies to rHuPH20 
present at baseline (prior to the first dose of study drug). Subjects were not asked to participate in 
longitudinal follow-up, as anti-rHuPH20 antibody titers remained at or below the baseline level 
for each subject by the end of the study. 
In Study SHP616-103, a total of 26 healthy volunteers were enrolled in the study. Twenty-three 
(23) subjects received a single SC dose of both 1000 and 2000 IU, and 1 subject only received a 
single SC dose of the 1000 IU C1 esterase inhibitor [human] liquid for injection. Therefore 24 
unique subjects have been exposed to 47 doses of C1 esterase inhibitor [human] liquid for 
injection.
Subcutaneous administration of 1000 IU and 2000 IU C1 esterase inhibitor [human] liquid for 
injection was generally well tolerated and the clinical safety data were consistent with previous 
CINRYZE IV or SC studies. Overall 19 (73.1%) of the 26 subjects reported at least 1 TEAE in the 
study: 62% (16/26), 29% (7/24), and 44% (10/23) of subjects administered 1000 U IV CINRYZE, 
1000 IU and 2000 IU of SC C1 esterase inhibitor [human] liquid for injection, respectively.


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With regard to the local tolerability of SC administration of 1000 IU and 2000 IU C1 esterase 
inhibitor [human] liquid for injection, there was no clear difference in the overall incidence of 
injection site reactions with respect to dose (1000 IU versus 2000 IU). Twenty-three of 24 
(95.8%) subjects reported injection site reactions, all were mild (58.3%) to moderate (37.5%) in 
severity, and the majority resolved within 2 hours postdose. The majority of reported reactions 
were erythema (mild or moderate) and a warm sensation (all mild).
1.2.1.2
Clinical Efficacy
The Phase 2 dose-ranging, crossover Study 0624-206 was designed to determine if there was a 
difference in efficacy between 2 SC doses of CINRYZE (1000 U and 2000 U co-administered with 
rHuPH20). The study was terminated before enrollment was complete (at the request of FDA 
due to the detection of anti-rHuPH20 antibodies in some subjects). Of the 47 subjects enrolled, 
22 completed both treatment periods. Thus, due to the early termination of the study, the final 
sample size of the intent-to-treat efficacy population was smaller than planned (22/47, 47%). 
Regardless, the statistical advantage of a crossover study is that patients serve as their own 
control and the relative effect of the experimental treatments can be determined most efficiently 
with respect to within-patient differences.
The experimental results favored twice weekly SC administration of CINRYZE 2000 U + 48,000 
U rHuPH20 compared with CINRYZE 1000 U + 24,000 U rHuPH20 for the primary and all 
secondary efficacy endpoints during treatment, most notably in the within-subject treatment 
comparison.
An analysis of primary and secondary efficacy endpoints during treatment was performed for the 
mean difference between treatments (2000 U – 1000 U SC CINRYZE), within subjects in a 
treatment sequence and overall, as shown below in Table 6.
For the primary endpoint of normalized number of angioedema attacks during treatment, a 
treatment effect favoring the 2000 U compared with the 1000 U SC CINRYZE dose was observed 
for the within-subject treatment comparison; the overall mean difference (95% confidence 
interval [CI]) between treatments was -0.61 (-1.23, 0.01) and achieved borderline significance 
(p=0.0523).
With regard to secondary efficacy endpoints, statistically significant (p<0.05) treatment effects 
favoring the 2000 U compared with the 1000 U SC CINRYZE dose were observed for the within-
subject treatment comparisons for both cumulative attack severity and for the number of attacks 
requiring acute treatment, with overall mean differences between treatments of -1.33 (p=0.0277) 
and -0.56 (p=0.0315), respectively.
No sequence effect was observed for the mean difference between the 2000 U and 1000 U SC 
CINRYZE doses within subjects in Sequences A/B or B/A for the primary or for any secondary 
endpoint (p-value for sequence effect across endpoints: ≥0.6290).
These findings indicated that CINRYZE at a dose of 2000 U SC was superior to a dose of 1000 U 
in terms of clinical efficacy improvement. The results are more compelling in light of their 
arising from truncated enrollment and consequently, an underpowered study.


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Table 6
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population (Study 0624-206)
Endpoints (Normalized)
Sequence A/B
Difference: B-A
N=12
Sequence B/A
Difference: B-A
N=10
Overall
Difference: B-A
N=22
Treatment
Comparison
p-valuea
Primary
Number of angioedema attacks
-0.72
(-1.71, 0.27)
-0.48
(-1.36, 0.40)
-0.61
(-1.23, 0.01)
0.0523
Secondary
Cumulative attack severity
-1.53
(-3.41, 0.35)
-1.09
(-2.74, 0.57)
-1.33
(-2.49, -0.16)
0.0277
Cumulative daily severity
-1.53
(-4.42, 1.36)
-2.19
(-6.06, 1.69)
-1.83
(-3.98, 0.32)
0.0912
Cumulative symptomatic days
-0.95
(-2.64, 0.74)
-0.87
(-3.35, 1.62)
-0.91
(-2.23, 0.41)
0.1660
Number of attacks requiring acute 
treatment
-0.67
(-1.20, -0.14)
-0.43
(-1.47, 0.62)
-0.56
(-1.06, -0.05)
0.0315
CI=confidence interval; ITT-E=intent-to-treat efficacy; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
Note: Data are presented as the mean (95% CI). Treatment A=1000 U SC CINRYZE + 24,000 U rHuPH20; Treatment B=2000 U 
SC CINRYZE + 48,000 U rHuPH20. Subjects who were dosed but did not have any attacks in the period were assigned a value of 
zero for each of the efficacy parameters. Only subjects who completed both treatment periods are included in the ITT-E 
population.
a p-value for paired t-test.
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid 
for Injection
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis of 
CINRYZE
Population PK and PK/PD modeling of C1 INH and C4 were developed based on data collected 
in 10 clinical studies with healthy volunteers and HAE patients who received IV or SC 
administrations of CINRYZE. Exposure-response analyses were performed based on 2 studies for 
the use of CINRYZE for the prophylactic treatment to prevent HAE. 
The final population PK model of C1 INH was a 1-compartment model with endogenous 
C1 INH levels. The absorption of CINRYZE following SC dosing was characterized with a 
first-order rate and relative absorption fraction (Frel). Based on the population PK model, the 
relative bioavailability of CINRYZE following SC dosing without rHuPH20 was 38.8%. Typical 
CL of C1 INH was 0.0864 L/h (1.44 mL/min) in HAE patients with a typical body weight of 70 
kg. The t1/2 of C1 INH in a typical 18.0, 36.6, and 80.0-year-old patient weighing 70 kg were 
32.0, 29.0, and 26.0 hours, respectively.
The effect of rHuPH20 on the rate and extent of absorption of C1 INH was included in the 
model. The use of rHuPH20 with SC administration appears to have little to no improvement on 
C1 INH exposure. This was illustrated in the Phase 1 study with healthy volunteers (Study 0624-
102) where CINRYZE 1000 U SC administered with 200, 2000, or 20,000 U rHuPH20 was not 


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statistically different in Cmax and AUClast compared with CINRYZE alone. In addition, the 
population PK model estimated only a 10% increase in bioavailability with rHuPH20, which 
reached saturation with increasing rHuPH20 concentrations as presented in Figure 1.
Figure 1
The Effect of Increasing rHuPH20 Concentration on Relative SC Bioavailability 
of C1 INH Functional Activity
C1 INH=C1 esterase inhibitor; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
The population PK model was used to support the assessment of the exposure-response 
relationship of CINRYZE during prophylactic treatment of angioedema attacks for C1 INH and 
C4. The response criterion originally used in Study 0624-400 was used to define responder 
status, whereby a response was defined as ≤1 angioedema attack/month, since this criterion has 
been deemed clinically meaningful by both expert clinicians and patients with HAE. A logistic 
regression model was used to link Cmin values of C1 INH (continuous) with the probability of 
response (binary) following IV dosing of 1000 U of CINRYZE in studies LEVP 2005-1/B and 
LEVP 2006-4 (Section 1.2). The exposure-response relationship of Cmin values of C1 INH 
following IV dosing of CINRYZE is presented in Figure 2.


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Figure 2
Exposure-response Relationship Following IV Dosing of CINRYZE (Probability 
of ≤1.0 Angioedema Attack/Month)
C1 INH=C1 esterase inhibitor; ROC=receiver-operating characteristic
Higher Cmin values of C1 INH were associated with a higher probability of response in patients 
with HAE (p<0.001). The above exposure-response relationship was to be used to predict the 
probability of response for any Cmin values of C1 INH in subjects with HAE. For example, 
typical Cmin values of 0.207, 0.289, 0.380, and 0.556 U/mL (corresponding to first, second, third, 
and fourth quartiles of Cmin of C1 INH, respectively) would be expected to result in response 
probabilities of 54.4%, 61.5%, 68.8%, and 80.5%, respectively. Typical C1 INH plasma 
functional activity levels in HAE patients range from 5–30% of normal (0.05-0.3 U/mL) (Cugno 
et al. 1990).
Receiver-operating characteristic analysis was used to identify an optimal Cmin cutoff of C1 INH 
that would optimize the probability of avoiding an angioedema attack. Based on data from study 
LEVP 2006-4 with IV administration of 1000 U CINRYZE approximately twice weekly, the 
optimal Cmin cutoff was 0.479 U/mL. When considering a 2-week period of delay, the optimal 
Cmin cutoff was 0.433 U/mL. Based on the above ROC analyses, a targeted C1 INH Cmin value of 
0.45 U/mL was used to determine the expected response following SC dosing of 2000 U of 
CINRYZE. Based on the exposure-response model, a C1 INH Cmin value of >0.45 U/mL would 
achieve at least a 70% probability of success (≤1 angioedema attack/month).
No statistically significant relationship was observed between minimum C4 concentrations and 
the probability of response.


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The combination of the population PK model and exposure-response relationship model was 
used to simulate C1 INH Cmin following SC dosing of CINRYZE to support the dosing rationale 
and improve the likelihood of success at achieving an efficacious dose in patients with HAE 
(Figure 3).
Figure 3
Simulated Concentration-time Profiles of C1 INH in Adult Patients with HAE –
Twice-weekly Dose Regimen
C1 INH=C1 esterase inhibitor; HAE=hereditary angioedema
From these simulations, results show that a dose of 2000 U would maintain mean (blue line) 
functional C1 INH Cmin values above the targeted level of 0.45 U/mL (red horizontal line).
In studies LEVP 2005-1/B and LEVP 2006-4, in which subjects with HAE received IV doses of 
1000 U CINRYZE approximately twice weekly, mean pre-infusion functional C1 INH 
concentrations ranged from 0.38-0.41 U/mL and 0.37-0.52 U/mL, respectively, during the 
treatment period. 
In the recent Phase 2 clinical study 0624-206, in which subjects with HAE received twice weekly 
SC doses of 1000 U CINRYZE with 24,000 U rHuPH20 or 2000 U CINRYZE with 48,000 U 
rHuPH20 in two 8-week crossover periods, higher exposure with the 2000 U CINRYZE dose was 
observed (Figure 4). The mean baseline-corrected Cmax and AUC0-168 of antigenic C1 INH for 
2000 U SC CINRYZE + 48,000 U rHuPH20 were 1.8- and 2.3-fold higher, respectively, compared 
to those observed for 1000 U SC CINRYZE + 24,000 U rHuPH20. The mean baseline-corrected 


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Cmax and AUC0-168 of functional C1 INH activity for 2000 U SC CINRYZE + 48,000 U rHuPH20 
were 2.0- and 2.6 fold higher, respectively, compared to their respective means for 1000 U SC 
CINRYZE + 24,000 U rHuPH20. The observed mean minimum concentration (Cmin) of functional 
C1 INH activity at steady-state for the 2000 U dose of SC CINRYZE with rHuPH20 was above the 
physiologically relevant level of 0.4 U/mL compared with 1000 U dose of SC CINRYZE with 
rHuPH20 (0.408 and 0.319 U/mL, respectively). 
Figure 4
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH Antigen 
(left) and Functional C1 INH Activity (right) vs. Time after SC Administration 
of CINRYZE with rHuPH20 in Subjects with HAE (Protocol 0624-206)
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid for 
Injection
In Study SHP616-103, new bioanalytical assays were developed and validated for the 
quantitative determination of C1 INH protein and functional binding of C1 INH in human 
plasma. These assays differed from those used in previous Cinryze SC studies to determine 
plasma concentrations of C1 INH antigen and functional C1 INH activity. 
Following SC administration of 1000 IU and 2000 IU C1 esterase inhibitor [human] liquid for 
injection, injected C1 INH was slowly absorbed with median tmax ranging from 36–48 hours for 
both C1 INH antigen and functional C1 INH binding. Mean baseline-corrected Cmax and 
AUClast PK parameters for both C1 INH antigen and functional C1 INH binding after IV and 
SC administration are shown in Figure 5 and Figure 6, respectively. 


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Figure 5
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Figure 6
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Subcutaneous administration of C1 esterase inhibitor [human] liquid for injection was less than 
dose proportional, with a 2-fold increase in dose resulting in 1.76- and 1.58-fold increase in Cmax
and AUClast respectively for C1 INH antigen, and 0.99- and 1.09-fold increase in Cmax and 
AUClast respectively for functional C1 INH binding. 
The baseline-corrected point estimates of the AUClast ratios and 90% confidence intervals for C1 
INH antigen and functional C1 INH binding was used to determine the relative bioavailability of 
1000 and 2000 IU C1 esterase inhibitor [human] liquid for injection with 1000 U IV CINRYZE.
The relative bioavailabilities for the 1000 IU and 2000 IU SC dose of C1 esterase inhibitor 
[human] liquid for injection were approximately 69% (44–110%) and 60% (38–95%) 
respectively for C1 INH antigen, and 67% (34–130%) and 39% (20–77%) respectively for C1 
INH functional binding (in non-HAE subjects).
1.2.2.3
Dose Selection
The approach for preventative therapy in HAE patients is to provide enough CINRYZE to achieve 
or exceed a threshold C1 INH functional activity concentration in plasma that has a >70% 


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likelihood of preventing an angioedema attack. The combined data from prior SC CINRYZE
studies (including the evaluation of bioavailability) along with the demonstration of similar 
bioavailability achieved in the completed Phase 1 single dose study of C1 esterase inhibitor 
[human] liquid for injection, support dose selection of 2000 IU C1 esterase inhibitor [human] 
liquid for injection for further evaluation in a Phase 3 study. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The sponsor has developed a new, ready-to-use liquid formulation of CINRYZE (C1 esterase 
inhibitor [human]). The CINRYZE liquid product (C1 esterase inhibitor [human] liquid for 
injection) is intended for the same indication as the licensed, lyophilized powder formulation of 
CINRYZE: routine prophylaxis against angioedema attacks in adolescent and adult patients with 
HAE. The route of administration will be SC injection, and the dosing regimen will be 2000 IU 
every 3 or 4 days. Shire ViroPharma anticipates that patients will benefit from the inherent 
advantages of SC administration, as well as the ready-to-use liquid, lower volume product 
compared with one requiring reconstitution. In addition, the CINRYZE liquid product is more 
concentrated than the licensed CINRYZE product (500 vs 100 U/mL), which should enable more 
rapid administration of the drug and may improve tolerability, without an expected change or 
compromise in efficacy.
The sponsor has selected 2000 IU of C1 esterase inhibitor [human] liquid for injection as the 
appropriate active dose for this Phase 3 study. This dose is based on the results of a recently 
completed Phase 2, randomized, double-blind, dose-ranging, crossover study that evaluated SC 
administration of CINRYZE with rHuPH20 (a dispersing agent) for the prevention of angioedema 
attacks in adolescents and adults with HAE (Study 0624-206). Results revealed greater clinical 
benefit with 2000 U of CINRYZE compared with 1000 U. In addition, the 2000 IU dose is 
supported by PK results from Study 0624-206, by the results of population PK and exposure-
response modeling, and by PK data from a Phase 1 study (0624-102) that demonstrated the 
minimal influence of rHuPH20 on functional C1 INH activity when co-administered with 
CINRYZE (Section 1.2.2.1). Finally, the 2000 IU dose is further supported by the PK and 
bioavailability data from the Phase 1 study of C1 esterase inhibitor [human] liquid for injection 
(Protocol SHP616-103).
The study design was chosen as the best way to jointly address the protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, adequate numbers of subjects for 
precision of estimation in detecting potential safety signals). Additionally, this design maximizes 
the number of patients exposed to C1 esterase inhibitor [human] liquid for injection and 
minimizes patient exposure to placebo while having adequate patient exposure to placebo to 
assess efficacy. Thus, the proposed study is described as a “partial” crossover because 
2 treatment sequences involve crossing over to the other experimental agent and the third 
sequence does not. All subjects will receive active treatment during this study and will have an 
overall two-thirds probability to be randomized to active drug in any treatment period.


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2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to demonstrate superior efficacy of SC administration of 
2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo based on the normalized number of attacks (NNA) during a treatment 
period.
2.2.2
Secondary Objectives
The key secondary objectives are to demonstrate the superior efficacy of SC administration of 
2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by:
1. The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA 
during the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo period.
2. The NNA during each treatment period excluding the first 2 weeks.
3. The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA for 
the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period relative to the 
placebo period excluding the first 2 weeks of each treatment period.
Other secondary objectives are:

To assess the proportion of responders during treatment with 2000 IU C1 esterase inhibitor 
[human] liquid for injection relative to treatment with placebo, where the proportion of 
responders is defined as achieving at least a 50% reduction in the NNA during a treatment 
period relative to the pretreatment assessment (ie, the subject’s attack rate without 
prophylactic treatment)

To assess the severity of angioedema attacks during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of attack-free days during treatment with 2000 IU C1 esterase inhibitor 
[human] liquid for injection relative to treatment with placebo 

To assess the number of angioedema attacks requiring acute treatment during treatment with 
2000 IU C1 esterase inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the safety and tolerability of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection

To assess the immunogenicity of SC administration of 2000 IU C1 esterase inhibitor [human] 
liquid for injection 

To characterize the PK and PD of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment 
of acute angioedema attacks (applicable for subjects ≥18 years of age)


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
To assess disease activity as measured by the Angioedema Activity Score (AAS) 

To evaluate subject experience with self-administration of SC 2000 IU C1 esterase inhibitor 
[human] liquid for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient population
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial 
crossover study (Figure 7). The design was chosen to optimally address the joint protocol 
objectives of establishing efficacy (relative to placebo) and safety (ie, enrolling an adequate 
number of subjects to have precision of estimation to detect or rule out safety signals). 
Additionally, this design maximizes the number of subjects exposed to C1 esterase inhibitor 
[human] liquid for injection and minimizes subject exposure to placebo, while having adequate 
subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have a 
history (based on subject recall and medical records) of ≥2 attacks per month on average per 
inclusion criterion #3. At least 66 eligible subjects will be randomized to 1 of 3 treatment 
sequences prior to the first dose of investigational product in Treatment Period 1 (ie, Dosing Day 
1a) using interactive response technology (IRT). Randomization of subjects will be stratified by 
use of prophylactic therapy with C1 INH at the time enrollment. 
Figure 7
Study Design Flow Chart


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Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission 
of a washout period is to minimize the duration that subjects will be without active treatment. It 
is recommended that the twice weekly dosing schedule (every 3 or 4 days) be maintained 
between the last dose of investigational product in Treatment Period 1 and the first dose of 
investigational product in Treatment Period 2. Every effort should be made to complete 
scheduled dosing and to avoid situations where investigational product is not received. In order 
to prevent a missed dose, a less than 3-day interval may occur, with the recommendation of 
allowing at least 24 hours between doses.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be 
blinded to treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be 
administered at the investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both 
treatment periods. Other doses may be administered by qualified blinded personnel at the 
investigational site or at the subject’s home or other agreed upon location or self-administered by 
the subject (adolescent or adult) with or without supervision (qualified home health professional
or study site personnel), after receiving appropriate training by the investigator or designee.
Adolescent subjects self-administering the investigational product will be supervised by a 
parent/legal guardian/caregiver (if home health professional and/or study site personnel is not 
present). Alternatively, a parent/legal guardian/caregiver after receiving appropriate training, will 
be allowed to administer the investigational product to an adolescent subject with or without 
supervision.
Throughout the study, an electronic subject diary will be used to record specific information 
regarding the subject’s symptoms of HAE and details on self-administration as described in 
Sections 7.2.2.2 and 6.5.1 respectively. Additionally, quality of life questionnaires and surveys 
on SC administration of the investigational product will be also subject evaluated. Note: For 
adolescent subjects, a parent/legal guardian/caregiver is allowed to assist the subject in 
completing the electronic subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days 
after the last dose of investigational product. This includes events occurring during the screening 
phase of the study, regardless of whether or not the investigational product is administered. In 
addition, the investigator will report all SAEs that occur through 30 days after the last dose of 
investigational product to Shire Pharmacovigilance and the respective Independent Reviewing
Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of the investigational product in Treatment Period 2 for follow-up safety assessments. In 
addition, subjects will have blood samples collected for PK/PD and C1 INH antibody testing at 1 
month (±2) days after the last dose of the investigational product.
If a subject prematurely discontinues investigational product, regardless of the reason, the early 
discontinuation visit safety procedures listed in Table 3 are to be performed as completely as 
possible. Whenever possible, all discontinued subjects should also complete the 1-week and 1-
month post-treatment visits. 


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3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 9 months. The 
study will be completed in approximately 15 months. 
The Study Completion Date is defined as the date the final subject, across all sites, completes
their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. The Study Completion Date is used to ascertain timing for study
results posting and reporting.
3.3
Sites and Regions
Approximately 40 sites globally (North America and Europe) are expected to participate in this 
study.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Be ≥12 years of age, or in Germany and Israel, be ≥18 years of age.
2. Have a diagnosis of HAE (Type I or II) and a functional C1 INH level less than 50% of 
normal.
3. Meet one of the following criteria (attack rate may be based on subject recall in conjunction 
with the subject’s medical records):

If subject is adult (>18 years of age) and currently receiving prophylactic therapy with C1 
INH, have a history of ≥2.0 angioedema attacks per month (average) during the 
3 consecutive months prior to starting prevention therapy. 
OR

If subject is adolescent (>12 and <18 years of age) or adult and not receiving prophylactic 
therapy with C1 INH, have a history of ≥2.0 angioedema attacks per month (average) 
during the 3 consecutive months prior to the screening visit.
OR

If subject is adult (>18 years of age) and currently receiving a stable dose of attenuated 
androgens, have a history of ≥2.0 angioedema attacks per month (average) during the 
3 consecutive months prior to the screening visit.
4. For subjects ≥18 years of age, be willing to receive treatment with icatibant for any 
angioedema attacks that occur during the study that, in the opinion of the healthcare care 
provider, require medical intervention. Note: For subjects ≥12 to <18 years of age, standard 
of care therapy per local protocols should be provided.


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5. Agree to adhere to the protocol-defined schedule of assessments.
6. If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) 
pregnancy test at the screening visit and must have a negative urine pregnancy test prior to 
the first dose of investigational product (Visit 1a), and agree to comply with any applicable 
contraceptive requirements of the protocol. 
7. If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, 
abstinence, barrier control) from the screening visit through 2 months after the last dose of 
investigational product.
8. If an adult (≥18 years of age), be informed of the nature of the study and provide written 
informed consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of 
the study provide written informed consent for the child to participate in the study before any 
study-specific procedures are performed (with assent from the child when appropriate). 
Alternatively, certain sites/Independent Reviewing Authorities may permit adolescents who 
are <18 years of age to be informed of the nature of the study and provide written informed 
consent without consent from a parent(s)/legal guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved 
dosing regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with C1 
INH (not applicable to Germany and Israel).
3.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose 
of the investigational product in Treatment Period 1.
4.
Have received any C1 INH therapy or any blood product for the treatment or prevention of 
angioedema attacks within 3 calendar days prior to the first dose of investigational product 
in Treatment Period 1.
5.
If female, have started or changed the dose of any hormonal contraceptive regimen or 
hormone replacement therapy (ie, estrogen/progestin containing products) within 
2 months prior to the screening visit.
6.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism. 
7.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies. 
8.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), other blood products, or Firazyr (icatibant). 
9.
Be pregnant or breastfeeding. 


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10.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
11.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical 
or medical condition (including positive for hepatitis B, hepatitis C, or HIV infection; 
alcohol, drug, or medication abuse within 1 year before screening; or mental condition 
rendering the subject or parent(s)/legal guardian unable to understand the nature, scope of 
the study, and possible consequences of the study), or relationship to study staff or sponsor 
(including people accommodated in an institution as well as people who are dependent on 
the sponsor, CRO, site or the investigator) that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following 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 and 30 days following the last dose of investigational 
product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and aged 51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
Screening Visit and a negative urine pregnancy test prior to randomization (predose at 
Visit 1a). Females of childbearing potential must agree to abstain from sexual activity that
could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)
(Note: double-barrier methods are not an acceptable form of contraception in Germany)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 2 months prior to the Screening Visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods noted 
above in addition to a hormonal contraceptive for 30 days.


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4.3.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 2 months after the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible. If the sponsor discovers conditions arising during the study that are 
unexpected, are significant, or pose an unacceptable risk to patients, mandatory discontinuation 
of the investigational product will occur.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Early Discontinuation Visit (Section 7.1.4) are to be performed as completely as possible. 
Whenever possible, all discontinued subjects should also complete the 1-week and 1-month Post-
treatment visits. Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination, date of stopping investigational 
product, and the total amount of investigational product taken must be recorded in the case report 
form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow up

Lack of efficacy

Other (specify; in Germany, must indicate if mandatory reason [see Section 4.4]) 
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 


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these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
4.4.3
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, investigational product will be discontinued, 
and the subject will follow the schedule of assessments for early discontinuation (Table 3).
Subjects already enrolled will continue with study drug administration and procedures. 
4.4.4
Thrombotic or Thromboembolic Event
If a thrombotic/thromboembolic (T/TE) event occurs in any subject, no further enrollment will 
occur pending a complete review of all available data. Already enrolled subjects will continue 
with investigational product administration and study procedures. Following a safety review of 
the T/TE event, study enrollment may be restarted if the medical monitor determines that the 
event was unrelated or unlikely to be related to investigational product or other C1 inhibitors, 
which may have been administered for an angioedema attack. Unblinding of the randomization 
code for that subject may be required (see below).
If a T/TE event occurs in any subject, investigational product administration for that subject will 
be discontinued (in Germany) or interrupted (in other countries); however, other study 
procedures will continue, as clinically appropriate. Diagnosis and management of all suspected 
T/TE events should be per local standard of care; Appendix 4 and Appendix 5 present a 
suggested medical algorithm for diagnosis and management of such conditions. Investigators 
must also comply with all reporting and/or procedures for AEs/SAEs as indicated in the 
suggested algorithm. Following a complete medical review by the sponsor in conjunction with 
the investigator, and if determined safe to do so, dosing with investigational product may be 
resumed (in all countries except Germany) to complete a total of 28 doses in the treatment period 
that was interrupted. Study procedures, including PK/PD testing, will resume relative to dosing. 
If investigational product cannot be restarted within 30 days of the temporary interruption, the 
subject will be discontinued from treatment and will follow the schedule of assessments for early 
discontinuation (Table 3). If unblinding is required, a physician external to the study will review 
relevant safety information, including the subject’s assigned treatment. The unblinded physician 
will relay his or her findings and recommendations to the medical monitor, exercising caution 
not to reveal the subject’s randomization to anyone associated with the conduct of the study.
5.
PRIOR AND CONCOMITANT TREATMENT
Prior and concomitant medications that will be recorded on the appropriate CRF page include 
prescription medications, blood products (eg, albumin, packed red blood cells, whole blood, 
fresh frozen plasma, platelets), dietary supplements/vitamins, electrolyte supplementation, and 
over-the-counter medications. Topical medications (non-prescription) will be recorded only if 
used as treatment for an AE.


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5.1
Prior Treatment
Any therapy received during the 12 months prior to randomization for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and the 
HAE indication (ie, acute treatment, long-term prevention, short-term [preprocedural] 
prevention).  
In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the CRF.
5.2
Concomitant Treatment and Medical/Surgical Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the 1-month post-treatment visit, inclusive. All prescription and over-
the-counter medications being taken by subjects during this time period are regarded as 
concomitant treatments. For any medication that is administered, the investigator will document 
the drug name, amount, route of administration, frequency, and duration administered, as well as 
the reason for administering the medication on the appropriate CRF page.
Elective procedures should be postponed, where possible. Medical/surgical procedures 
performed during the study will be recorded on the CRF, along with the date, time, and reason 
for the procedure. Pre-procedure prophylaxis may be provided (and documented as outlined 
above) if medically indicated and according to local standard of care.
5.2.1
Management of Angioedema Attacks 
If a subject (≥18 years of age) experiences an acute angioedema attack at any time during the 
study that in the opinion of the investigator requires medical intervention, icatibant should be 
administered to treat the attack. Commercial icatibant labeled for clinical trial use will be 
supplied in a single-dose pre-filled glass syringe delivering 3 mL of solution containing 30 mg 
icatibant and should be stored at or below 25°C (must not be frozen). Icatibant is to be 
administered by the SC route in the abdominal area. The entire volume in the syringe should be 
administered and the injection should occur over at least 30 seconds. If response is inadequate or 
symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 
hours. Do not administer more than 3 injections in 24 hours. The subject will be allowed to self-
administer icatibant if already trained by a health care provider or after receiving instructions on 
the use and appropriate training by study site personnel or a qualified home health professional. 
If a laryngeal attack occurs (ie, swelling of the airways), the subject should inject icatibant and 
proceed immediately to the nearest medical care facility. If it is the opinion of the investigator 
that the subject still needs medication for his/her acute angioedema attack after icatibant 
administration, then other standard of care therapy (eg, C1 INH, ecallantide) may be provided 
per locally approved product information. 
For subjects ≥12 to <18 years of age (not applicable to Germany and Israel), standard of care 
therapy per local protocols should be provided, such as (where approved for adolescents) C1 
esterase inhibitor (human), C1 esterase inhibitor (recombinant), and ecallantide. 


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The determination of the necessity for therapy to alleviate subject symptoms will be at the
discretion of the investigator. Administration of investigational product and study procedures 
will continue without alteration to the protocol schedule, even if a subject receives any treatment 
for an angioedema attack.
For all medications (including fluids, anti-emetics, analgesics) associated with management of 
acute angioedema attacks, study personnel will record start/stop dates, time of administration, 
dose, unit, frequency, and route of administration in the subject’s CRF page. Adverse events 
associated with medications used in the treatment of acute angioedema attacks will be captured 
on the AE CRF and attributed to the concomitant medication administered (Section 8.1.2). 
Adult subjects receiving long-term prophylaxis with C1 INH prior to randomization may be 
randomized to treatment sequences that contain a placebo treatment period (ie, A/B or B/A); 
such subjects remain eligible for on-demand therapy as outlined above.  If, after receipt of at 
least 3 weeks of investigational product, the subject’s quality of life significantly deteriorates and 
interferes with daily living routines, and the subject experiences a 2-fold increase in attack 
frequency with greater severity (relative to the subject’s baseline without  prophylaxis), 
following discussion of the investigator with the sponsor, subject may be discontinued from the 
treatment.  
The investigator will be responsible for entering information about the subject’s discontinuation 
from study drug in the CRF and where applicable, perform study related procedures as outlined 
in Table 3. The investigator will also ensure the subject receives appropriate treatment based on 
the subjects past HAE treatment and according to local standard of care.  Angioedema attacks 
will not be considered AEs; however, events satisfying the serious criteria should be recorded as 
a SAE and reported to Shire Pharmacovigilance (Section 8.1.4). Data on angioedema attacks will 
be collected separately from general reports of AEs and will be used in the evaluation of efficacy 
(Section 7.2.2). In addition, if applicable, subjects will record their response to icatibant therapy 
when used for treating an angioedema attack, as well as any associated side effects or tolerability 
issues. This information will be recorded in the electronic subject diary (Section 7.2.2.4).
5.2.2
Prohibited Treatment
Use of C1 INH therapy (other than investigational product) for prophylaxis against angioedema 
attacks is prohibited during this study (from the first dose of investigational product through the 
1-month post-treatment visit). 
The initiation of androgen therapy is prohibited during the study (from the first dose of 
investigational product through the 1-month post-treatment visit). 
5.2.3
Nonpharmacologic Treatments and Procedures
To the extent possible, subjects will postpone elective procedures (eg, dental work) while 
participating in the study. In the event a procedure cannot be postponed, the subject will record 
this information in the subject diary and notify the site. Pre-procedure prophylaxis may be 
provided if medically indicated and according to local standard of care. 


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Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
during the treatment periods, as well as any medications associated with the procedure, will be 
recorded in the eCRF (see Section 5.2).
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is C1 esterase inhibitor [human] liquid for injection, which is supplied in clear 
glass vials containing 1000 IU of C1 INH in 2 mL of sterile liquid. The solution also contains the 
following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for injection.
The reference product is placebo, which is supplied in an identical 2 mL presentation as the 
active investigational product minus the C1 INH protein. The inactive ingredients in the solution 
are the same as the active drug product: sodium phosphate, sorbitol, glycine, and water for 
injection.
No reconstitution or dilution is required for the test or reference product. Vials must be stored at 
2–8oC (36–46oF) and protected from light.
Instructions for handling of investigational product and for SC injection site selection and 
preparation are provided in Appendix 1 and Appendix 2, respectively.
Commercial icatibant labeled for clinical trial use will be supplied as rescue medication for the 
treatment of acute angioedema attacks (Section 5.2.1).
6.2
Administration of Investigational Product
Blinded investigational product (C1 esterase inhibitor [human] liquid for injection or placebo) 
will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate 
treatment periods. Every effort should be made to complete scheduled dosing and to avoid 
situations where investigational product is not received. In order to prevent a missed dose, a less 
than 3-day interval may occur, with the recommendation of allowing at least 24 hours between 
doses. The contents of 2 vials of investigational products (a total volume of 4 mL) will be drawn 
into a silicone-free syringe for each SC injection. Following appropriate SC injection site 
selection and preparation (Appendix 2), the needle will be inserted in the subject’s abdominal 
area in order to administer the SC injection as quickly as tolerated by the subject. 
Investigational product will be administered at the investigational site for Dosing Visits 1, 8, 16, 
24, and 28 during both treatment periods. Other doses may be administered by qualified blinded 
personnel at the investigational site or at the subject’s home or other agreed upon location or 
self-administered by the subject (adolescent or adult) with or without supervision (qualified 
home health professional and/or study site personnel), after receiving appropriate training by the 
investigator or designee. Adolescent subjects self-administering investigational product will be 
supervised by a parent/legal guardian/caregiver (if a qualified home health professional and/or 
study site personnel is not present). Alternatively, a parent/legal guardian/caregiver after 


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receiving appropriate training will be allowed to administer the investigational product to an 
adolescent subject with or without supervision.
6.3
Allocation of Subjects to Treatment Sequence
This is a double-blind, placebo-controlled, 2-period, 3-sequence, partial crossover study. At least 
66 eligible subjects will be randomized to 1 of 3 treatment sequences (Table 7) prior to the first 
dose of investigational product in Treatment Period 1. The actual treatment sequence given to 
individual subjects is determined by a randomization schedule automatically assigned by the 
IRT. 
Table 7
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects 
Randomized
1
A/B
26
2
B/A
26
3
A/A
14
Treatment A=2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly 
(every 3 or 4 days) for 14 weeks. 
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
level of use of prophylactic therapy with C1 INH across sites, the subject number is assigned to 
subjects according to the sequence of presentation for study participation. Subject number is 
unique within a protocol.
The randomization number represents a unique number corresponding to treatment sequence 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IRT at the baseline visit (predose Visit 1a) after subject eligibility has been 
confirmed using the randomization criteria. The randomization schedule will be stratified for use 
of prophylactic therapy with C1 INH at the time of enrollment versus no prophylactic therapy 
with C1 INH at the time of enrollment. Subjects will be randomized to the treatment sequence 1 
(A/B), 2 (B/A), or 3 (A/A) in the randomization ratio of 2:2:1. 
The subject’s treatment sequence will be held in strict confidence. The treatment sequence for an 
individual subject may be broken in cases of emergency or for reasons of subject safety, as 
described in Section 6.4.1.
6.4
Blinding of Treatment
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence. 


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To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo will have an 
identical presentation, including its packaging and labeling, such that the contents of the glass 
vials within the prepackaged study kits will be indistinguishable from each other. As described in 
Section 6.6, investigational product will be identified only by a unique study drug kit number. 
Each prepackaged study kit will contain 2x2 mL vials of investigational product (a total volume 
of 4 mL), which will be required to be drawn into a silicone-free syringe for each SC injection. If 
possible, a different individual should draw up the investigational product into the syringe than 
the individual administering the SC injection to the study subject. 
Knowledge of the PK/PD data would compromise the study blind. As such, the independent 
external laboratory performing the PK/PD analyses will keep the results in strict confidence until 
the study is unblinded.
Additionally, a limited number of representatives of the sponsor responsible for the IRT and 
product labeling will be unblinded to treatment assignment in order to review drug accountability 
on an ongoing basis throughout the study (Section 6.7).
6.4.1
Unblinding the Treatment Assignment
The randomization code for an individual subject may only be broken by the investigator or the 
sponsor for reasons of subject safety or in an emergency when knowledge of the product 
administered would be important for the treatment of the subject. If the blind is broken by the 
investigator, he/she must notify the Shire ViroPharma Medical Monitor immediately and must 
document the date, time, and reason for the code break in a note to file.
6.5
Treatment Compliance
Investigational product will be administered either by study site personnel or a qualified home 
health professional or may occur under their direct supervision for subjects (or parent/legal 
guardian/caregiver) who elect to self-administer during Treatment Periods 1 and 2 (Section 6.2). 
Therefore, full subject compliance with treatment is expected in this study.
6.5.1
Self-Administration
Instruction for subjects who elect to self-administer investigational product (or when needed, 
icatibant as rescue medication; see Section 5.2.1) with or without supervision (qualified home 
health professional and/or study site personnel), after receiving appropriate training by the 
investigator or designee will include:

Transportation and recommended storage conditions of investigational product from the 
study site to the home location.

Maintenance of accurate records regarding each administration of investigational product
including supply identification (ie, lot/kit number), date and time of injection, and if for any 
reason the SC injection could not be completed as instructed.

Retention of all used and unused vials of investigational product for drug accountability 
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6.6
Packaging and Labeling
C1 esterase inhibitor [human] liquid for injection and placebo will be packaged and labeled such 
that the products will be indistinguishable from each other by the investigator, study site 
personnel, home health professionals, and subjects.
Investigational product will be supplied in a prepackaged study kit. Each study kit will contain 2 
vials of investigational product (C1 esterase inhibitor [human] liquid for injection or placebo). 
Both the vials and carton (kit) will be appropriately labeled according to local regulations and 
bear the unique study drug kit number.  
The investigative site will also be provided with ancillary supplies including silicone-free 
syringes and needles. The site has the option of using needles of a different gauge to aid subject 
comfort with each SC injection.
Subjects who elect to self-administer investigational product will be provided the following 
supplies at the investigational site:

4-week supply (8 study kits) of investigational product 

Ancillary supplies, including silicone-free syringes, needles, and a container for sharps
disposal

Transport container for investigational product

Subject accountability log to record investigational product storage conditions and 
administration details
All used and unused vials should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability.
Written instructions on investigational product and self-administration procedures will be 
provided to subjects at the screening or first dosing visit (Visit 1a). Refer to the Pharmacy 
Manual for additional details on the investigational product and its administration. 
6.7
Storage and Accountability
Investigational product will shipped refrigerated to the study site at 2–8oC. Vials of 
investigational product must be stored at 2–8oC (36–46oF) and protected from light. Do not 
freeze investigational product.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log. The date and time of administration of the investigational product must be documented on 
the appropriate CRF.
The principal investigator, study site personnel, or qualified home health professional must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 


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loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.
6.8
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an investigational product 
returns process/policy, the sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the site regulatory binder.
If the investigational product is to be destroyed by the sites, sites must follow their own 
process/policy that describes such activities. Sites must retain copies of these documents within 
the site regulatory binder. Sites must ensure that the clinical trial material accountability and 
destruction log is complete, accurate, and ready for review and/or audit at each monitoring visit.
All manifests documenting shipments of investigational product must be retained, as well as 
copies of any investigational product return forms.
Refer to the Pharmacy Manual for additional details.
7.
STUDY PROCEDURES
Subjects may be enrolled in the study after the nature and purpose of the protocol has been 
explained, written informed consent to participate has been voluntarily granted, and the 
eligibility criteria listed in Sections 4.1 and 4.2 have been met.
7.1
Study Schedule
Table 1 (Treatment Period 1), Table 2 (Treatment Period 2), Table 3 (early discontinuation visit, 
1-week and 1-month post-treatment follow-up visits), and Table 4 (blood sample collection for 
PK/PD Analyses) provide the timing of all study procedures and assessments. 
7.1.1
Screening Period
Informed consent must be obtained before any study-specific procedures are performed. Note 
that AEs will be collected from the time of informed consent through 7 days after the last dose of 
investigational product.
Subjects will have all screening procedures completed within 21 days prior to the first dose of 
investigational product (Visit 1a=Dosing Day 1) according to Table 1. The following procedures 
will occur:

Informed consent/assent

Adverse events (collection begins from the time of informed consent through 7 days after the 


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last dose of investigational product)

Inclusion/exclusion criteria

Medical history (includes HAE history with the documentation of attack rate for study entry 
criteria and if applicable, determination of C1 INH antigen level and/or C1 INH functional 
activity, Section 7.2.3.1)

Physical examination

Clinical laboratory testing (biochemistry, hematology, coagulation)

Virology screening 

Vital signs

ECG

Height and weight

Serum pregnancy test (in females of childbearing potential)

Recording of prior and concomitant medications
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 
7.1.2
Treatment Period 1
7.1.2.1
Visit 1a (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product at Visit 1a:

Collection of AEs

Randomization

Physical examination

Vital signs (≤30 min before the start of injection)

Clinical laboratory testing (biochemistry, hematology, coagulation)

Urinalysis testing with microscopy

Urine pregnancy test (in females of childbearing potential)

Recording of concomitant medications (needed for confirmation of subject eligibility)

PK (C1 INH antigen, C1 INH functional, [includes measurement of C1q]) and PD (C4) 
sampling (within ≈15 min)

Immunogenicity (anti-C1 INH antibody)

Angioedema quality of life (AE-QoL) questionnaire, EuroQol 5-dimensional 5-level 


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descriptive system (EQ-5D-5L), Work Productivity and Activity Impairment-General Health 
(WPAI-GH) questionnaire, and Sheehan Disability Scare (SDS) assessments recorded in the 
electronic subject diary

Health resource utilization assessment (HRUA)-HAE
7.1.2.2
Visit 1a (postdose)
The following procedures will be performed after the administration of the first dose of 
investigational product at Visit 1a:

Collection of AEs

Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack (and the subject diary is to be updated daily; Section 7.2.2.2).

Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)

Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the injection)

Recording the daily AAS in the electronic subject diary
7.1.2.3
Visit 2a through Visit 28a
The following procedures will be performed throughout Treatment Period 1 at the visits 
indicated below:

All concomitant medication and AEs will be recorded at each visit (2a-28a)

Recording in the electronic subject diary daily any symptoms or occurrences of an 
angioedema attack (Visits 2a-28a)

Recording the daily AAS in the electronic subject diary (Visits 2a-28a)

Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2a, 3a, 4a, 8a, 16a, 24a, 28a). Note:  Vital sign measurements are not required at 
Visits 2a, 3a, and 4a for subjects self-administering investigational product without 
supervision (ie, assessment may not be possible).

Physical examination (Visits 8a, 16a, 24a, 28a)

Investigational product will be administered at each visit (2a-28a); Visits 8a, 16a, 24a, and 
28a must occur at the investigational site. 

Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at Visits 8a, 16a, 24a, and 28a. At Visit 28a, the 
overall impact of injection site reactions on daily living (yes/no) and duration will be 
assessed.

Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8a, 16a, 24a, 
and 28a

Urinalysis testing with microscopy at Visit 28a


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
Acceptability and self-administration survey assessment (recorded in the electronic subject 
diary) at Visit 28a

Quality of life assessments recorded in the electronic subject diary: AE-QoL (Visits 9a, 17a, 
25a), EQ-5D-5L (Visit 24a and on each day that a subject experiences signs or symptoms of 
an angioedema attack), and WPAI-GH and SDS (Visits 3a, 5a, 7a, 9a, 11a, 13a, 15a, 17a, 
19a, 21a, 23a, 25a, 27a)

HRUA-HAE (Visits 8a, 16a, 24a)

Immunogenicity (anti-C1 INH antibody) (predose Visits 8a, 16a, 24a, 27a or 28a)

PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2a, 8a, 16a, 
24a, 27a or 28a [within ≈15 min], and 48 h postdose Visits 27a or 28a [±3 hours]). Note: A 
predose Visit 2a blood sample is not required for subjects self-administering investigational 
product without supervision (ie, sample collection may not be possible).
7.1.3
Treatment Period 2
7.1.3.1
Visit 1b (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product in Treatment Period 2 at Visit 1b:

Collection of AEs

Physical examination

Vital signs (≤30 min before the start of injection)

Clinical laboratory testing (biochemistry, hematology, coagulation)

Urinalysis testing with microscopy

Urine pregnancy test (in females of childbearing potential)

Recording of concomitant medications 

PK (C1 INH antigen, C1 INH functional) and PD (C4) sampling (within ≈15 min)

Immunogenicity (anti-C1 INH antibody) blood sample collection

AE-QoL, EQ-5D-5L, WPAI-GH, and SDS assessments recorded in the electronic subject 
diary

HRUA-HAE
7.1.3.2
Visit 1b (postdose)
The following procedures will be performed after the administration of investigational product at 
Visit 1b:

Collection of AEs

Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
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
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)

Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the injection)

Recording the daily AAS in the electronic subject diary
7.1.3.3
Visit 2b through Visit 28b
The following procedures will be performed throughout Treatment Period 2 at the visits 
indicated below:

All concomitant medication and AEs will be recorded at each visit (2b-28b)

Recording in the subject diary daily any symptoms or occurrences of an angioedema attack 
(Visits 2b-28b)

Recording the daily AAS in the subject diary (Visits 2b-28b)

Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2b, 3b, 4b, 8b, 16b, 24b, 28b). Note:  Vital sign measurements are not required at 
Visits 2b, 3b, and 4b for subjects self-administering investigational product without 
supervision (ie, assessment may not be possible).

Physical examination (Visits 8b, 16b, 24b, 28b)

Investigational product will be administered at each visit (2b-28b); Visits 8b, 16b, 24b, and 
28b must occur at the investigational site. 

Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at Visits 8b, 16b, 24b, and 28b. At Visit 28b, the 
overall impact of injection site reactions on daily living (yes/no) and duration will be 
assessed.

Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8b, 16b, 24b, 
and 28b

Urinalysis testing with microscopy at Visit 28b

Quality of life assessments: AE-QoL (Visits 9b, 17b, 25b), EQ-5D-5L (Visit 24b and on each 
day that a subject experiences signs or symptoms of an angioedema attack), and WPAI-GH 
and SDS (Visits 3b, 5b, 7b, 9b, 11b, 13b, 15b, 17b, 19b, 21b, 23b, 25b, 27b) recorded in the 
electronic subject diary

HRUA-HAE (Visits 8b, 16b, 24b)

Acceptability survey and self-administration survey (recorded in the electronic subject diary) 
assessments at Visit 28b

Immunogenicity (anti-C1 INH antibody) (predose Visits 8b, 16b, 24b, 28b)

PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2b, 8b, 16b, 
24b, and 28b [within ≈15 min], and 24 hours (±3 hours) (optional time point), 48 hours 
(±3 hours), 72 h (±6 hours) (optional time point), and 96 hours (±6 hours) postdose Visit 


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28b). Note: A predose Visit 2b blood sample is not required for subjects self-administering 
investigational product without supervision (ie, sample collection may not be possible).
7.1.4
Early Discontinuation Visit
If a subject prematurely discontinues from investigational product, the following procedures are 
to be performed as completely as possible:

All concomitant medications and any new or ongoing AEs will be recorded

Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of discontinuation 
and/or at the 1-week and 1-month post-treatment Visits, as applicable

Recording the daily AAS in the electronic subject diary

Vital signs

Physical examination

Clinical laboratory testing (biochemistry, hematology, coagulation)

Urinalysis testing with microscopy

Urine pregnancy testing

Acceptability survey and self-administration survey (recorded in the electronic subject diary) 
assessments

AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments

PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)

Immunogenicity (anti-C1 INH antibody) 
7.1.5
Follow-up Period
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of investigational product for follow-up safety assessments (Table 3). The following 
procedures will occur:

All concomitant medications and any new or ongoing AEs will be recorded

Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of discontinuation 
and/or at the 1-week and 1-month post-treatment Visits, as applicable

Recording the daily AAS in the electronic subject diary

Vital signs

Physical examination

Clinical laboratory testing (biochemistry, hematology, coagulation)

Urinalysis testing with microscopy


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
Urine pregnancy testing

AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments

PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)

Immunogenicity (anti-C1 INH antibody) 
A second post-treatment visit will occur at the investigative site 1 month (±2 days) after the last 
dose of investigational product. The following procedures will occur:

All concomitant medications will be recorded

Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of discontinuation 
and/or at the 1-week and 1-month post-treatment Visits, as applicable

HRUA-HAE

PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)

Immunogenicity (anti-C1 INH antibody) 
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational 
product and related SAEs that occur >30 days after the last dose of investigational product to the 
Shire Pharmacovigilance Department.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic details, medical history (including HAE history, Section 7.2.3.1), prior and 
concomitant medication data, vital signs, height, weight, physical examination, 12-lead ECG, 
biochemistry, hematology, coagulation, virology screening, and serum β-hCG pregnancy test 
will be collected at the time of enrollment at the Screening Visit. 
7.2.2
Efficacy
Analyses of the efficacy endpoints in this study require documentation of specific information 
regarding the subject’s symptoms of any angioedema attacks they may experience during the 
study. 
7.2.2.1
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported indication of swelling or pain at 
any location following a report of no swelling or pain on the previous day (ie, there must be a 
full symptom-free calendar day preceding the onset of symptoms for an attack to be considered a 
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
Attacks that progress from 1 site to another will be considered a single attack 

Attacks that begin to regress and then worsen before complete resolution will be considered 1 
attack 

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar day 
reported after the appearance of resolution will also be considered 1 attack 
Note: An angioedema attack does not include swelling due to trauma, arthritis, or symmetrical 
nonpainful swelling of the lower extremities.
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary
During the study, subjects will use an electronic subject diary each day to record any symptoms 
or occurrences of an angioedema attack. The investigator will complete a separate angioedema 
attack CRF for each attack based upon their review of the data in the subject diary. Information 
will include the following:

Date and time of onset and complete resolution of angioedema attack symptoms

Characterization of whether swelling or pain is (indicate all that apply):
Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)
Non-mucosal (truncal, extremity, facial)

Location (site) of the swelling or pain (indicate all that apply):
Upper airway (includes laryngeal or pharyngeal)
Note: Pharyngeal or oral swelling that results in airway compromise will be 
classified as a laryngeal attack.
Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)
Genitourinary (including scrotum or vulva)
Cutaneous (facial)
Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, 
trunk])

Severity (intensity) of the sign/symptom at each location listed:
Absent
Mild: the angioedema attack sign/symptom(s) is noticeable but is easily tolerated 
by the subject and does not interfere with routine activities.
Moderate: the angioedema attack sign/symptom(s) interferes with the subject’s 
ability to attend work/school or participate in family life and social/recreational 
activities.


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Severe: the angioedema attack sign/symptom(s) significantly limits the subject’s 
ability to attend work/school or participate in family life and social/recreational 
activities.

Visual Analogue Scale (VAS) pain measurement score

Angioedema attack trigger(s)

Answer to the question, “Was treatment administered for the attack?” If yes, record the date, 
time, and name of treatment administered.
7.2.2.3
Angioedema Activity Score
Subject self-assessment of disease activity will be assessed daily by the AAS. Subjects will 
respond to questions in the electronic subject diary about any swelling episode that has occurred 
within the previous 24 hours. Each AAS item (or question) is scored between 0 and 3 points, 
with the minimum and maximum daily AAS ranging between 0 and 15 points (Weller et al. 
2013).
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks
Efficacy endpoints are based on subject-assessed symptom improvement as a measure of 
response to icatibant therapy. When a subject receives treatment with icatibant for an acute 
angioedema attack, they will record the date and time of administration of the SC injection in the 
electronic subject diary and will monitor the following events:
Initial Symptom Improvement

Report date and time when you feel that your symptoms start to improve.
Complete Symptom Resolution

Report date and time when you feel that your symptoms have completely resolved.
Tolerability

Report any side effects associated with administration of icatibant therapy.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical and Medication History
A medical history will be taken at the screening visit. All medical history findings that have been 
present/active within the 5 years prior to enrollment will be entered into the CRF regardless of 
clinical relevance or presence at study start. Medical history findings that have not been present 
within the 5 years prior to enrollment will be recorded if deemed clinically relevant by the 
investigator to the conduct of the study. The medical history should include any history of 
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HAE History
The following information associated with HAE history will be recorded in the CRF at the 
screening visit. If there is no documented C1 INH antigen level and/or C1 INH functional 
activity in the subject’s medical record, a blood sample can be collected at screening and sent to 
a local or central laboratory (as appropriate) to confirm HAE diagnosis (Type I or II). Repeat 
blood sampling is allowed if the test is non-confirmatory despite a suspected diagnosis of HAE.
(Note: the attack rate may be estimated based on subject or parent/caregiver recall as well as the 
subject’s medical records):  

HAE type (I or II)

Estimated date of last angioedema (swelling) attack prior to the screening visit

Any therapy received during the last 12 months for management of HAE (Section 5.1)

Total number, typical locations and average overall duration (days), and average overall 
severity of angioedema attacks experienced:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.

Typical score, estimated on a scale from 0-100, for the subject’s angioedema attack pain:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.
7.2.3.2
Physical Examination (Including Height and Weight)
The investigator or designee will perform physical examinations at the time points specified in 
Table 1, Table 2, and Table 3. General physical examinations will be performed in accordance 
with standard practices at the study site. Physical examination abnormalities observed prior to 
the screening visit will be entered into the medical history section of the CRF. Any new or 
worsening of pre-existing abnormalities noted at post-screening examinations should be captured 
as an AE on the AE CRF page, per investigator’s judgment. 
Body weight and height will be measured at the time points specified in Table 1 and Table 2. 
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed (Section 8.1).


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7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse and will be measured at the time points specified in 
Table 1, Table 2, and Table 3. During the study, additional vital signs measurements will be 
performed if clinically indicated. Vital signs performed on a dosing day should be obtained 
immediately (≤30 minutes) before the start of the injection of investigational product, 
immediately after completion of the injection of investigational product (≤10 minutes), and then 
between 30 minutes and 1 hour after completion of the injection of investigational product. 
Every effort should be made to measure vital signs prior to any blood sample collection. Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study). Any clinically significant deviations from Baseline (predose Visit 
1a) vital signs that are deemed clinically significant in the opinion of the investigator are to be 
recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 6 mL) for biochemistry will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Aspartate aminotransferase (AST)
Albumin
Alanine aminotransferase (ALT)
Total protein
Alkaline phosphatase (ALP)
Glucose
Creatine phosphokinase (CPK)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Chloride
Carbon dioxide
Phosphorus


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Hematology
Blood samples (approximately 2 mL) for hematology will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Hemoglobin
Red blood cell count
Hematocrit
Platelet count
White blood cell count – total and differential
Coagulation
Blood samples (approximately 3 mL) for coagulation will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
International normalized ratio (INR)
Prothrombin time (PT)
D-dimer a
Activated partial thromboplastin time (aPTT)
a In addition, D-dimer should be evaluated in any subject who presents with signs and symptoms consistent with 
suspected venous thromboembolism.
Virology
Blood samples (approximately 6 mL) will be taken according to Table 1. The following 
parameters will be assessed:
Human immunodeficiency virus (HIV; single 
assay/INNO-LIA)
Hepatitis (hepatitis B surface antigen and 
hepatitis C antibody)
Urinalysis with microscopy
Urine samples (approximately 10 mL) will be taken according to Table 1, Table 2, and Table 
3. The following parameters will be assessed:
pH
Specific gravity
Dipstick (protein, glucose, ketones, 
hemoglobin)
Microscopic evaluation (red blood cells, 
white blood cells, crystals, casts, bacteria)
In addition, a local or central laboratory (as appropriate) will be used for screening C1 INH 


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diagnostic assessments for subjects without documented C1 INH antigen level and/or C1 INH 
functional activity in their medical history.
7.2.3.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all females of childbearing potential at the 
screening visit and a urine pregnancy test is performed thereafter according to the time points 
specified in Table 1, Table 2, and Table 3. Pregnancy test results must be confirmed as negative 
before subjects proceed in the study. 
7.2.3.7
Electrocardiogram 
Subjects will have a 12-lead ECG recorded at the screening visit, as specified in Table 1. During 
the study, additional ECGs will be performed if clinically indicated. The following ECG data 
will be entered into the CRF: heart rate, PR interval, QRS duration, and QT interval. The PQ 
interval may be used if the PR interval is not reported on the 12-lead ECG. The investigator will 
be responsible for providing the interpretation of all ECGs (clinically significant/not clinically 
significant). The subject’s ECG(s) should be consistently recorded in the same position (supine).
7.2.3.8
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur from 
the first dose of investigational product through the 1-week post-treatment visit will be recorded 
in the CRF (Section 5.2).
7.2.3.9
Thrombotic or Thromboembolic Events
Monitoring for Venous Thromboembolism or Arterial Thromboembolism
Study personnel will actively monitor subjects for possible venous thromboembolism (VTE), 
encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), and arterial 
thromboembolism (ATE) with medical history, physical examinations, review of AEs, routine 
coagulation laboratory testing, and/or other diagnostic tests as applicable per local standard of 
care at the time points specified in Table 1, Table 2, and Table 3. 
Subjects will also receive instruction on how to recognize symptoms associated with potential
thrombotic events and to seek medical attention for these symptoms in addition to informing 
their investigator. Treatment procedures, when applicable, will be provided per local standard of 
care.
Suspected Venous Thromboembolism or Arterial Thromboembolism
In subjects who present with signs and symptoms that are suspicious of a possible VTE (DVT or 
PE) based on clinical history and physical examination, the Wells Prediction Rules (Appendix 3) 
in conjunction with D-dimer assessment and/or other diagnostic tests, as applicable per local 
standard of care, are suggested to help guide the physician. Diagnostic and/or treatment 
procedures, when applicable, will be provided per local standard of care.
Based on the Wells Prediction Rule scores, the following procedures are recommended:

If the Wells Prediction DVT risk score is ≥1, coagulation studies and an imaging study (eg, 


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lower extremity ultrasound or contrast venography) may be performed as described below. 

If the Wells Prediction PE risk score is ≥2, coagulation studies and 1 or more imaging studies 
(eg, ventilation-perfusion scan, multidetector helical computed axial tomography, or 
pulmonary angiography) may be performed as described below. 
In the setting of suspected VTE events, site personnel will complete the Wells Prediction Rule 
CRF.
Diagnosis and management of all suspected VTE and ATE events should be per local standard of 
care; Appendix 4 and Appendix 5 also presents a suggested medical algorithm for diagnosis and 
management of such conditions. Investigators must also comply with all reporting and/or 
concerning procedures for AEs/SAEs as indicated in the suggested algorithm. Confirmed 
diagnoses of T/TE events will be reported as SAEs (Section 8.2). However, superficial 
thrombophlebitis and catheter-related thrombosis will be reported as either a nonserious AE or 
an SAE based on investigator assessment and standard AE/SAE definitions.
7.2.3.10
Injection Site Reactions
Investigational product SC injection site reactions will be captured in the local tolerability CRF. 
Site personnel will distinguish between injection site reactions related to the procedure (eg, will 
check for redness after needle is inserted and prior to investigational product administration) vs 
the actual investigational product. Injection site reactions that do not meet the criteria of an SAE 
will not need to be reported as an AE.
Subcutaneous injection site reactions will be assessed at the following post-injection time points 
in each treatment period: 15 minutes, 30 minutes, and 1 hour post-injection. Study personnel will 
examine injection sites for erythema or swelling and will question the subject to collect 
information on cutaneous pain, burning sensation, itching/pruritus, and warm sensation. The 
diameter of any erythema or swelling should be measured to obtain the severity grading. The 
injection site reactions will be graded as absent, mild, moderate, or severe using the scoring 
criteria shown in Table 8. Both the severity score and the measurement of any erythema or 
swelling are to be captured in the CRF. In addition, the overall impact of injection site reactions 
on daily living (yes/no) and duration will be assessed at the last visit of each treatment period 
(Visits 28a and 28b).


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Table 8
Severity Scoring for Injection Site Reactions
Reaction
Severity
Mild
Moderate
Severe
Erythema
>0 to 5 cm
>5 to 10 cm
>10 cm
Swelling
>0 to 5 cm
>5 to 10 cm
>10 cm
Cutaneous pain
Mild discomfort to touch
Discomfort with movement
Significant discomfort at rest
Burning sensation
Mild burning sensation, 
which is easily tolerated
Moderate burning sensation, 
causing some discomfort
Severe burning sensation, 
causing significant discomfort
Itching/pruritus
Mild itching/pruritus, which 
is easily tolerated
Moderate itching/pruritus, 
causing some discomfort
Severe itching/pruritus, causing 
significant discomfort
Warm sensation
Mild warmth to touch
Moderate warmth to touch
Significant warmth to touch
Injection site reactions resulting from the administration of icatibant (as rescue medication for 
acute angioedema attacks) will be reported as an AE with causality linked to icatibant.
7.2.4
Others
7.2.4.1
Clinical Pharmacology Assessments
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Subjects will have blood samples (7 mL) collected for the determination of plasma 
concentrations of C1 INH antigen, functional C1 INH, complement C4, and C1q at time points 
specified in Table 4. Serum samples (5 mL) will be collected prior to the first dose of 
investigational product on Visit 1a (Dose 1 of Treatment Period 1), Visit 1b (Dose 1 of 
Treatment Period 2), and throughout both treatment periods for the analysis of anti-C1 INH 
antibodies (Table 1 and Table 2). Additional blood samples for PK/PD and C1 INH antibody 
testing will be collected at the early discontinuation visit (if applicable) and the 1-week and 
1-month post treatment visits (Table 3). Blood samples collected from subjects for PD 
assessments may also be used for exploratory HAE biomarker assays.
The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH activity, complement C4 and C1q 
concentrations, and serum samples for the evaluation of anti-C1 INH antibodies will be analyzed 
using validated methods. All PK/PD and immunogenicity samples will be processed according to 
the procedure outlined in the laboratory manual.
Selected samples may be analyzed to investigate incurred sample reproducibility of the 
bioanalytical methods. These analyses are only to investigate the reproducibility of the 
bioanalytical methods used to determine C1 INH antigen and functional C1 INH concentrations 
in study samples. All incurred sample reproducibility results will be reported in a separate table 
in the bioanalytical report. Details of disposal will be documented and maintained with the study 
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7.2.4.2
Health-related Quality of Life Assessments
Angioedema Quality of Life Questionnaire
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema (Weller et al. 2012). It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and food. Subjects will be asked how often 
they were restricted by—as well as the difficulties and problems that could be associated with—
recurrent swellings (angioedema) during the previous 4 weeks. The AE-QoL will be completed 
in the electronic subject diary at the time points specified in Table 1, Table 2, and Table 3. 
Details about the use of the AE-QoL instrument are provided in a separate study manual. 
Health-related Quality of Life Questionnaire
The EQ-5D-5L1 is a descriptive system of health-related quality of life states consisting of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of 
which can take 1 of 5 responses. The responses record 5 levels of severity within a particular 
dimension. The EQ-5D-5L will be completed in the electronic subject diary at the time points 
specified in Table 1, Table 2, and Table 3, as well as on each day that a subject experiences signs 
or symptoms of an angioedema attack. Details about the use and administration of the EQ-5D-5L 
instrument are provided in a separate study manual. 
Work Productivity and Activity Impairment-General Health Questionnaire
The WPAI-GH questionnaire includes 6 questions about work and activity impairment due to 
health problems during the past 7 days (Reilly et al. 1993). Outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less work or 
productivity. The WPAI-GH will be completed in the electronic subject diary at the time points 
specified in Table 1, Table 2, and Table 3. Details about the use of the WPAI-GH instrument are 
provided in a separate study manual.
Sheehan Disability Scale
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a subject’s 
disability due to an illness or health problem interferes with work/school, social life/leisure 
activities, and family life/home responsibilities (Sheehan 1983). The SDS will be completed in 
the electronic subject diary at the time points specified in Table 1, Table 2, and Table 3.
7.2.4.3
Health Resource Utilization Assessment
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. The Health Resource Utilization 
Assessment (HRUA-HAE) will be completed at the time points specified in Table 1, Table 2, 
and Table 3. Study personnel will enter the survey responses into the appropriate CRF.
                                                
1
EQ-5D™ is a trademark of the EuroQol Group.


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7.2.4.4
Survey of Acceptability of SC Administration
Study personnel will ask subjects to rate their overall experience in receiving twice weekly SC 
injections of investigational product at the time points specified in Table 1, Table 2, and Table 3.
For subjects who have previously received C1 INH products via IV administration, they will be 
asked to indicate the preferred route for medication administration. Study personnel will enter 
the subject’s survey responses into the electronic subject diary.
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) on 
the route to administer medications to prevent angioedema attacks. 
7.2.4.5
Self-administration Survey Assessment
After receiving appropriate training, subjects are allowed to self-administer investigational 
product during Treatment Periods 1 and 2 with or without direct supervision (qualified home 
health professional and/or study site personnel). Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/caregiver (if home health 
professional and/or study site personnel is not present). Alternatively, a parent/legal 
guardian/caregiver after having received appropriate training will be allowed to administer the 
investigational product to an adolescent subject with or without supervision. For those subjects 
who choose to self-administer or have a parent/legal guardian/caregiver administer the 
investigational product, study personnel will ask specific questions about their experience with 
self-administration of SC medication (Table 2 and Table 3). Study personnel will enter the 
subject’s survey responses into the electronic subject diary.
7.2.5
Volume of Blood to Be Drawn From Each Subject
Table 9
Approximate Volume of Blood to Be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
PK/PD 
7
20b
140
Immunogenicity (anti-C1 INH antibodies)
5
13
65
Safety
Biochemistry and -HCGa
6
13
78
Hematology
2
13
26
Coagulation
3
13
39
Virology
6
1
6
All assessments (mL)
354
Β-hCG=beta human chorionic gonadotrophin; C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a -hCG testing for females of childbearing potential at the Visit 1a (predose) only.
b Two of the 20 samples are optional as indicated in Table 4.
During this study, it is expected that maximum volume of blood to be drawn from each subject 
will be 354 mL, as shown in Table 9.


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Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
drawn may vary according to the instructions provided by the manufacturer or laboratory for an 
individual assessment; however, the total volume drawn over the course of the study should be 
approximately 354 mL. When more than 1 blood assessment is done at the same time 
point/period, if they require the same type of tube, the assessments may be combined. 
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:


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Mild:
A type of AE 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:
A type of AE that is usually alleviated with 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 subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product and/or other study product (eg, icatibant) is compelling and/or 
follows a known or suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and/or other study 
product (eg, icatibant) and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

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
Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (angioedema attacks) should not be captured as AEs as 
long as they are within the normal day-to-day fluctuation or expected progression of the disease 
and are part of the efficacy data to be collected in the study; however, events satisfying the 
serious criteria should be recorded as a SAE and reported to Shire Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range (either while continuing 
treatment or after the end of treatment with the investigational product), and the range of 
variation of the respective parameter within its reference range must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire ViroPharma 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 postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire Clinical 
Trial Serious Adverse Event Form. Note: An elective abortion is not considered an SAE.


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In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form. The test date of the 
first positive serum/urine -hCG test or ultrasound result will determine the pregnancy onset 
date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: This includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
higher than the protocol-specified dose.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Medication errors should be collected and reported to the sponsor for all products under 
investigation. The following should be considered as examples of reportable medication errors:

The administration and/or use of the unassigned treatment

The administration and/or use of an expired investigational product

Violation of storage or refrigeration requirements for the investigational product
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
All investigational products administered to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
8.1.8
Adverse Events of Special Interest
In addition, the following adverse events of special interest will be closely monitored and 
reported throughout the study, regardless of relationship to study medication:

Any serious anaphylactic reaction (see Section 4.4.3).


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
Any serious thrombotic or thromboembolic event; stopping rules related to thrombotic or 
thromboembolic events are described in Section 4.4.4.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, which 
the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or e-mail 
the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical Trial Serious 
Adverse Event Form (and any applicable follow-up reports) must also be sent to the contract 
research organization (CRO)/Shire ViroPharma Medical Monitor using the details specified in 
the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as an SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 


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surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be reported 
to the Shire Pharmacovigilance Department and  Medical Monitor within 24 hours of the first 
awareness of the event until 30 days after the last dose of investigational product. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational 
product and related SAEs that occur >30 days after the last dose of investigational product to 
Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central Institutional Review Boards (IRBs)/EU central ethics committees (ECs) of 
related, unexpected SAEs.


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In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
All statistical analyses will be performed using SASVersion 9.1 or higher (SAS Institute,
 
). 
PPD
PPD


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The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee in this 
study.
9.6
Sample Size Calculation and Power Considerations
For the primary efficacy endpoint, the NNA, a sample of 44 subjects from the crossover 
sequences will provide approximately 90% power at an alpha level of 0.025 (1-sided) to detect a 
difference of 1.0 attacks per month between active treatment and placebo assuming a between-
subject standard deviation of 2.0. This target is supported by the recently completed, dose-
ranging, Phase 2 study with CINRYZE (0624-206).
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR
relative to placebo, 44 subjects will provide >90% power to test the hypothesis H0: proportion 
≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided).
Previous communications have occurred between regulatory authorities and the sponsor 
regarding a Phase 3 study for the SC CINRYZE development program. The regulatory authority 
indicated that the Phase 3 study should be of sufficient size to have a 95% probability for 
detection of safety signals occurring with an incidence of 5% or greater of subjects.
With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.
The sample size calculation was conducted using nQuery + nTerim 2.0.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have signed an informed consent and some 
study procedures have begun.
The Randomized Set will consist of all subjects in the Screened Set for whom a randomization 
number has been assigned.


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The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The Full Analysis Set will consist of all subjects in the Safety Set who have at least 
1 post-baseline (eg, randomization) primary efficacy assessment.
The Per-protocol Set will consist of all subjects in the Full Analysis Set who complete 
scheduled primary assessments for 6 study weeks and who do not have pre-defined protocol 
deviations that may affect the primary efficacy endpoint. 
The Completer Set will consist of all subjects in the Full Analysis Set who have completed the 
final scheduled primary assessment for the study.
The Pharmacokinetic and Pharmacodynamic Set will consist of all subjects in the Safety Set 
for whom the primary PK and PD data are considered sufficient and interpretable. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the NNA during a treatment period. The NNA is 
expressed as the number of attacks per month (ie, 30.4 days) of exposure:
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period)
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.
The primary efficacy analysis will be conducted for the subjects in the Full Analysis Set (Section 
9.7) that are randomized to Treatment Sequence 1 (A/B) or 2 (B/A) to evaluate of the efficacy of 
SC administration of C1 esterase inhibitor [human] liquid for injection compared to placebo. The 
null hypothesis to be tested is that the NNA of C1 esterase inhibitor [human] liquid for injection 
is greater than or equal to the NNA of placebo, and the alternative hypothesis is that the NNA of 
C1 esterase inhibitor [human] liquid for injection is less than the NNA of placebo as below:
H0: µ C1 INH - µ placebo >0 vs
H1: µ C1 INH - µ placebo <0
The primary efficacy endpoint will be analyzed by using a linear mixed effect model with period, 
sequence, stratification factor (use of prophylactic therapy with C1 INH), and treatment as fixed 
effects, and subject nested within sequence as a random effect. The mean treatment difference (µ 
C1 INH - µ placebo) will be estimated with a 95% CI.
To assess any carryover effect, a sensitivity analysis will exclude from the evaluation of the 
NNA any attacks occurring within the first 2 weeks of Treatment Period 2 for both sequences 
when carryover is suspected to be maximal. Since carryover should occur only with the 
A/B treatment sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] 


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liquid for injection efficacy into the placebo treatment period, thereby diluting the efficacy of C1 
INH and favoring the null hypothesis of the primary efficacy analysis; it is not anticipated that 
any placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection within 
the B/A treatment sequence. The study is powered to demonstrate superior efficacy even in the 
presence of carryover effects. Additional sensitivity analyses may be developed and included in 
the SAP.
Adjustments for multiplicity: To control the overall type 1 error, the primary and key secondary 
endpoints will be tested at the 0.05 significance level in the pre-specified order of the primary 
endpoint, key secondary endpoint 1, key secondary endpoint 2, and key secondary endpoint 3. 
Once one hypothesis test is not significant, the significance of all subsequent tests will not be 
assessed. The determination of a successful study is based solely on the results of the primary 
endpoint analysis regardless of the results for the key secondary endpoints.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoints
1. The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA 
during the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo period.
2. The NNA excluding the first 2 weeks of each treatment period.
3. The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA for 
the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period relative to the 
placebo period excluding the first 2 weeks of each treatment period.
Key secondary efficacy endpoints 1 and 3 are defined as achieving a ≥50% reduction in the NNA 
(PR) during the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo period. Key secondary endpoints 1 and 3 will be analyzed as the 
proportion of subjects meeting criterion PR. The null hypothesis is that PR is less than or equal to 
0.2, and the alternative hypothesis is that PR is greater than 0.2. The proportion meeting criterion 
PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the proportion will 
be compared with 0.2. This is equivalent to testing the null hypothesis against the alternative 
hypothesis at a 1-sided alpha level of 0.025 using the normal approximation to the binomial 
distribution.
Analysis of key secondary endpoint 2 will follow the same methods (ie, the linear mixed effect 
model) used for the primary efficacy endpoint.
9.8.2.2
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints to be evaluated in this study are:

To determine the proportions of subjects achieving at least a 50% reduction in the NNA 
during a treatment period relative to the pretreatment assessment.

Cumulative attack severity. This score is the sum of the maximum symptom severity 
recorded for each angioedema attack in a treatment period.


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
Cumulative daily severity. This score is the sum of the severity scores recorded for every day 
of reported symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day.

Results of the AE-QoL questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema 
attack by:

Time to subject-assessed initial symptom improvement (TISI)

Time to subject-assessed complete symptom resolution (TCSR)
Subjects in the Full Analysis Set (Section 9.7) that are randomized to Treatment Sequence 1 
(A/B) or 2 (B/A) will be used to assess the secondary efficacy endpoints in the evaluation of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection compared to 
placebo. The treatment differences in clinical responder rate, both of which are defined within 
treatments, will be analyzed using McNemar’s test for testing equality of proportions of 
responders within treatments. All other secondary endpoints will be analyzed using a linear 
mixed effect model with period, sequence, stratification factor (use of prophylactic therapy with 
C1 INH), and treatment as fixed effects, and subject nested within sequence as a random effect. 
The results of all secondary efficacy analyses will be summarized by the point estimate of 
within-subject treatment differences or response rates and the corresponding 95% CI. Descriptive 
statistics (n, median, 25% and 75% quartiles, and range) will be provided to summarize 
icatibant-related efficacy endpoints (TISI and TCSR) by treatment and icatibant-treated 
angioedema attack for all subjects in the Full Analysis Set. Where appropriate (for subjects ≥12 
to <18 years of age), other rescue medications used to treat acute angioedema attacks will also be 
summarized using descriptive statistics. In addition, angioedema attacks will be summarized by 
the maximum symptom severity and treatment for all subjects in the Full Analysis Set. 
9.8.3
Exploratory Efficacy Endpoints
There are no exploratory efficacy endpoints in this study.
9.9
Safety Analyses
Adverse events will be coded using the MedDRA. The number of events, incidence, and 
percentage of TEAEs will be calculated overall, by system organ class, preferred term, and 
treatment. Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, AEs of special interest, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings 
will be summarized by treatment and visit. Potentially clinically important findings will also be 
summarized or listed.


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The incidence and severity (mild, moderate, severe) of SC injection site reactions will be 
summarized by treatment and visit. The overall impact of injection site reactions on daily living 
(yes/no) and duration will be summarized by treatment.
Results of C1 INH antibody testing will be reported for individual subjects.
The tolerability of icatibant therapy for acute angioedema attacks will be summarized.
To assess the influence of any carryover effect on adverse reporting, a sensitivity analysis may 
be conducted by attributing TEAEs that occur during the first 2 weeks of Treatment Period 2 to 
Treatment Period 1 for the A/B (C1 INH to placebo) treatment sequence. In other words, 
C1 esterase inhibitor [human] liquid for injection may account for any TEAEs in the first 2 
weeks of the placebo treatment, when the carryover effect (if present) is suspected to be 
maximal. 
9.10 Other Analyses
9.10.1
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, C1 INH functional, and complement C4 and C1q for 
individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics (number, geometric mean, coefficient of variation, mean, 
standard deviation, median, minimum, and maximum) for values at each time point. C1q 
concentrations will only be assessed at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic/pharmacodynamic (PK/PD) parameters will be calculated using observed and 
baseline-corrected concentration-vs-time data using non-compartmental analysis for C1 INH 
antigen, functional activity, and C4 levels. The following PK/PD parameters will be calculated, 
as appropriate, using both unadjusted and baseline-adjusted concentrations for SC 
administration: Cmax, tmax, and AUCtau. Additional PK parameters will be calculated using only 
baseline-adjusted concentrations, including t1/2, AUCtau, AUCt, and CL/F. Other PK parameters 
may be calculated as deemed appropriate. 
Exploratory PK/PD analyses might be performed based on the correlation of plasma 
concentrations of C1 INH antigen, functional C1 INH, and C4 complement in conjunction with 
various safety parameters (eg, selected AEs, clinical laboratory results, antibodies generation, 
frequency, severity, or anatomic location of the angioedema attack, etc.). Correlations that will 
be analyzed will be determined based on observed data. The PK/PD properties of SC C1 esterase 
inhibitor [human] liquid for injection will be characterized by population PK/PD modeling, and 
exposure-response will be explored. The report of these analyses will be issued separately.
Blood samples collected from subjects for PD assessments may also be used for exploratory 
HAE biomarker assays. The report of these analyses, if and when conducted, will be issued 
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9.10.2
Health-related Quality of Life Analyses
Results of the EQ-5D-5L health status instrument will be presented in accordance with the 
EQ-5D-5L user guide (version 2.0) by treatment.
Results of the WPAI-GH questionnaire will be summarized by treatment.
Results of the SDS will be summarized by treatment.
9.10.3
Surveys on SC Administration and Self-administration of Investigational 
Product
Results of the surveys for subject acceptability of SC administration and subject experience with 
self-administration of investigational product will be summarized.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. These regulations and 
guidelines also constitute compliance with the ethical principles described in the Declaration of 
Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.


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10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for conditions 
indicating that the clinical investigation should be halted due to an unacceptable patient risk or 
other reasons. If the study is suspended or terminated, the sponsor will ensure that applicable 
sites, regulatory agencies and IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.


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A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.


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The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 


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subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent form 
where applicable) which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator, or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor.


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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market C1 esterase inhibitor [human] liquid for injection; national or local regulatory authorities; 
and the IRBs/ECs which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire ViroPharma will endeavor to publish the results of all qualifying, applicable, and covered 
studies according to external guidelines in a timely manner regardless of whether the outcomes 
are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma adheres to 
external guidelines (eg, Good Publication Practices 2) when forming a publication steering 
committee, which is done for large, multicenter Phase 2-4 and certain other studies as determined 
by Shire ViroPharma. The purpose of the publication steering committee is to act as a non-
commercial body that advises or decides on dissemination of scientific study data in accordance 
with the scope of this policy.
All publications relating to Shire ViroPharma products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma agreement to publish prior to 
release of information. The review is aimed at protecting the sponsor’s proprietary information 
existing either at the commencement of the study or generated during the study. To the extent 
permitted by the publisher and copyright law, the principal investigator will own (or share with 
other authors) the copyright on his/her publications. To the extent that the principal investigator 
has such sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 


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medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, the institution and 
principal investigator shall withhold submission of such publication for up to an additional 60 
days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.


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11.
REFERENCES
Agostoni A, Cicardi M 1992. Hereditary and acquired C1-inhibitor deficiency: biological and 
clinical characteristics in 235 patients. Medicine (Baltimore); 71(4): 206-15.
Aygören-Pürsün E, Bygum A, Beusterien K, et al. 2014. Socioeconomic burden of hereditary 
angioedema: results of the hereditary angioedema burden of illness study in Europe. Orphanet J 
Rare Dis;9:99.
Banerji A 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol; 111(5): 329-36. 
Bernstein JA 2011. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma 
Proc; 32(6): 408-12.
Bork K, Barnstedt SE, Koch B, Traupe H 2000a. Hereditary angioedema with normal C1-
inhibitor activity in women. Lancet; 356(9225): 213-17.
Bork K, Siedlecki K, Bosch S, Schopf  RE, Kreuz W 2000b. Asphyxiation by laryngeal edema in 
patients with hereditary angioedema. Mayo Clin Proc; 75(4): 349-54. 
Bork K, Gül D, Hardt J, Dewald G 2007. Hereditary angioedema with normal C1 inhibitor: 
clinical symptoms and course. Am J Med; 120(11):987-92.
Bowen T, Cicardi M, Farkas H, et al. 2010. 2010 International consensus algorithm for the 
diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol; 
6(1): 24.
Bygum A, Aygören-Pürsün E, Beusterien K, et al. 2015. Burden of illness in hereditary 
angioedema: a conceptual model. Acta Derm Venereol; [Epub ahead of print].
Caballero T, Aygören-Pürsün E, Bygum A, et al. 2014. The humanistic burden of hereditary 
angioedema: results from the burden of illness study in Europe. Allergy Asthma Proc; 35:47-53.
Cicardi M, Igarashi T, Rosen FS, Davis AE 3rd 1987. Molecular basis for the deficiency of 
complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest; 79(3): 698-702.
Cugno M, Nussberger J, Cicardi M, Agostoni A 2003. Bradykinin and the pathophysiology of 
angioedema. Int Immunopharmacol; 3: 311-7.
Cugno M, Nuijens J, Hack E, et al. 1990. Plasma levels of C1 inhibitor complexes and cleaved 
C1 inhibitor in patients with hereditary angioneurotic edema. J Clin Invest; 85:1215-20.
Farkas H, Harmat G, Füst G, Varga L, Visy B 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol; 13(3): 153-61.
Farkas H, Jakab L, Temesszentandrási G, et al. 2007. Hereditary angioedema: a decade of human 
C1-inhibitor concentrate therapy. J Allergy Clin Immunol; 120(4): 941-7.


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Frank MM, Gelfand JA, Atkinson JP 1976. Hereditary angioedema: the clinical syndrome and its 
management. Ann Intern Med; 84(5): 580-93. 
Georgy MS, Pongracic JA 2012. Chapter 22: Hereditary and acquired angioedema. 
Allergy Asthma Proc; 33(Suppl 1): S73-6. 
Gompels MM, Lock RJ, Abinun M, et al. 2005. C1 inhibitor deficiency: consensus document. 
Clin Exp Immunol; 139(3): 379-94.
Kaplan AP 2010. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of 
C1 inhibitor therapy. J Allergy Clin Immunol; 126(5): 918-25. 
Kaplan AP, Joseph K 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol; 104(3): 193-204. 
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT 2010. The 
humanistic burden of hereditary angioedema: Impact on health-related quality of life, 
productivity, and depression. Allergy Asthma Proc; 31(5): 407-14.
Ohela K 1977. Hereditary angioneurotic oedema in Finland. Clinical, immunological and 
genealogical studies. Acta Med Scand; 201(5): 415-27.
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65.
Sheehan DV 1983. The Anxiety Disease. New York, NY, USA: Charles Scribner’s Sons.
Weis M 2009. Clinical review of hereditary angioedema: diagnosis and management. 
Postgrad Med; 121(6): 113-20. 
Weller K, Groffik A, Magerl M, et al. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67(10): 1289-98.
Weller K, Groffik A, Magerl M, et al. 2013. Development, validation, and initial results of the 
angioedema activity score. Allergy; 68(9): 1185-92.
Zuraw BL 2003. Diagnosis and management of hereditary angioedema: an American approach. 
Transfus Apher Sci; 29(3): 239-45.
Zuraw BL 2008. Hereditary angioedema: a current state-of-the-art review, IV: short- and long-
term treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy 
Asthma Immunol; 100(1 Suppl 2): S13-18.
Zuraw BL, Christiansen SC 2009. Pathogenesis and laboratory diagnosis of hereditary 
angioedema. Allergy Asthma Proc; 30(5): 487-92.


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Zuraw BL, Bork K, Binkley KE, et al. 2012. Hereditary angioedema with normal C1 inhibitor 
function: Consensus of an international expert panel. Allergy Asthma Proc; 33(Suppl 1): S145-
56.


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12.
APPENDICES


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APPENDIX 1 HANDLING OF INVESTIGATIONAL PRODUCT FOR 
SUBCUTANEOUS INJECTION 
The procedures below are provided for the handling of the investigational product. Since 
treatment assignment to C1 esterase inhibitor [human] liquid for injection and placebo 
(Treatments A and B, respectively) is to be blinded, the following instructions apply for all SC 
administrations in Treatment Periods 1 and 2. Always work on a clean surface and wash hands 
before performing the following procedures.
Handling

Prior to administration, investigational product should be protected from light.

No reconstitution or additional dilution of investigational product is required.

A silicone-free syringe is to be used for withdrawal of the product from the vial and for 
administration.

Important Notes: (1) when withdrawing the product from the vial, and during administration, 
the plunger of the syringe should be moved back and forth carefully and slowly, avoid 
introducing any air bubbles, and pulling the plunger past the stop on the syringe; (2) there is 
no need for excessive shaking of either the vial or syringe during the preparation for the SC 
injection.

Investigational product should be inspected carefully for particulate matter or any
discoloration prior to administration, whenever solution and container permit. The product 
should be colorless to slightly blue or colorless to slightly yellow and free from visible 
particles. Do not use if turbid or discolored.

Any vial that has been punctured should be used promptly.

Do not mix investigational product with other materials.

Do not freeze.

Do not use after expiration date.
NOTE: For this protocol, 2 vials of investigational product will be required for each SC 
injection (2x2 mL=4 mL total injection volume).
1. Aseptic technique should be used during handling.
2. Bring vials of investigational product to room temperature.
3. Remove caps from investigational product vials.
4. Cleanse stopper(s) with alcohol swab or germicidal solution, and allow them to dry prior to 
use.
5. Transfer the investigational product to a syringe for administration. Draw up the contents of 
2 vials of investigational for a total volume of 4 mL.
Be sure to safely dispose of the used needle and syringe.
Retain all used vials of investigational product for drug accountability purposes.


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APPENDIX 2 SUBCUTANEOUS INJECTION SITE SELECTION AND 
PREPARATION
Subcutaneous injections of investigational product will be administered in the abdominal area. 
Injection sites on the abdomen are depicted in the figure below. An abdominal site that is 
approximately at the level of the navel (as allowed by skin condition) and approximately 15 cm 
(minimum 10 cm) away from the margin of the navel should be selected. The lateral portion of 
the abdomen is preferred over the midline area. The selected site should include fatty tissue. 
Administer the first injection in the right side (#1 in illustration) and the second injection in the 
left side (#2 in illustration). Keep alternating injection sites to the right side and then to the left
side for all subsequent injections in Treatment Periods 1 and 2.
Illustration of Injection Sites on the Abdomen
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s 
position: 30-45º) and in a supine position immediately following injection for the evaluation of 
the injection site (ie, laying flat on back).
After the injection site for SC administration has been chosen, the investigational product will be 
administered as a single 4 mL SC injection as described briefly below.

Wipe skin with alcohol to cleanse. Allow to dry.

Gently pinch and lift the skin of the abdomen (ie, “tenting”).

Insert the needle with bevel up close to parallel to the skin or at an angle that is <20°. Once 
the needle is inserted, gently release the pinched and lifted skin (“untent the skin”). When the 
skin is in its normal state, the needle should have a slight upward angle of 20-30°. If the 
subject is obese, a steeper angle for needle insertion can be used but it is recommended 
keeping the angle <45°. In practical terms, the needle placement should resemble the angle of 
an IV needle placement in the arm. The purpose of pinching and lifting the skin is to make 
sure the needle is properly inserted in the SC space and is not intradermal.

Release the subcutaneous tissue. The needle will not back out during the injection if properly 
placed.

Care should be taken to avoid inadvertent IV or IM injection.
It may be necessary to adjust the needle by pulling the needle slightly back if there appears to be 
a resistance to flow.
1
2


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APPENDIX 3 WELLS PREDICTION RULE FOR THE DIAGNOSIS OF 
VENOUS THROMBEMBOLISM
Table A.
Wells Prediction Rule for Diagnosing Deep Venous Thrombosis: Clinical 
Evaluation Table for Predicting Pretest Probability of Deep Venous 
Thrombosisa
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months, or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within 12 weeks requiring general anesthesia 
or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Alternative diagnosis at least as likely as deep venous thrombosis
−2
a Clinical probability of deep venous thrombosis: Low= ≤0; Intermediate=1 to 2; High= ≥3. In patients with symptoms in 
both legs, the more symptomatic leg is used.
Data source: Qaseem et al. 2007
Table B.
Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical 
Evaluation Table for Predicting Pretest Probability of Pulmonary 
Embolisma
Clinical Characteristic
Score
Previous pulmonary embolism or deep venous thrombosis
+1.5
Heart rate >100 beats per minute
+1.5
Recent surgery or immobilization
+1.5
Clinical signs of deep venous thrombosis
+3
Alternative diagnosis less likely than pulmonary embolism
+3
Hemoptysis
+1
Cancerb
+1
a Clinical probability of pulmonary embolism: Low=0 to 1; Intermediate=2 to 6; High= ≥7
b For the purposes of this study, cancer will include “treatment ongoing, within previous 6 months, or palliative.”
Data Source: Qaseem et al. 2007
Reference
Qaseem A, Snow V, Barry P, et al. 2007. Current diagnosis of venous thromboembolism in 
primary care: A clinical practice guideline from the American Academy of Family Physicians 
and the American College of Physicians. Ann Fam Med; 146(6):454-58.


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APPENDIX 4 ALGORITHM FOR SUSPECTED VENOUS
THROMBOEMBOLISM 
Note: In Germany, investigational product will be discontinued in any subject that experiences a venous 
thromboembolic event.
References
National Heart, Lung, and Blood Institute. Pulmonary embolism 2011. http://www.nhlbi.nih. 
gov/book/export/html/4865. Accessed May 11, 2015. 
National Heart, Lung, and Blood Institute. Deep vein thrombosis 2011. http://www.nhlbi.nih. 
gov/book/export/html/4871. Accessed May 11, 2015. 
Ozaki A, Bartholomew JR. Venous thromboembolism (deep venous thrombosis & pulmonary 
embolism). In: Carey WD, Rae-Grant A, Rimmerman C, ed. Disease Management Project. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous-
thromboembolism. Accessed May 11, 2015. 


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APPENDIX 5 ALGORITHM FOR SUSPECTED ARTERIAL 
THROMBOEMBOLISM
Note:  In Germany, investigational product will be discontinued in any subject that experiences an arterial 
thromboembolic event.
References
National Library of Medicine. Arterial embolism 2014. http://www.nlm.nih.gov/medlineplus/ 
ency/article/001102.htm. Accessed May 18, 2015.
Lyaker MR, Tulman DB, Dimitrova GT, Pin RH, Papadimos TJ 2013. Arterial embolism. Int J 
Crit Illn Inj Sci; 3(1): 77-87. 


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APPENDIX 6 PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
28 May 2015
Global
Protocol Amendment 1
22 Jul 2015
Global
Protocol Amendment 2
03 Sep 2015
Global
Protocol Amendment 3
11 Jan 2016
Global
Protocol Amendment 2.1
14 Apr 2016
Country Specific (DE)
Protocol Amendment 3.1
20 Jun 2016
Country Specific (DE)
Amendment 1 to Protocol SHP616-300 incorporates the following major changes:

Inclusion of final clinical data from Study SHP616-103, which are relevant to patient safety 
and the study rationale.

The baseline angioedema attack rate required for study inclusion has been modified.

Updates were made to some study procedures or requirements (eg, parent/legal 
guardian/caregiver performing and/or assisting an adolescent subject, photographs and 
measurements of injection site reactions, longitudinal follow-up to test for C1 INH antibody 
titers).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 Jul 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the title page to indicate that this will be a multicenter study.
Title page
Changed the baseline attack rate requirement for study entry from a 
history of ≥4 attacks per month average to ≥3 attacks per month average 
for inclusion criterion #3.
Synopsis
Section 4.1
Corrected the secondary efficacy endpoint for the Angioedema Activity 
Score (AAS), to indicate the “98-day AAS” will be calculated in each 
treatment period. 
Synopsis
Section 9.8.2.2
Results from a statistical simulation showed that at least 25% of 
randomized subjects with a baseline attack rate of ≥4 per month average 
need to be included in the efficacy analysis population in order to detect 
a significant reduction (<2) in NNA from baseline. This requirement was 
added to due the revision of the baseline attack rate from ≥4 to ≥3 in 
inclusion criterion #3.
Synopsis
Section 3.1
A parent/legal guardian/caregiver will be allowed to administer 
Synopsis


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 Jul 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
investigational product to an adolescent subject during Treatment Period 
2, after having received appropriate training and under the supervision of 
study site personnel or a qualified home health professional.
Section 3.1, Section 6.2, Section 6.5, 
Section 7.2.4.5
For adolescent subjects, a parent/legal guardian/caregiver is allowed to 
assist the subject in completing the electronic subject diary, including the 
quality of life questionnaires.
Synopsis
Section 3.1
Updated sections to include the final clinical data (safety and 
pharmacokinetics) from Study SHP616-103.
Section 1.2, Section 1.2.1.1, 
Section 1.2.2.2
Modified the presentation of the PK results from Study 0624-206 to 
clarify dose selection.
Section 1.2.2.1
Modified text on dose selection and rationale for the study based on 
results from Study SHP616-103.
Section 1.2.2.3, Section 2.1
Clarified guidelines regarding the treatment of acute angioedema attacks 
with icatibant. 
Section 5.2.1
Updated the details on subject randomization to specify that it will be 
conducted in two phases. 
Section 6.3
Removed the request for subjects to participate in longitudinal follow-up 
for C1 INH antibody titers if they had anti-C1 INH antibodies detected in 
their plasma samples. If warranted, subjects may be requested to 
participate in follow-up of C1 INH antibody titers via a separate study 
protocol.
Section 7.1.5, Section 7.2.4.1
Removed the request for study personnel to obtain a digital photograph 
of severe injection site reactions and clarified that measurements of any 
erythema or swelling should be captured in the CRF.
Section 7.2.3.10
Clarified the collection period for AEs.
Section 8.1
Clarified the population of subjects (ie, those randomized to Treatment 
Sequence 1 [A/B] or 2 [B/A]) to be used in the evaluation of the efficacy 
of SC administration of C1 esterase inhibitor [human] liquid for injection 
compared to placebo.
Section 9.8.1, Section 9.8.2.2


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Amendment 2 to Protocol SHP616-300 incorporates the following major changes:

The inclusion and exclusion criteria regarding the attack rate and baseline prophylactic 
therapy was modified.

A new exclusion criterion was added to prevent any changes of dose in hormonal 
products/therapies prior to study enrollment.

Self-administration is now allowed in both treatment periods (1 and 2), under supervision and 
after receiving adequate training by the site or home health professional.

Clarification added for the subjects who continue to have breakthrough attacks on the blinded 
investigational product despite receiving on-demand treatment for the management of 
angioedema attacks during the study.

Added a section to clarify nonpharmacologic treatments and procedures.

Added overall severity and duration assessment for injection site reactions.

Number of subjects randomized in each of the three treatment sequences (A/B, B/A, A/A) 
was modified along with the statistical power calculations. 

Removed “achieving a NNA <2.0” as a secondary efficacy endpoint.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the inclusion criterion # 3 to clarify the baseline prophylactic 
treatment requirement for both adults (≥18 yrs) and adolescents (>12-
<18 yrs).
Synopsis, Section 3.1
Section 4.1
Changed the baseline attack rate requirement for study entry from a 
history of ≥3 attacks per month average to ≥2 attacks per month average 
for inclusion criterion #3.
Synopsis, Section 3.1
Section 4.1
Exclusion criterion #1 was modified to only include adults.
Synopsis
Section 4.2
Added exclusion criterion #2 for adolescents receiving prophylactic 
therapy with C1 INH.
Synopsis
Section 4.2
Added exclusion criterion #5 to prevent females from changing the dose 
of any hormonal contraceptive regimen or hormone replacement therapy 
within 2 months prior to the screening visit.
Synopsis
Section 4.2


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number
2
Amendment Date
03 Sep 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Authorized self-administration for subjects in both treatment periods, 1 
and 2.
Synopsis, Section 3.1, Section 6.2
Section 6.5,
Section 7.2.4.5
The self-administration survey was added to the assessment schedule for 
Treatment Period 1 for Visit 28a.
Table 1
Section 7.1.2.3
The period required for stabilization of hormonal contraceptives was 
revised from 30 days to 2 months prior to the screening visit.
Section 4.3.1
Added clarification on the management of angioedema attacks for 
subjects who continue to have breakthrough attacks on the blinded 
investigational product despite on-demand therapy.
Section 5.2.1
Added a section to clarify nonpharmacologic treatments and procedures 
and to request that subjects postpone elective procedures during the 
study.
Section 5.2, Section 5.2.3
Added overall assessment of severity and duration for injection site 
reactions, in the CRF.
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3, 
Section 7.2.3.10
SAE reporting timeline was clarified to include 30 days after the last 
dose of investigational product.
Table 3, Section 8.2.4
Updated the new Medical Monitor for the study.
Protocol Signature Page, Emergency 
Contact Information section
Updated the HIV assay test from Western Blot to INNO-LIA.
Table 1, Section 7.2.3.5
Modified number of subjects randomized in each of the 3 treatment 
sequences (A/B, B/A, A/A).
Synopsis, Table 7, Section 6.3
Statistical power calculations were modified based on the change in the 
number of subjects randomized to each treatment sequence.
Section 9.6
Revised the secondary efficacy endpoint defining “clinical response to 
treatment” since one component (achieving a NNA <2.0) is no longer 
clinically meaningful given the study inclusion criterion is now >2 
attacks. The corresponding secondary objective of the study has also 
been revised.
Synopsis, Section 2.2.2, 
Section 9.8.2.2


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Amendment 3 to Protocol SHP616-300 incorporates the following major changes:

Allow subjects (adolescent or adult) the option to self-administer investigational product with 
or without supervision after receiving appropriate training by the investigator or designee. 
Adolescent subjects self-administering investigational product will be supervised by a 
parent/legal guardian/caregiver (if home health professional and/or study site personnel is not 
present).

Subjects who elect to self-administer investigational product will be instructed on 
investigational product transport, storage, treatment compliance, and retention of all used and 
unused product vials for drug accountability purposes. Written instructions on investigational 
product and self-administration procedures will be provided to subjects at the screening or 
first dosing visit.

Revised schedule for assessment of SC injection site reactions during Treatment Periods 1 
and 2; the assessments will be less frequent and only occur when investigational product is 
administered at the investigative site. An overall assessment of the impact on daily living and 
duration of injection sites reaction will occur at the last visit of each treatment period.

In order to prevent subjects from missing a scheduled dose of investigational product, 
additional guidance on the dosing interval has been provided.

For subjects without documented C1 INH antigen level and/or C1 INH functional activity as 
part of eligibility criteria to confirm HAE diagnosis, a blood sample will be collected at 
screening and sent to a local or central laboratory (as appropriate). 
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
11 Jan 2016
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Allow subjects (adolescent or adult) to self-administer investigational 
product with or without supervision (qualified home health professional 
and/or study site personnel) after receiving appropriate training by the 
investigator or designee. Adolescent subjects self-administering 
investigational 
product 
will 
be 
supervised 
by 
a 
parent/legal 
guardian/caregiver (if home health professional and/or study site 
personnel is not present). Alternatively, a parent/legal guardian/caregiver 
is also allowed to administer investigational product to an adolescent 
subject with or without supervision. 
Synopsis, Section 3.1,
Section 6.2, Section 7.2.4.5
Information on self-administration of investigational product will be 
recorded in the electronic subject diary.
Synopsis, Section 3.1
Added Firazyr (icatibant) to exclusion criterion #8 to exclude subjects 
with a history of an allergic reaction to icatibant from entering the study.
Synopsis, Section 4.2
Revised schedule for assessment of SC injection site reactions to occur 
only when investigational product is administered at the investigative site 
Table 1, Table 2,
Section 7.1.2.3, Section 7.1.3.3, 


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Protocol Amendment 4
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(Visits 1, 8, 16, 24, and 28 in each treatment period). An overall 
assessment of the impact on daily living and duration of injection site 
reactions will occur at the last visit of each treatment period (Visit 28a 
and 28b).
Section 7.2.3.10
Updated safety endpoints and analyses to include the impact on daily 
living and duration of injection site reactions.
Synopsis, Section 9.9
In order to prevent subjects from missing a dose of investigational 
product (if the every 3 to 4 day interval cannot be followed), a less than 
3-day interval may occur with the recommendation of allowing at least 
24 hours between doses. 
Synopsis, Section 3.1,
Section 6.2
Vital sign measurements are not required at Visits 2, 3, and 4 in each 
treatment period for subjects self-administering investigational product 
without supervision (ie, assessment may not be possible).
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3
A PK/PD predose blood sample at Visit 2a and 2b is not required for 
subjects self-administering investigational product without supervision 
(ie, collection of sample may not be possible).
Table 4, Section 7.1.2.3, 
Section 7.1.3.3
Provided details on the supply of commercial icatibant as rescue 
medication for the treatment of acute angioedema attacks. The product 
will be appropriately labeled for clinical trial use. Added recommended 
storage conditions for icatibant.
Section 5.2.1, Section 6.1
Subjects who self-administer investigational product (or when needed, 
icatibant as rescue medication) will be instructed on transport, storage, 
treatment compliance, and retention of all used and unused product vials 
for drug accountability purposes. Added details on investigational 
product and ancillary supplies to be provided to subjects at 
investigational site. Written instructions on investigational product and 
self-administration procedures will be provided to subjects at the 
screening or first dosing visit (Visit 1a).
Section 6.5.1, Section 6.6
For subjects without documented C1 INH antigen level and/or C1 INH 
functional activity as part of eligibility criteria to confirm HAE 
diagnosis, a blood sample will be collected at screening and sent to a 
local or central laboratory (as appropriate). Repeat blood sampling is 
allowed if the test is non-confirmatory despite a suspected diagnosis of 
HAE.
Section 7.1.1, Section 7.2.3.1, 
Section 7.2.3.5
Clarified that injection site reactions resulting from the administration of 
icatibant (as rescue medication for acute angioedema attacks) will be 
reported as an AE with causality linked to icatibant.
Section 7.2.3.10
Added “and/or other study product (eg, icatibant)” to clarify how the 
relatedness of AEs is to be captured in the CRF. 
Section 8.1.2
Updated product information for consistency with other patient 
instructions.
Appendix 1


Shire ViroPharma, Inc.
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Protocol Amendment 4
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08 Feb 2017
Amendment 2.1 DE (Country-specific Amendment: Germany) to Protocol SHP616-300 
incorporates the following changes:
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
14 Apr 2016
Global/Country/Site Specific
Germany
Description of Change
Section(s) Affected by Change
Revised inclusion criteria to allow enrollment of only adult (>18 years) 
HAE patients.
Synopsis, Section 4.1
Added “not applicable to Germany” to exclusion criteria for adolescent 
subjects.
Synopsis, Section 4.2
Revised exclusion criteria to exclude subjects positive for hepatitis B, 
hepatitis C, or HIV infection; alcohol, drug, or medication abuse within 
1 year before screening; or mental condition rendering the subject or 
parent(s)/legal guardian unable to understand the nature, scope of the study, 
and possible consequences of the study. Also excluding subjects with a 
relationship to study staff or sponsor (including people accommodated in 
an institution as well as people who are dependent on the sponsor, CRO, 
site or the investigator).
Synopsis, Section 4.2
Editorial revisions to clarify planned pharmacokinetic/pharmacodynamic 
analyses.
Synopsis, Section 9.10.1
Provided additional guidance on double-barrier methods of contraception.
Section 4.3.1
Added that mandatory discontinuation of investigational product would 
occur if the sponsor became aware of conditions that were unexpected, 
were significant, or posed an unacceptable risk to patients.
Sections 4.4 and 4.4.1
Added that if a thrombotic/thromboembolic event occurs in any subject, 
investigational product administration for that subject will be discontinued.
Section 4.4.4, Appendix 4, 
Appendix 5
Added a section to define events of special interest for CINRYZE. Adverse 
events of special interest will be summarized as a part of the safety 
analyses.
Section 8.1.8, Section 9.9
Clarified that the sponsor may terminate the study if conditions arise which 
indicate that the clinical investigation should be halted due to an 
unacceptable patient risk.
Section 10.1.4
Other minor editorial revisions (including changes for consistency and clarity) have been made 
throughout the protocol.


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Protocol Amendment 4
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08 Feb 2017
Amendment 3.1 DE (Country-specific Amendment: Germany) to Protocol SHP616-300 
incorporates the following major changes:

Allow subjects (adolescent or adult) the option to self-administer investigational product with 
or without supervision after receiving appropriate training by the investigator or designee. 
Adolescent subjects self-administering investigational product will be supervised by a 
parent/legal guardian/caregiver (if home health professional and/or study site personnel is not 
present).

Subjects who elect to self-administer investigational product will be instructed on 
investigational product transport, storage, treatment compliance, and retention of all used and 
unused product vials for drug accountability purposes. Written instructions on investigational 
product and self-administration procedures will be provided to subjects at the screening or 
first dosing visit.

Revised schedule for assessment of SC injection site reactions during Treatment Periods 1 
and 2; the assessments will be less frequent and only occur when investigational product is 
administered at the investigative site. An overall assessment of the impact on daily living and 
duration of injection sites reaction will occur at the last visit of each treatment period.

In order to prevent subjects from missing a scheduled dose of investigational product, 
additional guidance on the dosing interval has been provided.

For subjects without documented C1 INH antigen level and/or C1 INH functional activity as 
part of eligibility criteria to confirm HAE diagnosis, a blood sample will be collected at 
screening and sent to a local or central laboratory (as appropriate). 
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.


Shire ViroPharma, Inc.
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Protocol Amendment 4
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08 Feb 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
20 Jun 2016
Global/Country/Site Specific
Germany
Description of Change
Section(s) Affected by Change
Allow subjects (adolescent or adult) to self-administer investigational 
product with or without supervision (qualified home health professional 
and/or study site personnel) after receiving appropriate training by the 
investigator or designee. Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/ 
caregiver (if home health professional and/or study site personnel is not 
present). Alternatively, a parent/legal guardian/caregiver is also allowed to 
administer investigational product to an adolescent subject with or without 
supervision. 
Synopsis, Section 3.1,
Section 6.2, Section 7.2.4.5
Information on self-administration of investigational product will be 
recorded in the electronic subject diary.
Synopsis, Section 3.1
Added FIRAZYR (icatibant) to exclusion criterion #8 to exclude subjects 
with a history of an allergic reaction to icatibant from entering the study.
Synopsis, Section 4.2
Revised schedule for assessment of SC injection site reactions to occur 
only when investigational product is administered at the investigative site 
(Visits 1, 8, 16, 24, and 28 in each treatment period). An overall 
assessment of the impact on daily living and duration of injection site 
reactions will occur at the last visit of each treatment period (Visit 28a and 
28b).
Table 1, Table 2,
Section 7.1.2.3, Section 7.1.3.3, 
Section 7.2.3.10
Updated safety endpoints and analyses to include the impact on daily 
living and duration of injection site reactions.
Synopsis, Section 9.9
In order to prevent subjects from missing a dose of investigational product 
(if the every 3 to 4 day interval cannot be followed), a less than 3-day 
interval may occur with the recommendation of allowing at least 24 hours 
between doses. 
Synopsis, Section 3.1,
Section 6.2
Vital sign measurements are not required at Visits 2, 3, and 4 in each 
treatment period for subjects self-administering investigational product 
without supervision (ie, assessment may not be possible).
Table 1, Table 2, Section 7.1.2.3, 
Section 7.1.3.3
A PK/PD predose blood sample at Visit 2a and 2b is not required for 
subjects self-administering investigational product without supervision (ie, 
collection of sample may not be possible).
Table 4, Section 7.1.2.3, 
Section 7.1.3.3
Removed double-barrier methods as an acceptable form of female 
contraception.
Section 4.3.1
Provided details on the supply of commercial icatibant as rescue 
medication for the treatment of acute angioedema attacks. The product 
will be appropriately labeled for clinical trial use. Added recommended 
storage conditions for icatibant.
Section 5.2.1, Section 6.1
Subjects who self-administer investigational product (or when needed, 
icatibant as rescue medication) will be instructed on transport, storage, 
treatment compliance, and retention of all used and unused product vials 
for drug accountability purposes. Added details on investigational product 
and ancillary supplies to be provided to subjects at investigational site.
Written instructions on investigational product and self-administration 
procedures will be provided to subjects at the screening or first dosing visit
Section 6.5.1, Section 6.6


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Protocol Amendment 4
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
20 Jun 2016
Global/Country/Site Specific
Germany
Description of Change
Section(s) Affected by Change
(Visit 1a).
For subjects without documented C1 INH antigen level and/or C1 INH 
functional activity as part of eligibility criteria to confirm HAE diagnosis, a 
blood sample will be collected at screening and sent to a local or central 
laboratory (as appropriate). Repeat blood sampling is allowed if the test is 
non-confirmatory despite a suspected diagnosis of HAE.
Section 7.1.1, Section 7.2.3.1, 
Section 7.2.3.5
Clarified that injection site reactions resulting from the administration of 
icatibant (as rescue medication for acute angioedema attacks) will be 
reported as an AE with causality linked to icatibant.
Section 7.2.3.10
Added “and/or other study product (eg, icatibant)” to clarify how the 
relatedness of AEs is to be captured in the CRF. 
Section 8.1.2
Updated product information for consistency with other patient 
instructions.
Appendix 1

Prot_001.pdf: 
PROTOCOL: SHP616-300
TITLE:
A 
Phase 
3, 
Randomized, 
Double-blind, 
Placebo-controlled, 
Two-period, Three-sequence, Partial Crossover Study to Evaluate the 
Efficacy and Safety of Subcutaneous Administration of 2000 U of 
C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention 
of Angioedema Attacks in Adolescents and Adults with Hereditary 
Angioedema
DRUG:
SHP616, C1 esterase inhibitor [human] liquid for injection
IND:
16516
EUDRACT NO.:
2015-002478-19
SPONSOR: 
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
____________________
INVESTIGATORS: Multicenter
PROTOCOL 
HISTORY:
Amendment 1: 22 Jul 2015
Original Protocol: 28 May 2015
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used solely for the 
purposes for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Shire ViroPharma, Inc.


Shire ViroPharma, Inc. 
Protocol SHP616-300 
- - - - - - - - - - - - - - - - - - - -
CONFIDENTIAL 
Version 2.0, FINAL 
PROTOCOLSIGNATUREPAGE 
Sponsor's (Shire ViroPharma, Inc.) Approval 
22 Jul2015 
Page 2 of 108 
Signature:
I\.1'JJ 
Date: 
Investigator's Acknowledgement 
I have read this protocol for Shire ViroPharma Study SHP616-300. 
Title: A Phase 3, randomized, double-blind, placebo-controlled, two-period, three-sequence, 
partial crossover study to evaluate the efficacy and safety of subcutaneous administration of 
2000 U of Cl esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks in adolescents and adults with hereditary angioedema. 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ------------------ Date: 
PPD
PPD
PPD
PPD


Shire ViroPharma, Inc.
CONFIDENTIAL
22 Jul 2015
Protocol SHP616-300
Version 2.0, FINAL
Page 3 of 108
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Amendment 1 to Protocol SHP616-300 incorporates the following major changes:

Inclusion of final clinical data from Study SHP616-103, which are relevant to patient 
safety and the study rationale.

The baseline angioedema attack rate required for study inclusion has been modified.

Updates were made to some study procedures or requirements (eg, parent/legal 
guardian/caregiver performing and/or assisting an adolescent subject, photographs and 
measurements of injection site reactions, longitudinal follow-up to test for C1 INH 
antibody titers).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) that have been made throughout the 
protocol are not reflected below.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
22 July 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the title page to indicate that this will be a multicenter study.
Title page
Changed the baseline attack rate requirement for study entry from a 
history of ≥4 attacks per month average to ≥3 attacks per month average 
for inclusion criterion #3.
Synopsis
Section 4.1
Corrected the secondary efficacy endpoint for the Angioedema Activity 
Score (AAS), to indicate the “98-day AAS” will be calculated in each 
treatment period. 
Synopsis
Section 9.8.2.2
Results from a statistical simulation showed that at least 25% of 
randomized subjects with a baseline attack rate of ≥4 per month average 
need to be included in the efficacy analysis population in order to detect 
a significant reduction (<2) in NNA from baseline. This requirement was 
added to due the revision of the baseline attack rate from ≥4 to ≥3 in 
inclusion criterion #3.
Synopsis
Section 3.1
A parent/legal guardian/caregiver will be allowed to administer 
investigational product to an adolescent subject during Treatment Period 
2, after having received appropriate training and under the supervision of 
study site personnel or a qualified home health professional.
Synopsis
Section 3.1, Section 6.2, Section 6.5, 
Section 7.2.4.5
For adolescent subjects, a parent/legal guardian/caregiver is allowed to 
assist the subject in completing the electronic subject diary, including the 
quality of life questionnaires.
Synopsis
Section 3.1
Updated sections to include the final clinical data (safety and 
pharmacokinetics) from Study SHP616-103.
Section 1.2, Section 1.2.1.1, 
Section 1.2.2.2
Modified the presentation of the PK results from Study 0624-206 to 
clarify dose selection.
Section 1.2.2.1


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22 Jul 2015
Protocol SHP616-300
Version 2.0, FINAL
Page 4 of 108
Modified text on dose selection and rationale for the study based on 
results from Study SHP616-103.
Section 1.2.2.3, Section 2.1
Clarified guidelines regarding the treatment of acute angioedema attacks 
with icatibant.
Section 5.2.1
Updated the details on subject randomization to specify that it will be 
conducted in two phases. 
Section 6.3
Removed the request for subjects to participate in longitudinal follow-up 
for C1 INH antibody titers if they had anti-C1 INH antibodies detected in 
their plasma samples. If warranted, subjects may be requested to 
participate in follow-up of C1 INH antibody titers via a separate study 
protocol.
Section 7.1.5, Section 7.2.4.1
Removed the request for study personnel to obtain a digital photograph 
of severe injection site reactions and clarified that measurements of any 
erythema or swelling should be captured in the CRF.
Section 7.2.3.10
Clarified the collection period for AEs.
Section 8.1
Clarified the population of subjects (ie, those randomized to Treatment 
Sequence 1 [A/B] or 2 [B/A]) to be used in the evaluation of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for 
injection compared to placebo.
Section 9.8.1, Section 9.8.2.2
See Appendix 6 for protocol history, including all amendments.


Shire ViroPharma, Inc.
CONFIDENTIAL
22 Jul 2015
Protocol SHP616-300
Version 2.0, FINAL
Page 5 of 108
EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover) and are 
provided below. 
US and Canadian Sites
Fax: 
Email: 
EU/ROW Sites
Fax: 
Email: 
For protocol- or safety-related issues, the investigator must contact the Shire
ViroPharma Medical Monitor:
 MD, 
, Clinical Development; Medical Monitor
Office phone: 
Fax: 
Mobile phone: 
Email: 
If the medical monitor is unavailable, please contact:
, MD, FRCP(C), 
, Clinical Development 
Office phone: 
Fax: 
Mobile phone: 
Email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Shire ViroPharma, Inc.
CONFIDENTIAL
22 Jul 2015
Protocol SHP616-300
Version 2.0, FINAL
Page 6 of 108
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire
ViroPharma product (marketed or investigational) does not meet expectations (eg, inadequate 
or faulty closure, product contamination) or that the product did not meet the specifications 
defined in the application for the product (eg, wrong product such that the label and contents 
are different products). For instructions on reporting AEs related to product complaints, see 
Section 8.
Please report all Product Quality Complaints to:
PPD


Shire ViroPharma, Inc.
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22 Jul 2015
Protocol SHP616-300
Version 2.0, FINAL
Page 7 of 108
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................3
EMERGENCY CONTACT INFORMATION ..........................................................................5
PRODUCT QUALITY COMPLAINTS ....................................................................................6
LIST OF TABLES....................................................................................................................11
LIST OF FIGURES..................................................................................................................12
LIST OF APPENDICES ..........................................................................................................12
ABBREVIATIONS..................................................................................................................13
STUDY SYNOPSIS.................................................................................................................15
STUDY SCHEDULES.............................................................................................................22
1.
BACKGROUND INFORMATION.............................................................................28
1.1
Indication and Current Treatment Options...................................................................28
1.2
Product Background and Clinical Information ............................................................29
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection ...............................31
1.2.1.1
Clinical Safety.............................................................................................32
1.2.1.2
Clinical Efficacy..........................................................................................33
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid 
for Injection............................................................................................................35
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response 
Analysis of CINRYZE ...................................................................................35
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid 
for Injection .................................................................................................39
1.2.2.3
Dose Selection.............................................................................................40
2.
STUDY OBJECTIVES AND PURPOSE....................................................................42
2.1
Rationale for the Study.................................................................................................42
2.2
Study Objectives...........................................................................................................42
2.2.1
Primary Objectives ................................................................................................42
2.2.2
Secondary Objectives ............................................................................................43
3.
STUDY DESIGN.........................................................................................................45


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3.1
Study Design and Flow Chart ......................................................................................45
3.2
Duration and Study Completion Definition .................................................................47
3.3
Sites and Regions .........................................................................................................47
4.
STUDY POPULATION...............................................................................................48
4.1
Inclusion Criteria..........................................................................................................48
4.2
Exclusion Criteria.........................................................................................................49
4.3
Reproductive Potential .................................................................................................49
4.3.1
Female Contraception............................................................................................49
4.3.2
Male Contraception................................................................................................50
4.4
Discontinuation of Subjects..........................................................................................50
4.4.1
Reasons for Discontinuation..................................................................................51
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit ..................................51
4.4.3
Anaphylactic Reaction...........................................................................................51
4.4.4
Thrombotic or Thromboembolic Event.................................................................51
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................53
5.1
Prior Treatment.............................................................................................................53
5.2
Concomitant Treatment and Medical/Surgical Procedures..........................................53
5.2.1
Management of Angioedema Attacks....................................................................53
5.2.2
Prohibited Treatment .............................................................................................54
6.
INVESTIGATIONAL PRODUCT..............................................................................55
6.1
Identity of Investigational Product...............................................................................55
6.2
Administration of Investigational Product ...................................................................55
6.3
Allocation of Subjects to Treatment Sequence ............................................................55
6.4
Blinding of Treatment ..................................................................................................56
6.4.1
Unblinding the Treatment Assignment..................................................................57
6.5
Treatment Compliance .................................................................................................57
6.6
Packaging and Labeling ...............................................................................................57
6.7
Storage and Accountability ..........................................................................................58
6.8
Investigational Product Retention at Study Site...........................................................58
7.
STUDY PROCEDURES..............................................................................................59
7.1
Study Schedule.............................................................................................................59
7.1.1
Screening Period....................................................................................................59
7.1.2
Treatment Period 1.................................................................................................60
7.1.2.1
Visit 1a (predose) ........................................................................................60
7.1.2.2
Visit 1a (postdose).......................................................................................60


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7.1.2.3
Visit 2a through Visit 28a ...........................................................................61
7.1.3
Treatment Period 2.................................................................................................61
7.1.3.1
Visit 1b (predose) ........................................................................................61
7.1.3.2
Visit 1b (postdose).......................................................................................62
7.1.3.3
Visit 2b through Visit 28b...........................................................................62
7.1.4
Early Discontinuation Visit ...................................................................................63
7.1.5
Follow-up Period ...................................................................................................64
7.2
Study Evaluations and Procedures ...............................................................................65
7.2.1
Demographic and Other Baseline Characteristics .................................................65
7.2.2
Efficacy..................................................................................................................65
7.2.2.1
Definition of an Angioedema Attack ..........................................................65
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary...........65
7.2.2.3
Angioedema Activity Score ........................................................................66
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks .........67
7.2.3
Safety .....................................................................................................................67
7.2.3.1
Medical and Medication History.................................................................67
7.2.3.2
Physical Examination (Including Height and Weight)................................68
7.2.3.3
Adverse Event Collection............................................................................68
7.2.3.4
Vital Signs ...................................................................................................68
7.2.3.5
Clinical Laboratory Evaluations..................................................................68
7.2.3.6
Pregnancy Test ............................................................................................70
7.2.3.7
Electrocardiogram .......................................................................................70
7.2.3.8
Nonpharmacologic Treatments and Procedures..........................................71
7.2.3.9
Thrombotic or Thromboembolic Events.....................................................71
7.2.3.10 Injection Site Reactions...............................................................................72
7.2.4
Others.....................................................................................................................73
7.2.4.1
Clinical Pharmacology Assessments...........................................................73
7.2.4.2
Health-related Quality of Life Assessments................................................73
7.2.4.3
Health Resource Utilization Assessment ....................................................74
7.2.4.4
Survey of Acceptability of SC Administration ...........................................74
7.2.4.5
Self-administration Survey Assessment......................................................75
7.2.5
Volume of Blood to be Drawn From Each Subject...............................................75
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................76
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................76
8.1.1
Severity Categorization..........................................................................................76
8.1.2
Relationship Categorization...................................................................................77


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8.1.3
Outcome Categorization ........................................................................................77
8.1.4
Symptoms of the Disease Under Study .................................................................77
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................78
8.1.6
Pregnancy...............................................................................................................78
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................79
8.2
Serious Adverse Event Procedures...............................................................................80
8.2.1
Reference Safety Information................................................................................80
8.2.2
Reporting Procedures.............................................................................................80
8.2.3
Serious Adverse Event Definition .........................................................................80
8.2.4
Serious Adverse Event Collection Time Frame ....................................................81
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................81
8.2.6
Fatal Outcome........................................................................................................81
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................82
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................83
9.1
Data Collection.............................................................................................................83
9.2
Clinical Data Management...........................................................................................83
9.3
Data Handling Considerations......................................................................................83
9.4
Statistical Analysis Process..........................................................................................83
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........84
9.6
Sample Size Calculation and Power Considerations....................................................84
9.7
Study Population ..........................................................................................................84
9.8
Efficacy Analyses.........................................................................................................85
9.8.1
Primary Efficacy Endpoint ....................................................................................85
9.8.2
Secondary Efficacy Endpoints...............................................................................86
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................86
9.8.2.2
Other Secondary Efficacy Endpoints ..........................................................86
9.8.3
Exploratory Efficacy Endpoints.............................................................................87
9.9
Safety Analyses ............................................................................................................87
9.10
Other Analyses .............................................................................................................88
9.10.1 Pharmacokinetic and Pharmacodynamic Analyses ...............................................88
9.10.2 Health-related Quality of Life Analyses................................................................88
9.10.3 Surveys on SC Administration and Self-administration of Investigational 
Product...................................................................................................................89
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................90
10.1
Sponsor’s Responsibilities ...........................................................................................90


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10.1.1 Good Clinical Practice Compliance.......................................................................90
10.1.2 Public Posting of Study Information .....................................................................90
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................90
10.1.4 Study Suspension, Termination, and Completion .................................................91
10.2
Investigator’s Responsibilities .....................................................................................91
10.2.1 Good Clinical Practice Compliance.......................................................................91
10.2.2 Protocol Adherence and Investigator Agreement..................................................91
10.2.3 Documentation and Retention of Records.............................................................92
10.2.3.1 Case Report Forms......................................................................................92
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................92
10.2.3.3 Audit/Inspection..........................................................................................93
10.2.3.4 Financial Disclosure....................................................................................93
10.3
Ethical Considerations..................................................................................................93
10.3.1 Informed Consent ..................................................................................................93
10.3.2 Institutional Review Board or Ethics Committee..................................................94
10.4
Privacy and Confidentiality..........................................................................................94
10.5
Study Results / Publication Policy ...............................................................................95
11.
REFERENCES.............................................................................................................97
12.
APPENDICES............................................................................................................100
LIST OF TABLES
Table 1:
Schedule of Assessments – Treatment Period 1....................................................22
Table 2:
Schedule of Assessments – Treatment Period 2....................................................24
Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits..............................................................................................26
Table 4:
Blood Sample Collection for PK/PD Analyses .....................................................27
Table 5:
Exposure to SC CINRYZE.......................................................................................32
Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)...................................................................................................35
Table 7:
Treatment Sequences.............................................................................................56
Table 8:
Severity Scoring for Injection Site Reactions........................................................72
Table 9:
Approximate Volume of Blood to be Drawn From Each Subject.........................75


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LIST OF FIGURES
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity .....................................................36
Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)..................................................37
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice Weekly Dose Regimen ...................................................................38
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE 
(Protocol 0624-206)...............................................................................................39
Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103) .............40
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)........40
Figure 7:
Study Design Flow Chart.......................................................................................45
LIST OF APPENDICES
Appendix 1 Handling of Investigational Product for Subcutaneous Injection.......................101
Appendix 2 Subcutaneous Injection Site Selection and Preparation......................................103
Appendix 3 Wells Prediction Rule for the Diagnosis of Venous Thrombembolism .............105
Appendix 4 Algorithm For Suspected Venous Thromboembolism .......................................106
Appendix 5 Algorithm For Suspected Arterial Thromboembolism.......................................107
Appendix 6 Protocol History..................................................................................................108


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ABBREVIATIONS
AE
adverse event
AE-QoL
angioedema quality of life (questionnaire)
AAS
Angioedema Activity Score
ATE
arterial thromboembolism
AUC
area under the curve
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
C1 INH
C1 esterase inhibitor or C1 inhibitor
CI
confidence interval
CL
clearance
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
Cmin
minimum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAE
hereditary angioedema
Β-hCG
beta human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRUA
health resource utilization assessment


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ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
λz
first order rate constant associated with the terminal (log-linear) portion of 
the curve
NNA
normalized number of attacks
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDS
Sheehan Disability Scale
t1/2
terminal half-life
T/TE
thrombotic/thromboembolic
TCSR
time-to-subject-assessed-complete-symptom resolution
TEAE
treatment-emergent adverse event
TISI
time-to-subject-assessed-initial-symptom improvement
tmax
time of maximum observed concentration sampled during a dosing 
interval
US
United States
VAS
Visual Analogue Scale
VTE
venous thromboembolism
WPAI-GH
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire)


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STUDY SYNOPSIS
Protocol number: SHP616-300
Drug: C1 esterase inhibitor [human] liquid for injection
Title of the study: A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, 
Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 U of C1 
Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and 
Adults with Hereditary Angioedema.
Number of subjects (total and for each treatment arm):
Approximately 75 subjects will be screened
At least 66 subjects will be enrolled and randomized to ensure that 54 subjects complete both treatment periods
At least 22 subjects will be randomized to each of the 3 treatment sequences 
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites globally (North America and Europe)
Study period (planned):
2015-2017
Clinical phase:
3
Objectives:
Primary:  
To demonstrate the superior efficacy of subcutaneous (SC) administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
normalized number of attacks (NNA) during a treatment period.
Key Secondary:  
To demonstrate the superior efficacy of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection for the prevention of angioedema attacks relative to placebo as measured by the proportion of subjects 
meeting the criterion of at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] 
liquid for injection treatment period relative to the placebo period.
Other Secondary:

To assess the proportion of responders during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo, where the proportion of responders is defined as:
-
Achieving at least a 50% reduction in the NNA during a treatment period relative to the 
pretreatment assessment (ie, the subject’s attack rate without prophylactic treatment)
-
Achieving a NNA <2.0 during a treatment period

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of attack-free days during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo

To assess the number of angioedema attacks requiring acute treatment during treatment with 2000 U C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo

To assess the safety and tolerability of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SC administration of 2000 U 


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C1 esterase inhibitor [human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment of acute 
angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS)

To evaluate subject experience with self-administration of SC 2000 U C1 esterase inhibitor [human] liquid 
for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient population
Rationale:
Shire ViroPharma has developed a new, ready-to-use liquid formulation of CINRYZE® for SC administration. 
This product, C1 esterase inhibitor [human] liquid for injection, obviates the need for reconstitution by the 
patient or health care provider and, owing to its higher concentration, affords the opportunity for more rapid 
administration of the drug and may improve tolerability, without an expected change or compromise in efficacy.
Subcutaneous administration represents a convenient alternative method of administering prophylaxis to 
hereditary angioedema (HAE) patients overall and for whom accessing peripheral veins is difficult or in patients 
where placement of central venous catheters are contraindicated, as well as a means to minimize the potential 
adverse effects of intravenous (IV) administration.
Investigational product, dose, and mode of administration:

C1 esterase inhibitor [human] liquid for injection is supplied in clear glass vials containing 1000 U of 
C1 INH in 2 mL of sterile liquid. The solution also contains the following inactive ingredients: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.

Placebo is supplied in the identical 2 mL presentation as the active investigational product minus the 
C1 INH protein. The inactive ingredients in the 2 mL solution are the same as the active product: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.
Blinded investigational product (Treatments A or B: 2000 U C1 esterase inhibitor [human] liquid for injection 
or placebo) will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate treatment 
periods. Each dose of investigational product will be administered in the subject’s abdomen as a single 4 mL SC 
injection.
Methodology:
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial crossover study. 
This design was chosen as the best way to jointly address the protocol objectives of establishing efficacy 
(relative to placebo) and safety (ie, enrolling an adequate number of subjects for precision of estimation in 
detecting potential safety signals). Additionally, this design maximizes the number of subjects exposed to 
C1 esterase inhibitor [human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have a history (based 
on subject recall and medical records) of ≥3 attacks per month on average per inclusion criterion #3. Based on 
statistical simulation, at least 25% of randomized subjects with a baseline attack rate ≥4.0 per month average 
need to be included in this study for the efficacy analysis population in order to detect a significant reduction 
(<2) in NNA from baseline. At least 66 eligible subjects will be randomized to 1 of 3 treatment sequences prior 
to the first dose of investigational product in Treatment Period 1 using interactive response technology (see table 
below). Randomization of subjects will be stratified by use of prophylactic therapy with C1 INH at the time 
enrollment.


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Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects Randomized
1
A/B
22
2
B/A
22
3
A/A
22
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 
3 or 4 days) for 14 weeks.
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission of a washout 
period is to minimize the duration that subjects will be without active treatment. It is recommended that the 
twice weekly dosing schedule (every 3 or 4 days) be maintained between the last dose of investigational product 
in Treatment Period 1 and the first dose of investigational product in Treatment Period 2.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be blinded to 
treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be administered at the 
investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both treatment periods. Other doses may be 
administered by qualified blinded personnel at the investigational site or at the subject’s home or other agreed 
upon location. During Treatment Period 2, after having received appropriate training, subjects will be allowed to 
self-administer the investigational product with direct supervision by study site personnel or a qualified home 
health professional. Alternatively, a parent/legal guardian/caregiver will be allowed to administer the 
investigational product to an adolescent subject, after having received appropriate training and under the 
supervision of study site personnel or a qualified home health professional. Throughout the study, an electronic 
subject diary will be used to record specific information regarding the subject’s symptoms of HAE. This will 
include signs and symptoms of angioedema attacks, location (including whether mucosal or non-mucosal), 
triggers for angioedema attacks, medications used for the acute treatment of angioedema attacks, elective 
procedures, and interruptions in activities of daily living due to an angioedema attack. Additionally, quality of 
life questionnaires and surveys on SC administration of the investigational product will be also subject 
evaluated. Note: For adolescent subjects, a parent/legal guardian/caregiver is allowed to assist the subject in 
completing the electronic subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product is administered. In addition, the investigator will report all SAEs that 
occur through 30 days after the last dose of investigational product to Shire Pharmacovigilance and the 
respective Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last dose of 
investigational product in Treatment Period 2 for follow-up safety assessments. In addition, subjects will have 
blood samples collected for PK/PD and C1 INH antibody testing at 1 month (±2 days) after the last dose of 
investigational product.
If a subject prematurely discontinues investigational product, early discontinuation visit procedures (Table 3) 
are to be performed as completely as possible. Whenever possible, all discontinued subjects should also 
complete the 1-week and 1-month post-treatment visits.  
The schedules of study procedures are provided immediately following the study synopsis:

Table 1: Clinical study assessments – Treatment Period 1 (Visits 1a to 24a).

Table 2: Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Table 3: Clinical study assessments – Early discontinuation visit, 1-week post-treatment and 1-month 
post-treatment visits.

Table 4: Blood sample collection schedule – PK/PD assessments


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Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 inhibitor (C1 INH) level less than 50% of 
normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in conjunction with the 
subject’s medical records):

If currently receiving prophylactic therapy with C1 INH, have a history of ≥3.0 angioedema 
attacks per month (average) during the 3 consecutive months prior to starting prevention therapy. 
OR

If not receiving prophylactic therapy with C1 INH, have a history of ≥3.0 angioedema attacks per 
month (average) during the 3 consecutive months prior to the screening visit.
OR

If currently receiving a stable dose of attenuated androgens, have a history of ≥3.0 angioedema 
attacks per month (average) during the 3 consecutive months prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any angioedema attacks 
that occur during the study that, in the opinion of the healthcare care provider, requires medical 
intervention. Note: For subjects ≥12 to <18 years of age, standard of care therapy per local protocols 
should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) pregnancy test at 
the screening visit and must have a negative urine pregnancy test prior to the first dose of 
investigational product (Visit 1a), and agree to comply with any applicable contraceptive requirements 
of the protocol.
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, 
barrier control) from the screening visit through 2 months after the last dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide written informed 
consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study 
provide written informed consent for the child to participate in the study before any study-specific 
procedures are performed (with assent from the child when appropriate). Alternatively, certain 
sites/Independent Reviewing Authorities may permit adolescents who are <18 years of age to be 
informed of the nature of the study and provide written informed consent without consent from a 
parent(s)/legal guardian.
Exclusion Criteria:
1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 1000 U every 3 or 
4 days (receiving a weekly dose >2000 U).
2.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose of 
investigational product in Treatment Period 1.
3.
Have received any C1 INH therapy or any blood product for the treatment or prevention of angioedema 
attacks within 3 calendar days prior to the first dose of investigational product in Treatment Period 1.
4.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism.
5.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies.
6.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of 


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CINRYZE), or other blood products.
7.
Be pregnant or breastfeeding.
8.
Have received an investigational drug within 30 days prior to the first dose of investigational product in 
Treatment Period 1.
9.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical or medical 
condition that could interfere with the administration of investigational product or interpretation of 
study results.
Maximum duration of subject involvement in the study:
Individual participation from the screening visit through the 1-month post-treatment visit will be approximately 
9 months.

Planned duration of screening period: Up to 21 days

Planned duration of enrollment period: 6 months

Planned duration of treatment period: Treatment Periods 1 and 2 are 14 weeks each (total 28 weeks) with 
no washout between periods

Planned duration of follow-up: 1 month follow-up in total, with safety assessments at both 1-week and 
1-month post-treatment
Endpoints and statistical analysis:
Primary Efficacy Endpoint: The NNA recorded during each treatment period. The NNA is computed as the 
number of attacks per month (ie, 30.4 days) of exposure (NNA = 30.4 x [number of attacks during treatment 
period]/[days of treatment period]). If a subject discontinues during the treatment period, the denominator of the 
NNA will be the days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation. 
The primary analysis of the primary efficacy endpoint will test against the null hypothesis that the NNA of C1 
esterase inhibitor [human] liquid for injection is greater than or equal to the NNA of placebo 
(H0: µ C1 INH - µ placebo >0; H1: µ C1 INH - µ placebo <0). The primary efficacy endpoint will be analyzed by using a 
mixed effect linear model with period, sequence, and treatment as fixed effects, and subject nested within 
sequence as a random effect. The mean treatment difference (µ C1 INH - µ Placebo) will be estimated with a 
95% confidence interval (CI).
To control the overall type 1 error, the primary and key secondary endpoints will be tested hierarchically, so that 
the significance of the key secondary endpoint is contingent on whether the primary endpoint is significant.
Key Secondary Efficacy Endpoint: The clinical response to treatment relative to placebo. This is defined as 
achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion PR. The null 
hypothesis is that PR is less than or equal to 0.2 and the alternative hypothesis is that PR is greater than 0.2. The 
proportion meeting criterion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. 
Other Secondary Efficacy Endpoints:

To determine the proportions of subjects with a clinical response to treatment as defined by: 
-
Achieving at least a 50% reduction in the NNA during a treatment period relative to the pretreatment 
assessment
-
Achieving a NNA <2.0 during a treatment period 

Cumulative attack severity. This score is the sum of the maximum symptom severity recorded for each 
angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every day of reported 


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symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment during a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS during a treatment 
period, where the daily AAS is the sum of AAS items per day.

Results of the Angioedema Quality of Life (AE-QoL) questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema attack by:
-
Time to subject-assessed initial symptom improvement (TISI).
-
Time to subject-assessed complete symptom resolution (TCSR). 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC administration of C1 
esterase inhibitor [human] liquid for injection. The treatment differences in clinical responder rate, both of 
which are defined within treatments, will be analyzed using McNemar’s test for testing equality of proportions 
of responders within treatments. All other secondary endpoints will be analyzed using a linear mixed effect 
model with period, sequence, and treatment as fixed effects, and subject nested within sequence as a random 
effect. The results of all secondary efficacy analyses will be summarized by the point estimate of within-subject 
treatment differences or response rates and the corresponding 95% CI. Descriptive statistics (n, median, 25% 
and 75% quartiles, and range) will be provided to summarize icatibant-related efficacy endpoints (TISI and 
TCSR) by treatment and icatibant-treated angioedema attack for all subjects in the Full Analysis Set. Where 
appropriate (for subjects ≥12 to <18 years of age) other rescue medications used to treat acute angioedema 
attacks will also be summarized using descriptive statistics. In addition, angioedema attacks will be summarized 
by the maximum symptom severity and treatment for all subjects in the Full Analysis Set.
Safety Endpoints:

Number of subjects experiencing AEs, including severity and causality. AEs will also be assessed by time 
of onset (eg, during administration of investigational product or within 24 hours after the end of injection of 
investigational product). 

Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings will be 
summarized by treatment and visit. Potentially clinically important findings will also be summarized or 
listed. 

Incidence and severity (mild, moderate, severe) of SC injection site reactions. 

Results of C1 INH antibody testing will be reported for individual subjects and summarized. 

Tolerability of icatibant therapy for acute angioedema attacks will be summarized.
PK/PD Endpoints: Plasma concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
and C1q for individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics for values at each time point. C1q concentrations will only be assessed 
at baseline (ie, pre-injection, Dosing Visit 1a).
PK parameters will be calculated using observed and baseline-corrected concentration-vs-time data using non-
compartmental techniques for C1 INH antigen and functional activity, and results will be summarized using 
descriptive statistics.
Other Endpoints:

Results of the EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) health status instrument will 
be presented in accordance with the EQ-5D-5L user guide (Version 2.0). 

Results of the Work Productivity and Activity Impairment−General Health (WPAI-GH) questionnaire will 
be summarized. 

Results of the Sheehan Disability Scale (SDS) will be summarized.

Results of the survey of subject acceptability of SC administration of investigational product will be 


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summarized.

Results of the survey of subject experience with self-administration of investigational product will be 
summarized. 


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STUDY SCHEDULES
Table 1:
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a 26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj




























Acceptability surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m,
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c,n
c,n
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4


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AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report 
form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; HRUA=health
resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; 
PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the 
injection.
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
g HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection.
k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see Table 
4).


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Table 2:
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg




























Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4


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AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; 
INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan 
Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site.
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing 
days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.
d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection.
h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.


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Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits
Procedures
Early Discontinuation 
Visita
[If Applicable]
1-Week (±1 day)
Post-treatment 
Visit
[All Subjects]
1-Month (±2 days)
Post-treatment
Visit
[All Subjects]
Concomitant medications


Physical examination


Vital signs (BP, pulse)b


Safety labsc


UA with microscopy


Pregnancy testingd


Adverse events


Angioedema attack monitoringe, f


AASe


Acceptability surveye

Self-administration surveye

AE-QoL questionnairee


EQ-5D-5Le


WPAI-GH and SDSe


HRUA-HAE

Immunogenicity (anti-C1 INH antibodies)



PK/PD



AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; 
BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level 
descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs 
that occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department.
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits. 
b Vital signs will be measured using standard methods at each investigational site. 
c Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer).  
d A urine pregnancy test will be performed for all female subjects of childbearing potential.
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation or at the 
1-week post-treatment visit.
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary.


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Table 4:
Blood Sample Collection for PK/PD Analyses
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Pointsa
C1 INH Antigen, C1 INH Functional, C4
1a / Dose 1b
Predose 1 (within 15 min) 
2a / Dose 2
Predose 2 (within 15 min)
8a / Dose 8
Predose 8 (within 15 min)
16a / Dose 16
Predose 16 (within 15 min) 
24a / Dose 24
Predose 24 (within 15 min)
Either 27a or 28a / Dose 27 or 28c
Predose 27 or 28 (within 15 min) 
48 hours postdose 27 or 28 (±3 hours)
TREATMENT PERIOD 2
1b / Dose 1
Predose 1 (within 15 min)
2b / Dose 2
Predose 2 (within 15 min)
8b / Dose 8
Predose 8 (within 15 min)
16b / Dose 16
Predose 16 (within 15 min)
24b / Dose 24
Predose 24 (within 15 min)
28b / Dose 28
Predose 28 (within 15 min)
24 hours postdose 28 (±3 hours) – optional sampling time point
48 hours postdose 28 (±3 hours) 
72 hours postdose 28 (±6 hours) – optional sampling time point
96 hours postdose 28 (±6 hours)
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT
Early discontinuation
1-week (± 1 day)
1-month (± 2 days)
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for 
guidance is as an approximate value.
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a).
c To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose
sample to be collected at either Visit 27a or 28a. 


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Hereditary angioedema (HAE) is an autosomal dominant disease caused by a gene mutation 
on chromosome 11 that results in a quantitative or functional deficiency of C1 esterase 
inhibitor (C1 INH) protein (Bernstein 2011). C1 INH is produced mainly by hepatocytes and 
acts as a “suicide inhibitor” by forming complexes with target serine proteases that result in 
their inactivation and the consumption of C1 INH. C1 INH regulates the activity of several 
components of the complement, contact (bradykinin-forming), and fibrinolytic systems 
(Kaplan 2010). Dysregulation of these cascades (particularly the contact system) due to 
C1 INH deficiency causes the uninhibited production of bradykinin, which promotes 
inflammation through increased vascular permeability and excessive accumulation of fluid in 
body tissues (Kaplan and Joseph 2010). Thus, patients with HAE are susceptible to recurrent 
episodes of debilitating swelling throughout the body. During acute angioedema attacks, the 
plasma levels of bradykinin in HAE patients can increase from 2 to 12 times (18.0–90.0 pM) 
the upper limit of normal (0.2-7.1 pM; Cugno et al. 2003). Serum concentrations of C1 INH 
in patients with HAE are 5% to 30% of normal (Cicardi et al. 1987), thus necessitating C1 
INH replacement therapy to prevent manifestations of the disease.
The diagnosis of a C1 INH deficiency is suggested by a history that includes recurrent attacks 
of angioedema, characterized by non-itching swelling of the skin or mucosa. Serum C4, 
C1 INH antigen, and functional C1 INH levels can be measured to assist with the diagnosis of 
HAE. There are 2 main types of HAE: Type I HAE (85% of cases), characterized by a low 
level of C1 INH antigen, and Type II HAE (15% of cases), characterized by “normal” levels 
of functionally deficient C1 INH protein (Frank et al. 1976). There is no clinical difference 
between Type I and Type II HAE. A third form of HAE, where patients have normal C1 INH 
levels, was initially described and referred to as Type III (Bork et al. 2000a). Patients with this
type of HAE, more frequently women, have normal complement levels (including normal 
C1 INH), but a well-defined history of angioedema in the absence of concurrent urticaria 
(Zuraw and Christiansen 2009; Bernstein 2011). Mutations in the gene for coagulation factor 
XII (F12) have been identified in a minority of affected families (Bork et al. 2007). There are
subtle phenotypic differences between patients with HAE due to C1 INH deficiency and those 
with normal C1 INH levels, including age at symptom onset, attack location(s), period of 
disease-free intervals, and inheritance pattern (Zuraw et al. 2012). The pathogenesis of HAE 
with normal C1 INH remains to be fully elucidated.  
Hereditary angioedema with C1 INH deficiency can present as early as the first year of life 
(Ohela 1977; Farkas et al. 2002), however, the median age at onset of initial symptoms is 
between 9 and 12 years (Farkas et al. 2007). Nearly all affected individuals experience 
symptoms of the disease; however, the symptoms vary in both their frequency and severity 
throughout a patient’s lifetime (Gompels et al. 2005; Zuraw 2003). Angioedema attacks may 
or may not have a triggering event. Trauma, medical or dental procedures, psychological 
stress, menstruation, infections, oral contraceptive use, and the use of other medications, such 
as angiotensin-converting enzyme inhibitors have been identified as possible triggers (Georgy 
and Pongracic 2012; Bowen et al. 2010). Angioedema attacks can affect the face, tongue, 


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larynx, gastrointestinal tract, genitourinary system, and extremities (Zuraw 2008). Laryngeal 
swelling can occlude the airway and cause death by asphyxiation, and these attacks primarily 
account for the mortality risk associated with C1 INH deficiency (Agostoni and Cicardi 1992; 
Bork et al. 2000b). Gastrointestinal involvement can mimic an acute surgical emergency, and 
misdiagnosis often results in unnecessary procedures to remove normal appendices and 
gallbladders (Weis 2009). Hence, angioedema attacks require prompt treatment, often in an 
emergency room.  
In addition to the impact on physical and mental health, the burden of illness in patients with 
HAE is considerable with respect to missed educational and career opportunities, work 
productivity, and a substantial economic burden for the cost of treatment (Lumry et al. 2010; 
Aygören-Pürsün et al. 2014). Hereditary angioedema not only causes short-term disability 
associated with attacks, but patients endure long-term effects on their daily lifestyle, 
emotional health, family life, and it may also affect caregivers’ quality of life (Bygum et al. 
2015). Effective management of HAE, including optimization of therapy, may reduce the 
clinical burden and have an overall favorable impact on the quality of life for individual HAE 
patients and their families (Banerji 2013; Caballero et al. 2014).
1.2
Product Background and Clinical Information
CINRYZE® (C1 esterase inhibitor [human]) was developed by the sponsor for the management 
of HAE. CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of C1 INH 
produced 
from 
human 
plasma. 
The 
manufacturing 
process 
includes 
3 
virus 
inactivation/removal 
steps: 
polyethylene 
glycol 
precipitation, 
pasteurization, 
and 
nanofiltration. CINRYZE is a normal human plasma protein that is not subject to cytochrome 
P450 metabolism, excretion, or pharmacokinetic (PK) drug-drug interactions exhibited by low 
molecular weight compounds. 
Intravenous administration of 1000 U of CINRYZE every 3 or 4 days is approved for routine 
prevention (prophylaxis) of angioedema attacks in patients with HAE in the United States 
(2008), European Union (2011), Australia (2012), Canada (2012), and Switzerland (2013). In 
several of these countries, CINRYZE is also approved for the acute treatment and preprocedure 
prevention of angioedema attacks.
The clinical efficacy of CINRYZE for the prevention of angioedema attacks in patients with 
HAE was demonstrated in 1
randomized, double-blind, placebo-controlled study 
(LEVP 2005-1/B) and 1
open-label study (LEVP 2006-4). Study LEVP 2005-1/B 
demonstrated that preventive therapy with CINRYZE resulted in both a statistically significant 
and clinically meaningful decrease in the rate, severity, and duration of acute attacks 
compared to placebo/on-demand therapy. Therapy with CINRYZE also increased antigenic 
C1 INH and functional C1 INH levels. These results were supported by Study LEVP 2006-4 
(that provided data for longer periods of preventive therapy across a wider age range of 
subjects), which demonstrated a reduction in the frequency of attacks while on CINRYZE
compared to a historical baseline. The open-label study also demonstrated that the efficacy of 
CINRYZE for the prevention of angioedema attacks did not diminish over time periods of at 
least 1 year. 


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The sponsor initiated a clinical development program for subcutaneous (SC) administration of 
CINRYZE for prevention of angioedema attacks using the same lyophilized formulation as that 
approved for IV injection. The initial program focused on safety, tolerability, and relative 
bioavailability of SC administration of CINRYZE (Studies 0624-100 and 0624-200). 
Preliminary assessments confirmed that CINRYZE can be absorbed after SC administration. 
However, because the exposure profile differed from that following IV administration, it was 
not known whether or to what extent SC administration would confer efficacy for the 
management of HAE.  
Based on results from nonsponsor studies conducted with recombinant human hyaluronidase 
(rHuPH20) and other injectable protein products, it was hypothesized that co-administration 
with rHuPH20 would increase dispersion and absorption of subcutaneously injected CINRYZE. 
Subsequently, 
the 
development 
program 
evaluated 
the 
safety, 
tolerability, 
PK/pharmacodynamics (PD), and efficacy of SC administration of CINRYZE with rHuPH20 
(Studies 0624-101, 0624-102, 0624-204, and 0624-206). However, in August 2013, the FDA 
directed the sponsor to stop administration of rHuPH20 in the ongoing Phase 2 study (0624-
206) of CINRYZE with rHuPH20 due to the development of anti-rHuPH20 antibodies in some 
patients. Dosing was also terminated in an ongoing Phase 1 healthy volunteer study (0624-
102) of CINRYZE with rHuPH20. Because the combination product (CINRYZE with rHuPH20) 
was being studied in these 2 trials, administration of CINRYZE was also discontinued. The 
FDA encouraged the sponsor to further the clinical development of CINRYZE alone 
administered via SC injection. Hence the evolution of the clinical development program with 
the new low volume, ready-to-use liquid formulation (C1 esterase inhibitor [human] liquid for 
injection) for SC administration. 
C1 esterase inhibitor [human] liquid for injection has been evaluated in an in vitro 
hemocompatibilitiy assay using human blood and plasma, a tissue irritation study in New 
Zealand White rabbits, and a 14-day repeat-dose toxicity study in Sprague Dawley rats. 
Incubation with whole blood at a concentration of 225 U/mL C1 esterase inhibitor [human] 
liquid for injection did not elicit hemolysis nor did the same concentration induce 
flocculation, precipitation, or coagulation. In the tissue irritation study in rabbits, microscopic 
examination of the injection sites showed minimal to mild inflammation that was most 
pronounced for perivascular injection route, followed by SC and then IV injection routes. In 
the 14-day repeat-dose study in rats, doses of 0 (sodium phosphate, glycine, and sorbitol), 
200, 400, and 1000 U/kg/day were administered subcutaneously once a day, while a fifth 
group of rats received 1000 U/kg/day intravenously. The only signs of toxicity were related to 
the expected immunogenic response to a human protein. Therefore, the no observed adverse
effect level is considered to be 1000 U/kg/day of C1 esterase inhibitor [human] liquid for 
injection for both the SC and IV routes of administration. Therefore, the toxicity profile for 
this ready-to-use liquid formulation is generally comparable to the lyophilized product even 
when a higher dose of the new formulation was tested. 
An initial clinical assessment of the new liquid formulation was conducted in a Phase 1 study 
in healthy volunteers (SHP616-103). This study evaluated the safety, tolerability, and relative 
bioavailability of the SC administration of 1000 U and 2000 U C1 esterase inhibitor [human] 
liquid for injection compared with the marketed formulation of CINRYZE (1000 U IV). This 


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single-center, open-label study consisted of a single-dose IV administration of CINRYZE
(lyophilized formulation) in Treatment Period 1 followed by a randomized, open-label, 2x2 
crossover design (Treatment Periods 2 and 3) to evaluate SC C1 esterase inhibitor [human] 
liquid for injection. The safety and pharmacokinetic results from Study SHP616-103 are
presented in Sections 1.2.1.1 and 1.2.2.2, respectively.
High-level summaries of the clinical experience with SC administration of both CINRYZE
(CINRYZE alone and CINRYZE + rHuPH20) and C1 esterase inhibitor [human] liquid for 
injection are provided below. Always refer to the latest version of the CINRYZE investigator’s 
brochure for the overall risk/benefit assessment and the most accurate and current information 
regarding the drug metabolism, pharmacokinetics, efficacy, and safety of CINRYZE and C1 
esterase inhibitor [human] liquid for injection. 
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection
Studies that evaluated SC administration of CINRYZE alone and CINRYZE with rHuPH20 
provided valuable data that informed key elements of this Phase 3 study of C1 esterase 
inhibitor [human] liquid for injection. Both programs enrolled healthy volunteers and subjects 
with HAE; 86 healthy volunteers (215 doses administered) and 72 subjects with HAE 
(1321 doses administered) have received 1 or more doses of SC CINRYZE in the development 
program to date (Table 5).


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Table 5:
Exposure to SC CINRYZE
Program
Study Number
Total Number of 
Subjects Exposed 
Number of SC Doses Administered
500 U
1000 U
2000 U
Total Doses
Healthy Volunteers
CINRYZE Alone
Study 0624-100a
9
1
0
14
15
Study 0624-102b
37 
0
37
0
37
CINRYZE with rHuPH20
Study 0624-101
24
0
0
47
47
Study 0624-102b
51 
0
116
0
116
Healthy Volunteers Total
86
1
153
61
215
Subjects with HAE
CINRYZE Alone
Study 0624-200
25
0
52
48
100
CINRYZE with rHuPH20
Study 0624-204
12 d
0
24
24
48
Study 0624-206
47
0
578
595
1173
Subjects with HAE Total
72
0
654
667
1321
OVERALL TOTAL
158
1
807
728
1536
HAE=hereditary angioedema; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
a CINRYZE via SC infusion and SC injection.
b A total of 53 subjects were enrolled in Study 0624-102 and received SC CINRYZE either alone (N=37) or co-administered 
with rHuPH20 (N=51).
c These 12 subjects received SC CINRYZE alone in Study 0624-200 and SC CINRYZE with rHuPH20 in Study 0624-204.
1.2.1.1
Clinical Safety 
Across the 2 studies of SC CINRYZE alone (Studies 0624-100 and 0624-200), 9 healthy adults 
and 25 subjects with HAE received CINRYZE doses of 1000 U and/or 2000 U. In healthy adult 
subjects, a single dose of 2000 U CINRYZE administered via the SC route was associated with 
mild injection/infusion site discomfort; however, no subjects were discontinued from study 
drug due to an AE. In HAE subjects, multiple doses of CINRYZE (1000 U or 2000 U) 
administered via the SC route were associated with generally mild to moderate injection site 
reactions, most notably pain, which was commonly characterized as burning or stinging. No 
subjects were discontinued from study drug due to an injection site reaction. No SAEs 
occurred during either SC study, and no subjects experienced a TEAE that was thrombotic or 
thromboembolic in nature. In addition, in both studies of SC CINRYZE, results of clinical 
laboratory evaluations and vital signs measurements were generally unremarkable and did not 
suggest any treatment-emergent abnormalities related to the administration of CINRYZE.
Across the 4 studies of SC CINRYZE + rHuPH20 (Studies 0624-101 0624-102, 0624-204 and 
0624-206), 77 healthy adults and 59 subjects with HAE received CINRYZE doses of 1000 U 


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and/or 2000 U. No SAEs occurred, no subjects were discontinued due to an AE, and no 
subjects experienced a TEAE that was thrombotic or thromboembolic in nature. The most 
commonly reported AEs were mild-moderate injection site reactions (eg, erythema, swelling, 
pain). Other safety parameters (clinical laboratory evaluations and vital signs measurements) 
were generally unremarkable and did not suggest any treatment-emergent abnormalities 
related to the administration of SC CINRYZE + rHuPH20. 
In Study 0624-206, a total of 21 (45%) subjects had detectable anti-rHuPH20 antibodies 
during the study, with 15 (32%) of the 21 subjects having a post-baseline titer of >1:20. All 
samples from these subjects were determined to be negative for rHuPH20-neutralizing 
activity. As requested by the FDA, the sponsor followed subjects who had treatment-emergent 
titers of ≥1:20 for 1 year post-treatment. There were no clinical sequelae observed in any 
subject and all titers declined during longitudinal follow-up. Three subjects in Study 0624-102 
had reportable anti-rHuPH20 antibodies at a titer ≥1:20; however, in all 3 cases, subjects had 
antibodies to rHuPH20 present at baseline (prior to the first dose of study drug). Subjects 
were not asked to participate in longitudinal follow-up, as anti-rHuPH20 antibody titers 
remained at or below the baseline level for each subject by the end of the study. 
In Study SHP616-103, a total of 26 healthy volunteers were enrolled in the study. Twenty-
three (23) subjects received a single SC dose of both 1000 and 2000 U, and 1 subject only
received a single SC dose of the 1000 U C1 esterase inhibitor [human] liquid for injection. 
Therefore 24 unique subjects have been exposed to 47 doses of C1 esterase inhibitor [human] 
liquid for injection.
Subcutaneous administration of 1000 U and 2000 U C1 esterase inhibitor [human] liquid for
injection was generally well tolerated and the clinical safety data were consistent with 
previous CINRYZE IV or SC studies. Overall 19 (73.1%) of the 26 subjects reported at least 1 
TEAE in the study: 62% (16/26), 29% (7/24), and 44% (10/23) of subjects administered 
1000 U IV CINRYZE, 1000 U and 2000 U of SC C1 esterase inhibitor [human] liquid for 
injection, respectively.
With regard to the local tolerability of SC administration of 1000 U and 2000 U C1 esterase 
inhibitor [human] liquid for injection, there was no clear difference in the overall incidence of 
injection site reactions with respect to dose (1000 U versus 2000 U). Twenty-three of 24 
(95.8%) subjects reported injection site reactions, all were mild (58.3%) to moderate (37.5%) 
in severity, and the majority resolved within 2 hours postdose. The majority of reported 
reactions were erythema (mild or moderate) and a warm sensation (all mild).
1.2.1.2
Clinical Efficacy
The Phase 2 dose-ranging, crossover Study 0624-206 was designed to determine if there was 
a difference in efficacy between 2 SC doses of CINRYZE (1000 U and 2000 U co-administered 
with rHuPH20). The study was terminated before enrollment was complete (at the request of 
FDA due to the detection of anti-rHuPH20 antibodies in some subjects). Of the 47 subjects 
enrolled, 22 completed both treatment periods. Thus, due to the early termination of the study, 
the final sample size of the intent-to-treat efficacy population was smaller than planned 


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(22/47, 47%). Regardless, the statistical advantage of a crossover study is that patients serve 
as their own control and the relative effect of the experimental treatments can be determined 
most efficiently with respect to within-patient differences.
The experimental results favored twice weekly SC administration of CINRYZE 2000 U + 
48,000 U rHuPH20 compared with CINRYZE 1000 U + 24,000 U rHuPH20 for the primary 
and all secondary efficacy endpoints during treatment, most notably in the within-subject 
treatment comparison.
An analysis of primary and secondary efficacy endpoints during treatment was performed for 
the mean difference between treatments (2000 U – 1000 U SC CINRYZE), within subjects in a 
treatment sequence and overall, as shown below in Table 6.
For the primary endpoint of normalized number of angioedema attacks during treatment, a 
treatment effect favoring the 2000 U compared with the 1000 U SC CINRYZE dose was 
observed for the within-subject treatment comparison; the overall mean difference (95% 
confidence interval [CI]) between treatments was -0.61 (-1.23, 0.01) and achieved borderline 
significance (p=0.0523).
With regard to secondary efficacy endpoints, statistically significant (p<0.05) treatment 
effects favoring the 2000 U compared with the 1000 U SC CINRYZE dose were observed for 
the within-subject treatment comparisons for both cumulative attack severity and for the 
number of attacks requiring acute treatment, with overall mean differences between 
treatments of -1.33 (p=0.0277) and -0.56 (p=0.0315), respectively.
No sequence effect was observed for the mean difference between the 2000 U and 1000 U SC 
CINRYZE doses within subjects in Sequences A/B or B/A for the primary or for any secondary 
endpoint (p-value for sequence effect across endpoints: ≥0.6290).
These findings indicated that CINRYZE at a dose of 2000 U SC was superior to a dose of 
1000 U in terms of clinical efficacy improvement. The results are more compelling in light of 
their arising from truncated enrollment and consequently, an underpowered study.


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Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)
Endpoints (Normalized)
Sequence A/B
Difference: B-A
N=12
Sequence B/A
Difference: B-A
N=10
Overall
Difference: B-A
N=22
Treatment
Comparison
p-valuea
Primary
Number of angioedema attacks
-0.72
(-1.71, 0.27)
-0.48
(-1.36, 0.40)
-0.61
(-1.23, 0.01)
0.0523
Secondary
Cumulative attack severity
-1.53
(-3.41, 0.35)
-1.09
(-2.74, 0.57)
-1.33
(-2.49, -0.16)
0.0277
Cumulative daily severity
-1.53
(-4.42, 1.36)
-2.19
(-6.06, 1.69)
-1.83
(-3.98, 0.32)
0.0912
Cumulative symptomatic days
-0.95
(-2.64, 0.74)
-0.87
(-3.35, 1.62)
-0.91
(-2.23, 0.41)
0.1660
Number of attacks requiring acute 
treatment
-0.67
(-1.20, -0.14)
-0.43
(-1.47, 0.62)
-0.56
(-1.06, -0.05)
0.0315
CI=confidence interval; ITT-E=intent-to-treat efficacy; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
Note: Data are presented as the mean (95% CI). Treatment A=1000 U SC CINRYZE + 24,000 U rHuPH20; 
Treatment B=2000 U SC CINRYZE + 48,000 U rHuPH20. Subjects who were dosed but did not have any attacks in the 
period were assigned a value of zero for each of the efficacy parameters.
a p-value for paired t-test.
b Only subjects who completed both treatment periods are included in the ITT-E population.
1.2.2
Pharmacokinetics of CINRYZE and C1 Esterase Inhibitor [Human] Liquid for 
Injection
1.2.2.1
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis of CINRYZE
Population PK and PK/PD modeling of C1 INH and C4 were developed based on data 
collected in 10 clinical studies with healthy volunteers and HAE patients who received IV or 
SC administrations of CINRYZE. Exposure-response analyses were performed based on 
2 studies for the use of CINRYZE for the prophylactic treatment to prevent HAE. 
The final population PK model of C1 INH was a 1-compartment model with endogenous 
C1 INH levels. The absorption of CINRYZE following SC dosing was characterized with a 
first-order rate and relative absorption fraction (Frel). Based on the population PK model, the 
relative bioavailability of CINRYZE following SC dosing without rHuPH20 was 38.8%. 
Typical CL of C1 INH was 0.0864 L/h (1.44 mL/min) in HAE patients with a typical body 
weight of 70 kg. The t1/2 of C1 INH in a typical 18.0, 36.6, and 80.0-year-old patient weighing 
70 kg were 32.0, 29.0, and 26.0 hours, respectively.
The effect of rHuPH20 on the rate and extent of absorption of C1 INH was included in the 
model. The use of rHuPH20 with SC administration appears to have little to no improvement 
on C1 INH exposure. This was illustrated in the Phase 1 study with healthy volunteers 


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(Study 0624-102) where CINRYZE 1000 U SC administered with 200, 2000, or 20,000 U 
rHuPH20 was not statistically different in Cmax and AUClast compared with CINRYZE alone. In 
addition, the population PK model estimated only a 10% increase in bioavailability with 
rHuPH20, which reached saturation with increasing rHuPH20 concentrations as presented in
Figure 1.
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity
C1 INH=C1 esterase inhibitor; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
The population PK model was used to support the assessment of the exposure-response 
relationship of CINRYZE during prophylactic treatment of angioedema attacks for C1 INH and 
C4. The response criterion originally used in Study 0624-400 was used to define responder 
status, whereby a response was defined as ≤1 angioedema attack/month, since this criterion 
has been deemed clinically meaningful by both expert clinicians and patients with HAE. A 
logistic regression model was used to link Cmin values of C1 INH (continuous) with the 
probability of response (binary) following IV dosing of 1000 U of CINRYZE in studies LEVP 
2005-1/B and LEVP 2006-4 (Section 1.2). The exposure-response relationship of Cmin values 
of C1 INH following IV dosing of CINRYZE is presented in Figure 2.


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Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)
C1 INH=C1 esterase inhibitor; ROC=receiver-operating characteristic
Higher Cmin values of C1 INH were associated with a higher probability of response in 
patients with HAE (p<0.001). The above exposure-response relationship was to be used to 
predict the probability of response for any Cmin values of C1 INH in subjects with HAE. For 
example, typical Cmin values of 0.207, 0.289, 0.380, and 0.556 U/mL (corresponding to first, 
second, third, and fourth quartiles of Cmin of C1 INH, respectively) would be expected to 
result in response probabilities of 54.4%, 61.5%, 68.8%, and 80.5%, respectively. Typical C1 
INH plasma functional activity levels in HAE patients range from 5–30% of normal 
(0.05-0.3 U/mL) (Cugno et al. 1990).
Receiver-operating characteristic analysis was used to identify an optimal Cmin cutoff of C1 
INH that would optimize the probability of avoiding an angioedema attack. Based on data 
from study LEVP 2006-4 with IV administration of 1000 U CINRYZE approximately twice 
weekly, the optimal Cmin cutoff was 0.479 U/mL. When considering a 2-week period of delay, 
the optimal Cmin cutoff was 0.433 U/mL. Based on the above ROC analyses, a targeted C1 
INH Cmin value of 0.45 U/mL was used to determine the expected response following SC 
dosing of 2000 U of CINRYZE. Based on the exposure-response model, a C1 INH Cmin value 
of >0.45 U/mL would achieve at least a 70% probability of success (≤1 angioedema 
attack/month).
No statistically significant relationship was observed between minimum C4 concentrations 
and the probability of response.


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The combination of the population PK model and exposure-response relationship model was 
used to simulate C1 INH Cmin following SC dosing of CINRYZE to support the dosing rationale 
and improve the likelihood of success at achieving an efficacious dose in patients with HAE 
(Figure 3).
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice Weekly Dose Regimen
C1 INH=C1 esterase inhibitor; HAE=hereditary angioedema
From these simulations, results show that a dose of 2000 U would maintain mean (blue line) 
functional C1 INH Cmin values above the targeted level of 0.45 U/mL (red horizontal line).
In studies LEVP 2005-1/B and LEVP 2006-4, in which subjects with HAE received IV doses 
of 1000 U CINRYZE approximately twice weekly, mean pre-infusion functional C1 INH 
concentrations ranged from 0.38-0.41 U/mL and 0.37-0.52 U/mL, respectively, during the 
treatment period. 
In the recent Phase 2 clinical study 0624-206, in which subjects with HAE received twice 
weekly SC doses of 1000 U CINRYZE with 24,000 U rHuPH20 or 2000 U CINRYZE with 
48,000 U rHuPH20 in two 8-week crossover periods, higher exposure with the 2000 U 
CINRYZE dose was observed (Figure 4). The mean baseline-corrected Cmax and AUC0-168 of 
antigenic C1 INH for 2000 U SC CINRYZE + 48,000 U rHuPH20 were 1.8- and 2.3-fold 
higher, respectively, compared to those observed for 1000 U SC CINRYZE + 24,000 U 
rHuPH20. The mean baseline-corrected Cmax and AUC0-168 of functional C1 INH activity for 


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2000 U SC CINRYZE + 48,000 U rHuPH20 were 2.0- and 2.6 fold higher, respectively, 
compared to their respective means for 1000 U SC CINRYZE + 24,000 U rHuPH20. The 
observed mean minimum concentration (Cmin) of functional C1 INH activity at steady-state 
for the 2000 U dose of SC CINRYZE with rHuPH20 was above the physiologically relevant 
level of 0.4 U/mL compared with 1000 U dose of SC CINRYZE with rHuPH20 (0.408 and 
0.319 U/mL, respectively). 
Figure 4:
Mean (SD) Steady-State (Week 8) Plasma Concentrations of C1 INH 
Antigen (left) and Functional C1 INH Activity (right) vs. Time after SC 
Administration of CINRYZE with rHuPH20 in Subjects with HAE
(Protocol 0624-206)
1.2.2.2
Pharmacokinetic Analysis of C1 Esterase Inhibitor [Human] Liquid for Injection
In Study SHP616-103, new bioanalytical assays were developed and validated for the 
quantitative determination of C1 INH protein and functional binding of C1 INH in human 
plasma. These assays differed from those used in previous CINRYZE SC studies to determine 
plasma concentrations of C1 INH antigen and functional C1 INH activity.
Following SC administration of 1000 U and 2000 U C1 esterase inhibitor [human] liquid for 
injection, injected C1 INH was slowly absorbed with median tmax ranging from 36–48 hours 
for both C1 INH antigen and functional C1 INH binding. Mean baseline-corrected Cmax and 
AUClast PK parameters for both C1 INH antigen and functional C1 INH binding after IV and 
SC administration are shown in Figure 5 and Figure 6, respectively


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Figure 5:
Individual and Mean (±SD) Baseline-corrected Cmax Across Treatments for 
C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Figure 6:
Individual and Mean (±SD) Baseline-corrected AUClast Across Treatments 
for C1 INH Antigen and Functional C1 INH Binding (Study SHP616-103)
Subcutaneous administration of C1 esterase inhibitor [human] liquid for injection was less 
than dose proportional, with a 2-fold increase in dose resulting in 1.76- and 1.58-fold increase 
in Cmax and AUClast respectively for C1 INH antigen, and 0.99- and 1.09-fold increase in Cmax
and AUClast respectively for functional C1 INH binding.
The baseline-corrected point estimates of the AUClast ratios and 90% confidence intervals for 
C1 INH antigen and functional C1 INH binding was used to determine the relative 
bioavailability of 1000 and 2000 U C1 esterase inhibitor [human] liquid for injection with 
1000 U IV CINRYZE. The relative bioavailabilities for the 1000 U and 2000 U SC dose of C1 
esterase inhibitor [human] liquid for injection were approximately 69% (44–110%) and 60% 
(38–95%) respectively for C1 INH antigen, and 67% (34–130%) and 39% (20–77%) 
respectively for C1 INH functional binding (in non-HAE subjects).
1.2.2.3
Dose Selection
The approach for preventative therapy in HAE patients is to provide enough CINRYZE to 
achieve or exceed a threshold C1 INH functional activity concentration in plasma that has a 


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>70% likelihood of preventing an angioedema attack. The combined data from prior SC 
CINRYZE studies (including the evaluation of bioavailability) along with the demonstration of 
similar bioavailability achieved in the completed Phase 1 single dose study of C1 esterase 
inhibitor [human] liquid for injection, support dose selection of 2000 U C1 esterase inhibitor 
[human] liquid for injection for further evaluation in a Phase 3 study. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The sponsor has developed a new, ready-to-use liquid formulation of CINRYZE (C1 esterase 
inhibitor [human]). The CINRYZE liquid product (C1 esterase inhibitor [human] liquid for 
injection) is intended for the same indication as the licensed, lyophilized powder formulation 
of CINRYZE: routine prophylaxis against angioedema attacks in adolescent and adult patients 
with HAE. The route of administration will be SC injection, and the dosing regimen will be 
2000 U every 3 or 4 days. Shire ViroPharma anticipates that patients will benefit from the 
inherent advantages of SC administration, as well as the ready-to-use liquid, lower volume 
product compared with one requiring reconstitution. In addition, the CINRYZE liquid product 
is more concentrated than the licensed CINRYZE product (500 vs 100 U/mL), which should 
enable more rapid administration of the drug and may improve tolerability, without an 
expected change or compromise in efficacy.
The sponsor has selected 2000 U of C1 esterase inhibitor [human] liquid for injection as the 
appropriate active dose for this Phase 3 study. This dose is based on the results of a recently 
completed Phase 2, randomized, double-blind, dose-ranging, crossover study that evaluated 
SC administration of CINRYZE with rHuPH20 (a dispersing agent) for the prevention of 
angioedema attacks in adolescents and adults with HAE (Study 0624-206). Results revealed 
greater clinical benefit with 2000 U of CINRYZE compared with 1000 U. In addition, the 
2000 U dose is supported by PK results from Study 0624-206, by the results of population PK 
and exposure-response modeling, and by PK data from a Phase 1 study (0624-102) that 
demonstrated the minimal influence of rHuPH20 on functional C1 INH activity when co-
administered with CINRYZE (Section 1.2.2.1). Finally, the 2000 U dose is further supported by 
the PK and bioavailability data from the Phase 1 study of C1 esterase inhibitor [human] liquid 
for injection (Protocol SHP616-103).
The study design was chosen as the best way to jointly address the protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, adequate numbers of subjects for 
precision of estimation in detecting potential safety signals). Additionally, this design 
maximizes the number of patients exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes patient exposure to placebo while having adequate patient exposure 
to placebo to assess efficacy. Thus, the proposed study is described as a “partial” crossover 
because 2 treatment sequences involve crossing over to the other experimental agent and the 
third sequence does not. All subjects will receive active treatment during this study and will 
have an overall two-thirds probability to be randomized to active drug in any treatment 
period.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to demonstrate superior efficacy of SC administration 
of 2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 


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attacks relative to placebo based on the normalized number of attacks (NNA) during a 
treatment period.
2.2.2
Secondary Objectives
The key secondary objective is to demonstrate the superior efficacy of SC administration of 
2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by the proportion of subjects meeting the criterion of 
at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
Other secondary objectives are:

To assess the proportion of responders during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo, where the 
proportion of responders is defined as:
-Achieving at least a 50% reduction in the NNA during a treatment period relative to 
the pretreatment assessment (ie, the subject’s attack rate without prophylactic 
therapy)
-Achieving a NNA <2.0 during a treatment period

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of attack-free days during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of angioedema attacks requiring acute treatment during treatment 
with 2000 U C1 esterase inhibitor [human] liquid for injection relative to treatment 
with placebo 

To assess the safety and tolerability of SC administration of 2000 U C1 esterase 
inhibitor [human] liquid for injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection 

To characterize the PK and PD of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the 
treatment of acute angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS) 


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
To evaluate subject experience with self-administration of SC 2000 U C1 esterase 
inhibitor [human] liquid for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient 
population


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial 
crossover study. The design was chosen to optimally address the joint protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, enrolling an adequate number of 
subjects to have precision of estimation to detect or rule out safety signals). Additionally, this 
design maximizes the number of subjects exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes subject exposure to placebo, while having adequate subject exposure 
to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. Subjects are required to have 
a history (based on subject recall and medical records) of ≥3 attacks per month on average per 
inclusion criterion #3. Based on statistical simulation, at least 25% of randomized subjects 
with a baseline attack rate ≥4.0 per month average need to be included in this study for the 
efficacy analysis population in order to detect a significant reduction (<2) in NNA from 
baseline. At least 66 eligible subjects will be randomized to 1 of 3 treatment sequences prior 
to the first dose of investigational product in Treatment Period 1 (ie, Dosing Day 1a) using 
interactive response technology (IRT). Randomization of subjects will be stratified by use of 
prophylactic therapy with C1 INH at the time enrollment. 
Figure 7:
Study Design Flow Chart
Each treatment period will be 14 weeks, without a washout between the 2 periods. The 
omission of a washout period is to minimize the duration that subjects will be without active 
treatment. It is recommended that the twice weekly dosing schedule (every 3 or 4 days) be 


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maintained between the last dose of investigational product in Treatment Period 1 and the first
dose of investigational product in Treatment Period 2.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be 
blinded to treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be 
administered at the investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both 
treatment periods. Other doses may be administered by qualified blinded personnel at the 
investigational site or at the subject’s home or other agreed upon location. During Treatment 
Period 2, after having received appropriate training, subjects will be allowed to 
self-administer the investigational product with direct supervision by the study site personnel 
or a qualified home health professional. Alternatively, a parent/legal guardian/caregiver will 
be allowed to administer the investigational product to an adolescent subject, after having 
received appropriate training and under the supervision of study site personnel or a qualified 
home health professional.
Throughout the study, an electronic subject diary will be used to record specific information 
regarding the subject’s symptoms of HAE. This will include signs and symptoms of 
angioedema attacks, triggers for angioedema attacks, location (including whether mucosal or 
non-mucosal), medications used for acute treatment of angioedema attacks, elective 
procedures, and interruptions in activities of daily living due to an angioedema attack. 
Additionally, quality of life questionnaires and surveys on SC administration of the 
investigational product will be also subject evaluated. Note: For adolescent subjects, a 
parent/legal guardian/caregiver is allowed to assist the subject in completing the electronic 
subject diary, including the quality of life questionnaires.
Adverse events will be recorded from the time the informed consent is signed through 7 days 
after the last dose of investigational product. This includes events occurring during the 
screening phase of the study, regardless of whether or not the investigational product is 
administered. In addition, the investigator will report all SAEs that occur through 30 days 
after the last dose of investigational product to Shire Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of the investigational product in Treatment Period 2 for follow-up safety assessments. In 
addition, subjects will have blood samples collected for PK/PD and C1 INH antibody testing 
at 1 month (±2) days after the last dose of the investigational product.
If a subject prematurely discontinues investigational product, regardless of the reason, the 
early discontinuation visit safety procedures listed in Table 3 are to be performed as 
completely as possible. Whenever possible, all discontinued subjects should also complete the 
1-week and 1-month post-treatment visits. 


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3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 9 months. 
The study will be completed in approximately 15 months. 
The Study Completion Date is defined as the date the final subject, across all sites, completes
their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. The Study Completion Date is used to ascertain timing for study
results posting and reporting.
3.3
Sites and Regions
Approximately 40 sites globally (North America and Europe) are expected to participate in 
this study.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria
below.
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 INH level less than 50% 
of normal.
3.
Meet one of the following criteria (attack rate may be based on subject recall in 
conjunction with the subject’s medical records):

If currently receiving prophylactic therapy with C1 INH, have a history of ≥3.0 
angioedema attacks per month (average) during the 3 consecutive months prior to 
starting prevention therapy. 
OR

If not receiving prophylactic therapy with C1 INH, have a history of ≥3.0
angioedema attacks per month (average) during the 3 consecutive months prior 
to the screening visit.
OR

If currently receiving a stable dose of attenuated androgens, have a history of ≥3.0
angioedema attacks per month (average) during the 3 consecutive months prior to 
the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any 
angioedema attacks that occur during the study that, in the opinion of the healthcare 
care provider, require medical intervention. Note: For subjects ≥12 to <18 years of 
age, standard of care therapy per local protocols should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) 
pregnancy test at the screening visit and must have a negative urine pregnancy test 
prior to the first dose of investigational product (Visit 1a), and agree to comply with 
any applicable contraceptive requirements of the protocol. 
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control 
(eg, abstinence, barrier control) from the screening visit through 2 months after the last 
dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide 
written informed consent before any study-specific procedures. 


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OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the 
nature of the study provide written informed consent for the child to participate in the 
study before any study-specific procedures are performed (with assent from the child 
when appropriate). Alternatively, certain sites/Independent Reviewing Authorities 
may permit adolescents who are <18 years of age to be informed of the nature of the 
study and provide written informed consent without consent from a parent(s)/legal 
guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 
1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first 
dose of the investigational product in Treatment Period 1.
3.
Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1.
4.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition 
for thromboembolism. 
5.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH 
antibodies. 
6.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), or other blood products. 
7.
Be pregnant or breastfeeding. 
8.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
9.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following 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 


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sexually active during the period of the study and 30 days following the last dose of 
investigational product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and aged
51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
Screening Visit and a negative urine pregnancy test prior to randomization (predose at 
Visit 1a). Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception 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 Screening Visit (Visit 1a), 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 a hormonal contraceptive for 30 days.
4.3.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 2 months after the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Early Discontinuation Visit are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also complete the 1-week and 1-month Post-
treatment visits. Comments (spontaneous or elicited) or complaints made by the subject must 
be recorded in the source documents. The reason for termination, date of stopping 
investigational product, and the total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.


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Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject

Lost to follow up

Lack of efficacy

Other (specify) 
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.4.3
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, investigational product will be discontinued, 
and the subject will follow the schedule of assessments for early discontinuation (Table 3). 
Subjects already enrolled will continue with study drug administration and procedures. 
4.4.4
Thrombotic or Thromboembolic Event
If a thrombotic/thromboembolic (T/TE) event occurs in any subject, no further enrollment 
will occur pending a complete review of all available data. Already enrolled subjects will 
continue with investigational product administration and study procedures. Following a safety 
review of the T/TE event, study enrollment may be restarted if the medical monitor 
determines that the event was unrelated or unlikely to be related to investigational product or 
other C1 inhibitors, which may have been administered for an angioedema attack. Unblinding 
of the randomization code for that subject may be required (see below).
If a T/TE event occurs in any subject, investigational product administration for that subject 
will be interrupted; however, other study procedures will continue, as clinically appropriate. 


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Diagnosis and management of all suspected T/TE events should be per local standard of care; 
Appendix 4 and Appendix 5 present a suggested medical algorithm for diagnosis and 
management of such conditions. Investigators must also comply with all reporting and/or 
concerning procedures for AEs/SAEs as indicated in the suggested algorithm. Following a 
complete medical review by the sponsor in conjunction with the investigator, and if 
determined safe to do so, dosing with investigational product may be resumed to complete a 
total of 28 doses in the treatment period that was interrupted. Study procedures, including 
PK/PD testing, will resume relative to dosing. If investigational product cannot be restarted 
within 30 days of the temporary interruption, the subject will be discontinued from treatment 
and will follow the schedule of assessments for early discontinuation (Table 3). If unblinding 
is required, a physician external to the study will review relevant safety information, including 
the subject’s assigned treatment. The unblinded physician will relay his or her findings and 
recommendations to the medical monitor, exercising caution not to reveal the subject’s 
randomization to anyone associated with the conduct of the study.


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5.
PRIOR AND CONCOMITANT TREATMENT
Prior and concomitant medications that will be recorded on the appropriate CRF page include 
prescription medications, blood products (eg, albumin, packed red blood cells, whole blood, 
fresh frozen plasma, platelets), dietary supplements/vitamins, electrolyte supplementation, 
and over-the-counter medications. Topical medications (non-prescription) will be recorded 
only if used as treatment for an AE.
5.1
Prior Treatment
Any therapy received during the 12 months prior to randomization for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and 
the HAE indication (ie, acute treatment, long-term prevention, short-term [preprocedural] 
prevention).  
In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the CRF.
5.2
Concomitant Treatment and Medical/Surgical Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the 1-week post-treatment visit, inclusive. All prescription and 
over-the-counter medications being taken by subjects during this time period are regarded as 
concomitant treatments. For any medication that is administered, the investigator will 
document the drug name, amount, route of administration, frequency, and duration 
administered, as well as the reason for administering the medication on the appropriate CRF 
page.
Medical/surgical procedures performed during the study will be recorded on the CRF, along 
with the date, time, and reason for the procedure. 
5.2.1
Management of Angioedema Attacks 
If a subject (≥18 years of age) experiences an acute angioedema attack at any time during 
study that in the opinion of the healthcare care provider requires medical intervention, 
icatibant should be administered to treat the attack. Icatibant is supplied in a single-dose pre-
filled glass syringe delivering 3 mL of solution containing 30 mg icatibant. Icatibant is to be 
administered by the SC route in the abdominal area. The entire volume in the syringe should 
be administered and the injection should occur over at least 30 seconds. If response is 
inadequate or symptoms recur, additional injections of 30 mg may be administered at 
intervals of at least 6 hours. Do not administer more than 3 injections in 24 hours. The subject 
will be allowed to self-administer icatibant after receiving instructions on the use and 
appropriate training by study site personnel or a qualified home health professional. If it is the 
opinion of the health care provider that the subject still needs medication for his/her acute 
angioedema attack after icatibant administration, then standard of care therapy (eg, C1 INH, 
ecallantide) may be provided per locally approved product information. For subjects ≥12 to 
<18 years of age standard of care therapy per local protocols should be provided, such as 


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(where approved for adolescents) C1 esterase inhibitor (human), C1 esterase inhibitor 
(recombinant), and ecallantide. The determination of the necessity for therapy to alleviate 
subject symptoms will be at the discretion of the investigator. Administration of 
investigational product and study procedures will continue without alteration to the protocol 
schedule, even if a subject receives any treatment for an angioedema attack.
For medications associated with management of acute angioedema attacks, study personnel 
will record start/stop dates, time of administration, dose, unit, frequency, and route of 
administration in the subject’s CRF page. Adverse events associated with medications used in 
the treatment of acute angioedema attacks will be captured on the AE CRF and attributed to 
the concomitant medication administered.
Angioedema attacks will not be considered AEs; however, events satisfying the serious 
criteria should be recorded as a SAE and reported to Shire Pharmacovigilance (Section 8.1.4). 
Data on angioedema attacks will be collected separately from general reports of AEs and will 
be used in the evaluation of efficacy (Section 7.2.2). In addition, if applicable, subjects will 
record their response to icatibant therapy when used for treating an angioedema attack, as well 
as any associated side effects or tolerability issues. This information will be recorded in the 
electronic subject diary (Section 7.2.2.4).
5.2.2
Prohibited Treatment
Use of C1 INH therapy (other than study drug) for prophylaxis against angioedema attacks is 
prohibited during this study (from the first dose of investigational product through the 
1-month post-treatment visit).
The initiation of androgen therapy is prohibited during the study (from the first dose of 
investigational product through the 1-month post-treatment visit). 


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is C1 esterase inhibitor [human] liquid for injection, which is supplied in 
clear glass vials containing 1000 U of C1 INH in 2 mL of sterile liquid. The solution also 
contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection.
The reference product is placebo, which is supplied in an identical 2 mL presentation as the 
active investigational product minus the C1 INH protein. The inactive ingredients in the 
solution are the same as the active drug product: sodium phosphate, sorbitol, glycine, and 
water for injection.
No reconstitution or dilution is required for the test or reference product. Vials must be stored 
at 2–8oC (36–46oF) and protected from light.
Instructions for handling of investigational product and for SC injection site selection and 
preparation are provided in Appendix 1 and Appendix 2, respectively.
6.2
Administration of Investigational Product
Blinded investigational product (C1 esterase inhibitor [human] liquid for injection or placebo) 
will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate 
treatment periods. The contents of 2 vials of investigational products (a total volume of 4 mL) 
will be drawn into a silicone-free syringe for each SC injection. Following appropriate SC 
injection site selection and preparation (Appendix 2), the needle will be inserted in the 
subject’s abdominal area in order to administer the SC injection as quickly as tolerated by the 
subject. 
Investigational product will be administered at the investigational site for Dosing Visits 1, 8, 
16, 24, and 28 during both treatment periods. Other doses may be administered by qualified 
blinded personnel at the investigational site or at the subject’s home or other agreed upon 
location. During Treatment Period 2, after having received appropriate training, subjects will 
be allowed to self-administer the investigational product with direct supervision by study site 
personnel or a qualified home health professional.
Alternatively, a parent/legal 
guardian/caregiver will be allowed to administer the investigational product to an adolescent 
subject, after having received appropriate training and under the supervision of study site 
personnel or a qualified healthcare professional.
6.3
Allocation of Subjects to Treatment Sequence
This is a double-blind, placebo-controlled, two-period, 3-sequence, partial crossover study. At 
least 66 eligible subjects will be randomized to 1 of 3 treatment sequences (Table 7) prior to 
the first dose of investigational product in Treatment Period 1. The actual treatment sequence 
given to individual subjects is determined by a randomization schedule automatically assigned 
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Table 7:
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects 
Randomized
1
A/B
22
2
B/A
22
3
A/A
22
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC 
twice weekly (every 3 or 4 days) for 14 weeks. 
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each level of use of prophylactic therapy with C1 INH across sites, the subject number is 
assigned to subjects according to the sequence of presentation for study participation. Subject 
number is unique within a protocol.
The randomization number represents a unique number corresponding to treatment sequence 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IRT at the baseline visit (predose Visit 1a) after subject eligibility has been 
confirmed using the randomization criteria. The randomization schedule will be stratified for 
use of prophylactic therapy with C1 INH at the time of enrollment versus no prophylactic 
therapy with C1 INH at the time of enrollment. The randomization will be conducted in two 
phases. For the first phase, subject 1 to 40 will be randomized to the treatment sequence 1 
(A/B), 2 (B/A), or 3 (A/A) in the randomization ratio of 2:2:1. For the second phase, subject 
41 to 66 will be randomized to the treatment sequence 1 (A/B), 2 (B/A), or 3 (A/A) in the 
randomization ratio of 1:1:2.
The subject’s treatment sequence will be held in strict confidence. The treatment sequence for 
an individual subject may be broken in cases of emergency or for reasons of subject safety, as 
described in Section 6.4.1.
6.4
Blinding of Treatment
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence. 
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo will have 
an identical presentation, including its packaging and labeling, such that the contents of the 
glass vials within the prepackaged study kits will be indistinguishable from each other. As 
described in Section 6.6, investigational product will be identified only by a unique study 
drug kit number. Each prepackaged study kit will contain 2x2 mL vials of investigational 
product (a total volume of 4 mL), which will be required to be drawn into a silicone-free 
syringe for each SC injection. If possible, a different individual should draw up the 


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investigational product into the syringe than the individual administering the SC injection to 
the study subject. 
Knowledge of the PK/PD data would compromise the study blind. As such, the independent 
external laboratory performing the PK/PD analyses will keep the results in strict confidence 
until the study is unblinded.
Additionally, a limited number of representatives of the sponsor responsible for the IRT and 
product labeling will be unblinded to treatment assignment in order to review drug 
accountability on an ongoing basis throughout the study (Section 6.7).
6.4.1
Unblinding the Treatment Assignment
The randomization code for an individual subject may only be broken by the investigator or 
the sponsor for reasons of subject safety or in an emergency when knowledge of the product 
administered would be important for the treatment of the subject. If the blind is broken by the 
investigator, he/she must notify the Shire ViroPharma Medical Monitor immediately and must 
document the date, time, and reason for the code break in a note to file.
6.5
Treatment Compliance
Investigational product will be administered either by study site personnel or a qualified home 
health professional or will occur under their direct supervision for subjects (or parent/legal 
guardian/caregiver) who elect to self-administer during Treatment Period 2 (Section 6.2). 
Therefore, full subject compliance with treatment is expected in this study. 
6.6
Packaging and Labeling
C1 esterase inhibitor [human] liquid for injection and placebo will be packaged and labeled 
such that the products will be indistinguishable from each other by the investigator, study site 
personnel, home health professionals, and subjects.
Investigational product will be supplied in a prepackaged study kit. Each study kit will 
contain 2 vials of investigational product (C1 esterase inhibitor [human] liquid for injection or 
placebo). Both the vials and carton (kit) will be appropriately labeled according to local 
regulations and bear the unique study drug kit number.  
The investigative site will also be provided with ancillary supplies including silicone-free 
syringes and needles. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection.
Refer to the Pharmacy Manual for additional details on the investigational product and its 
administration.


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6.7
Storage and Accountability
Investigational product will shipped refrigerated to the study site at 2–8oC. Vials of 
investigational product must be stored at 2–8oC (36–46oF) and protected from light. Do not 
freeze investigational product.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log. The date and time of administration of the investigational product must be documented 
on the appropriate CRF.
The principal investigator, study site personnel, or qualified home health professional must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.
6.8
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an investigational product 
returns process/policy, the sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the site regulatory binder.
If the investigational product is to be destroyed by the sites, sites must follow their own 
process/policy that describes such activities. Sites must retain copies of these documents 
within the site regulatory binder. Sites must ensure that the clinical trial material 
accountability and destruction log is complete, accurate, and ready for review and/or audit at 
each monitoring visit.
All manifests documenting shipments of investigational product must be retained, as well as 
copies of any investigational product return forms.
Refer to the Pharmacy Manual for additional details.


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7.
STUDY PROCEDURES
Subjects may be enrolled in the study after the nature and purpose of the protocol has been 
explained, written informed consent to participate has been voluntarily granted, and the 
eligibility criteria listed in Sections 4.1 and 4.2 have been met.
7.1
Study Schedule
Table 1 (Treatment Period 1), Table 2 (Treatment Period 2), Table 3 (early discontinuation 
visit, 1-week and 1-month post-treatment follow-up visits), and Table 4 (blood sample 
collection for PK/PD Analyses) provide the timing of all study procedures and assessments. 
7.1.1
Screening Period
Informed consent must be obtained before any study-specific procedures are performed. Note 
that AEs will be collected from the time of informed consent through 7 days after the last dose 
of investigational product.
Subjects will have all screening procedures completed with 21 days prior to the first dose of 
investigational product (Visit 1a=Dosing Day 1) according to Table 1. The following 
procedures will occur:
•
Informed consent/assent
•
Adverse events (collection begins from the time of informed consent through 7 days after 
the last dose of investigational product)
•
Inclusion/exclusion criteria
•
Medical history (includes HAE history with the documentation of attack rate for study 
entry criteria)
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Virology screening
•
Vital signs
•
ECG
•
Height and weight
•
Serum pregnancy test (in females of childbearing potential)
•
Recording of prior and concomitant medications
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 


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7.1.2
Treatment Period 1
7.1.2.1
Visit 1a (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Randomization
•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications (needed for confirmation of subject eligibility)
•
PK (C1 INH antigen, C1 INH functional, [includes measurement of C1q]) and PD (C4) 
sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody)
•
Angioedema quality of life (AE-QoL) questionnaire, EuroQol 5-dimensional 5-level 
descriptive system (EQ-5D-5L), Work Productivity and Activity Impairment-General 
Health (WPAI-GH) questionnaire, and Sheehan Disability Scare (SDS) assessments
recorded in the electronic subject diary
•
Health resource utilization assessment (HRUA)-HAE
7.1.2.2
Visit 1a (postdose)
The following procedures will be performed after the administration of the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack (and the subject diary is to be updated daily; Section 7.2.2.2).
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary


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7.1.2.3
Visit 2a through Visit 28a
The following procedures will be performed throughout Treatment Period 1 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2a-28a)
•
Recording in the electronic subject diary daily any symptoms or occurrences of an 
angioedema attack (Visits 2a-28a)
•
Recording the daily AAS in the electronic subject diary (Visits 2a-28a)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2a, 3a, 4a, 8a, 16a, 24a, 28a)
•
Physical examination (Visits 8a, 16a, 24a, 28a)
•
Investigational product will be administered at each visit (2a-28a); Visits 8a, 16a, 24a, and 
28a must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2a-28a)
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8a, 16a, 24a, 
and 28a
•
Urinalysis testing with microscopy at Visit 28a
•
Acceptability survey assessment at Visit 28a
•
Quality of life assessments recorded in the electronic subject diary: AE-QoL (Visits 9a, 
17a, 25a), EQ-5D-5L (Visit 24a and on each day that a subject experiences signs or 
symptoms of an angioedema attack), and WPAI-GH and SDS (Visits 3a, 5a, 7a, 9a, 11a, 
13a, 15a, 17a, 19a, 21a, 23a, 25a, 27a)
•
HRUA-HAE (Visits 8a, 16a, 24a)
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8a, 16a, 24a, 27a or 28a)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2a, 8a, 
16a, 24a, 27a or 28a [within ≈15 min], and 48 h postdose Visits 27a or 28a [±3 hours])
7.1.3
Treatment Period 2
7.1.3.1
Visit 1b (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product in Treatment Period 2 at Visit 1b:
•
Collection of AEs
•
Physical examination


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•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications 
•
PK (C1 INH antigen, C1 INH functional) and PD (C4) sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody) blood sample collection
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS assessments recorded in the electronic subject 
diary
•
HRUA-HAE
7.1.3.2
Visit 1b (postdose)
The following procedures will be performed after the administration of investigational 
product at Visit 1b:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.3.3
Visit 2b through Visit 28b
The following procedures will be performed throughout Treatment Period 2 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2b-28b)
•
Recording in the subject diary daily any symptoms or occurrences of an angioedema 
attack (Visits 2b-28b)
•
Recording the daily AAS in the subject diary (Visits 2b-28b)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2b, 3b, 4b, 8b, 16b, 24b, 28b)
•
Physical examination (Visits 8b, 16b, 24b, 28b)


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•
Investigational product will be administered at each visit (2b-28b); Visits 8b, 16b, 24b, 
and 28b must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2b-28b)
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8b, 16b, 24b, 
and 28b
•
Urinalysis testing with microscopy at Visit 28b
•
Quality of life assessments: AE-QoL (Visits 9b, 17b, 25b), EQ-5D-5L (Visit 24b and on 
each day that a subject experiences signs or symptoms of an angioedema attack), and 
WPAI-GH and SDS (Visits 3b, 5b, 7b, 9b, 11b, 13b, 15b, 17b, 19b, 21b, 23b, 25b, 27b)
recorded in the electronic subject diary
•
HRUA-HAE (Visits 8b, 16b, 24b)
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments at Visit 28b
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8b, 16b, 24b, 28b)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2b, 8b, 
16b, 24b, and 28b [within ≈15 min], and 24 hours (±3 hours) (optional time point), 
48 hours (±3 hours), 72 h (±6 hours) (optional time point), and 96 hours (±6 hours) 
postdose Visit 28b) 
7.1.4
Early Discontinuation Visit
If a subject prematurely discontinues from investigational product, the following procedures 
are to be performed as completely as possible:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments


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•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
7.1.5
Follow-up Period
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of investigational product for follow-up safety assessments (Table 3). The following 
procedures will occur:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
A second post-treatment visit will occur at the investigative site 1 month (±2 days) after the 
last dose of investigational product. The following procedures will be performed at this visit:
•
HRUA-HAE
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).


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Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to the Shire Pharmacovigilance Department.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic details, medical history (including HAE history), prior and concomitant 
medication data, vital signs, height, weight, physical examination, 12-lead ECG, 
biochemistry, hematology, coagulation, virology screening, and serum β-hCG pregnancy test 
will be collected at the time of enrollment at the Screening Visit. 
7.2.2
Efficacy
Analyses of the efficacy endpoints in this study require documentation of specific information 
regarding the subject’s symptoms of any angioedema attacks they may experience during the 
study. 
7.2.2.1
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported indication of swelling or pain at 
any location following a report of no swelling or pain on the previous day (ie, there must be a 
full symptom-free calendar day preceding the onset of symptoms for an attack to be 
considered a new attack). Therefore, 

Attacks that progress from 1 site to another will be considered a single attack 

Attacks that begin to regress and then worsen before complete resolution will be 
considered 1 attack

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar 
day reported after the appearance of resolution will also be considered 1 attack 
Note: An angioedema attack does not include swelling due to trauma, arthritis, or symmetrical 
nonpainful swelling of the lower extremities.
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary
During the study, subjects will use an electronic subject diary each day to record any 
symptoms or occurrences of an angioedema attack. The investigator will complete a separate 
angioedema attack CRF for each attack based upon their review of the data in the subject 
diary. Information will include the following:

Date and time of onset of angioedema attack symptoms

Characterization of whether swelling or pain is (indicate all that apply):


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
Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)

Non-mucosal (truncal, extremity, facial)

Location (site) of the swelling or pain (indicate all that apply):

Upper airway (includes laryngeal or pharyngeal)
Note: Pharyngeal or oral swelling that results in airway compromise will be 
classified as a laryngeal attack.
Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)

Genitourinary (including scrotum or vulva)

Cutaneous (facial)
Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, 
trunk])

Severity (intensity) of the sign/symptom at each location listed:

Absent
Mild: the angioedema attack sign/symptom(s) is noticeable but is easily 
tolerated by the subject and does not interfere with routine activities.
Moderate: the angioedema attack sign/symptom(s) interferes with the subject’s 
ability to attend work/school or participate in family life and social/recreational
activities.
Severe: the angioedema attack sign/symptom(s) significantly limits the 
subject’s ability to attend work/school or participate in family life and 
social/recreational activities.

Visual Analogue Scale (VAS) pain measurement score

Angioedema attack trigger(s)

Answer to the question, “Was treatment administered for the attack?” If yes, record the 
date, time, and name of treatment administered.
7.2.2.3
Angioedema Activity Score
Subject self-assessment of disease activity will be assessed daily by the AAS. Subjects will 
respond to questions in the electronic subject diary about any swelling episode that has 
occurred within the previous 24 hours. Each AAS item (or question) is scored between 0 and 
3 points, with the minimum and maximum daily AAS ranging between 0 and 15 points 
(Weller et al. 2013).


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7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks
Efficacy endpoints are based on subject-assessed symptom improvement as a measure of 
response to icatibant therapy. When a subject receives treatment with icatibant for an acute 
angioedema attack, they will record the date and time of administration of the SC injection in 
the electronic subject diary and will monitor the following events:
Initial Symptom Improvement

Report date and time when you feel that your symptoms start to improve.
Complete Symptom Resolution

Report date and time when you feel that your symptoms have completely resolved.
Tolerability

Report any side effects associated with administration of icatibant therapy.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical and Medication History
A medical history will be taken at the screening visit. All medical history findings that have 
been present/active within the 5 years prior to enrollment will be entered into the CRF 
regardless of clinical relevance or presence at study start. Medical history findings that have 
not been present within the 5 years prior to enrollment will be recorded if deemed clinically 
relevant by the investigator to the conduct of the study. The medical history should include 
any history of allergic reactions to drugs. 
HAE History
The following information associated with HAE history will be recorded in the CRF at the 
screening visit (Note: the attack rate may be estimated based on subject or parent/caregiver 
recall as well as the subject’s medical records):  

HAE type (I or II)

Estimated date of last angioedema (swelling) attack prior to the screening visit

Any therapy received during the last 12 months for management of HAE (Section 5.1)

Total number, typical locations and average overall duration (days), and average overall 
severity of angioedema attacks experienced:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.


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
Typical score, estimated on a scale from 0-100, for the subject’s angioedema attack 
pain:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.
7.2.3.2
Physical Examination (Including Height and Weight)
The investigator or designee will perform physical examinations at the time points specified 
in Table 1, Table 2, and Table 3. General physical examinations will be performed in 
accordance with standard practices at the study site. Physical examination abnormalities 
observed prior to the screening visit will be entered into the medical history section of the 
CRF. Any new or worsening of pre-existing abnormalities noted at post-screening 
examinations should be captured as an AE on the AE CRF page, per investigator’s judgment. 
Body weight and height will be measured at the time points specified in Table 1 and Table 2. 
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed (Section 8.1).
7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse and will be measured at the time points specified 
in Table 1, Table 2, and Table 3. During the study, additional vital signs measurements will 
be performed if clinically indicated. Vital signs performed on a dosing day should be obtained 
immediately (≤30 minutes) before the start of the injection of investigational product, 
immediately after completion of the injection of investigational product (≤10 minutes), and 
then between 30 minutes and 1 hour after completion of the injection of investigational 
product. Every effort should be made to measure vital signs prior to any blood sample 
collection. Blood pressure should be determined by cuff (using the same method, the same 
arm, and in the same position throughout the study). Any clinically significant deviations 
from Baseline (predose Visit 1a) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. Reference ranges are to be supplied by the laboratory and will be used to assess 
the clinical laboratory data for clinical significance and out-of-range pathological changes. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 


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clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 6 mL) for biochemistry will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Aspartate aminotransferase (AST)
Albumin
Alanine aminotransferase (ALT)
Total protein
Alkaline phosphatase (ALP)
Glucose
Creatine phosphokinase (CPK)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Chloride
Carbon dioxide
Phosphorus
Hematology
Blood samples (approximately 2 mL) for hematology will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Hemoglobin
Red blood cell count
Hematocrit
Platelet count
White blood cell count – total and differential


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Coagulation
Blood samples (approximately 3 mL) for coagulation will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
International normalized ratio (INR)
Prothrombin time (PT)
D-dimer a
Activated partial thromboplastin time (aPTT)
a In addition, D-dimer should be evaluated in any subject who presents with signs and symptoms consistent with 
suspected venous thromboembolism.
Virology
Blood samples (approximately 6 mL) will be taken according to Table 1. The following 
parameters will be assessed:
Human immunodeficiency virus (HIV; single 
assay/Western blot)
Hepatitis (hepatitis B surface antigen and 
hepatitis C antibody)
Urinalysis with microscopy
Urine samples (approximately 10 mL) will be taken according to Table 1, Table 2, and Table 
3. The following parameters will be assessed:
pH
Specific gravity
Dipstick (protein, glucose, ketones, 
hemoglobin)
Microscopic evaluation (red blood cells, 
white blood cells, crystals, casts, bacteria)
7.2.3.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all females of childbearing potential at the 
screening visit and a urine pregnancy test is performed thereafter according to the time points 
specified in Table 1, Table 2, and Table 3. Pregnancy test results must be confirmed as 
negative before subjects proceed in the study. 
7.2.3.7
Electrocardiogram 
Subjects will have a 12-lead ECG recorded at the screening visit, as specified in Table 1. 
During the study, additional ECGs will be performed if clinically indicated. The following 
ECG data will be entered into the CRF: heart rate, PR interval, QRS duration, and QT 
interval. The PQ interval may be used if the PR interval is not reported on the 12-lead ECG. 


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The investigator will be responsible for providing the interpretation of all ECGs (clinically 
significant/not clinically significant). The subject's ECG(s) should be consistently recorded in 
the same position (supine).
7.2.3.8
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
from the first dose of investigational product through the 1-week post-treatment visit will be 
recorded in the CRF (Section 5.2).
7.2.3.9
Thrombotic or Thromboembolic Events
Monitoring for Venous Thromboembolism or Arterial Thromboembolism
Study personnel will actively monitor subjects for possible venous thromboembolism (VTE), 
encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), and 
arterial thromboembolism (ATE) with medical history, physical examinations, review of AEs, 
routine coagulation laboratory testing, and/or other diagnostic tests as applicable per local 
standard of care at the time points specified in Table 1, Table 2, and Table 3. 
Subjects will also receive instruction on how to recognize symptoms associated with potential 
thrombotic events and to seek medical attention for these symptoms in addition to informing 
their investigator. Treatment procedures, when applicable, will be provided per local standard 
of care.
Suspected Venous Thromboembolism or Arterial Thromboembolism
In subjects who present with signs and symptoms that are suspicious of a possible VTE (DVT 
or PE) based on clinical history and physical examination, the Wells Prediction Rules 
(Appendix 3) in conjunction with D-dimer assessment and/or other diagnostic tests, as 
applicable per local standard of care, are suggested to help guide the physician. Diagnostic 
and/or treatment procedures, when applicable, will be provided per local standard of care.
Based on the Wells Prediction Rule scores, the following procedures are recommended:

If the Wells Prediction DVT risk score is ≥1, coagulation studies and an imaging 
study (eg, lower extremity ultrasound or contrast venography) may be performed 
as described below. 

If the Wells Prediction PE risk score is ≥2, coagulation studies and 1 or more 
imaging studies (eg, ventilation-perfusion scan, multidetector helical computed 
axial tomography, or pulmonary angiography) may be performed as described 
below. 
In the setting of suspected VTE events, site personnel will the complete the Wells Prediction 
Rule CRF.
Diagnosis and management of all suspected VTE and ATE events should be per local 
standard of care; Appendix 4 and Appendix 5 also presents a suggested medical algorithm for 
diagnosis and management of such conditions. Investigators must also comply with all 


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reporting and/or concerning procedures for AEs/SAEs as indicated in the suggested 
algorithm. Confirmed diagnoses of T/TE events will be reported as SAEs (Section 8.2). 
However, superficial thrombophlebitis and catheter-related thrombosis will be reported as 
either a nonserious AE or an SAE based on investigator assessment and standard AE/SAE 
definitions.
7.2.3.10 Injection Site Reactions
Investigational product SC injection site reactions will be captured in the local tolerability 
CRF. Injection site reactions that do not meet the criteria of a SAE will not need to be 
reported as an AE.
Subcutaneous injection site reactions will be assessed at the following post-injection time 
points in each treatment period: 15 minutes, 30 minutes, and 1 hour post-injection.. Study 
personnel will examine injection sites for erythema or swelling and will question the subject 
to collect information on cutaneous pain, burning sensation, itching/pruritus, and warm 
sensation. The diameter of any erythema or swelling should be measured to obtain the 
severity grading. The injection site reactions will be graded as absent, mild, moderate, or 
severe using the scoring criteria shown in Table 8. Both the severity score and the 
measurement of any erythema or swelling is to be captured in the CRF.
Table 8:
Severity Scoring for Injection Site Reactions
Reaction
Severity
Mild
Moderate
Severe
Erythema
>0 to 5 cm
>5 to 10 cm
>10 cm
Swelling
>0 to 5 cm
>5 to 10 cm
>10 cm
Cutaneous pain
Mild discomfort to touch
Discomfort with movement
Significant discomfort at rest
Burning sensation
Mild burning sensation, 
which is easily tolerated
Moderate burning sensation, 
causing some discomfort
Severe burning sensation, 
causing significant discomfort
Itching/pruritus
Mild itching/pruritus, 
which is easily tolerated
Moderate itching/pruritus, 
causing some discomfort
Severe itching/pruritus, causing 
significant discomfort
Warm sensation
Mild warmth to touch
Moderate warmth to touch
Significant warmth to touch
The injection site reaction data will be recorded on the local tolerability page of the CRF. Site 
personnel will distinguish between injection site reactions related to the procedure (eg, will 
check for redness after needle is inserted and prior to investigational product administration) 
vs the actual investigational product.


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7.2.4
Others
7.2.4.1
Clinical Pharmacology Assessments
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Subjects will have blood samples (7 mL) collected for the determination of plasma 
concentrations of C1 INH antigen, functional C1 INH, complement C4, and C1q at time 
points specified in Table 4. Serum samples (5 mL) will be collected prior to the first dose of 
investigational product on Visit 1a (Dose 1 of Treatment Period 1), Visit 1b (Dose 1 of 
Treatment Period 2), and throughout both treatment periods for the analysis of anti-C1 INH 
antibodies (Table 1 and Table 2). Additional blood samples for PK/PD and C1 INH antibody 
testing will be collected at the early discontinuation visit (if applicable) and the 1-week and 
1-month post treatment visits (Table 3). 
The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH activity, complement C4 and C1q 
concentrations, and serum samples for the evaluation of anti-C1 INH antibodies will be 
analyzed using validated methods. All PK/PD and immunogenicity samples will be processed 
according to the procedure outlined in the laboratory manual.
Selected samples may be analyzed to investigate incurred sample reproducibility of the 
bioanalytical methods. These analyses are only to investigate the reproducibility of the 
bioanalytical methods used to determine C1 INH antigen and functional C1 INH 
concentrations in study samples. All incurred sample reproducibility results will be reported 
in a separate table in the bioanalytical report. Details of disposal will be documented and 
maintained with the study file at the analytical laboratory.
7.2.4.2
Health-related Quality of Life Assessments
Angioedema Quality of Life Questionnaire
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema (Weller et al. 2012). It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and food. Subjects will be asked how often 
they were restricted by—as well as the difficulties and problems that could be associated 
with—recurrent swellings (angioedema) during the previous 4 weeks. The AE-QoL will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3. Details about the use of the AE-QoL instrument are provided in a separate study 
manual. 


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Health-related Quality of Life Questionnaire
The EQ-5D-5L1 is a descriptive system of health-related quality of life states consisting of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
of which can take 1 of 5 responses. The responses record 5 levels of severity within a 
particular dimension. The EQ-5D-5L will be completed in the electronic subject diary at the 
time points specified in Table 1, Table 2, and Table 3, as well as on each day that a subject 
experiences signs or symptoms of an angioedema attack. Details about the use and 
administration of the EQ-5D-5L instrument are provided in a separate study manual. 
Work Productivity and Activity Impairment-General Health Questionnaire
The WPAI-GH questionnaire includes 6 questions about work and activity impairment due to 
health problems during the past 7 days (Reilly et al. 1993). Outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less work or 
productivity. The WPAI-GH will be completed in the electronic subject diary at the time 
points specified in Table 1, Table 2, and Table 3. Details about the use of the WPAI-GH 
instrument are provided in a separate study manual.
Sheehan Disability Scale
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a 
subject’s disability due to an illness or health problem interferes with work/school, social 
life/leisure activities, and family life/home responsibilities (Sheehan 1983). The SDS will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3.
7.2.4.3
Health Resource Utilization Assessment
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. The Health Resource Utilization 
Assessment (HRUA-HAE) will be completed at the time points specified in Table 1, Table 2, 
and Table 3. Study personnel will enter the survey responses into the appropriate CRF.
7.2.4.4
Survey of Acceptability of SC Administration
Study personnel will ask subjects to rate their overall experience in receiving twice weekly 
SC injections of investigational product at the time points specified in Table 1, Table 2, and 
Table 3. For subjects who have previously received C1 INH products via IV administration, 
they will be asked to indicate the preferred route for medication administration. Study 
personnel will enter the subject’s survey responses into the electronic subject diary.
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) 
on the route to administer medications to prevent angioedema attacks.
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.


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7.2.4.5
Self-administration Survey Assessment
After receiving appropriate training, subjects are allowed to self-administer investigational 
product during Treatment Period 2 under the supervision of study site personnel or a qualified 
home health professional. Alternatively, a parent/legal guardian/cargive will be allowed to 
administer the investigational product to an adolescent subject, after having received 
appropriate training, and under the supervision of study site personnel or a qualified 
healthcare professional. For those subjects who choose to self-administer or have a 
parent/legal guardian/caregiver administer the investigational product, study personnel will 
ask specific questions about their experience with self-administration of SC medication (Table 
2 and Table 3). Study personnel will enter the subject’s survey responses into the electronic 
subject diary.
7.2.5
Volume of Blood to be Drawn From Each Subject
Table 9:
Approximate Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
PK/PD 
7
20b
140
Immunogenicity (anti-C1 INH antibodies)
5
13
65
Safety
Biochemistry and -hCGa
6
13
78
Hematology
2
13
26
Coagulation
3
13
39
Virology
6
1
6
All assessments (mL)
354
Β-hCG=beta human chorionic gonadotrophin; C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a -hCG testing for females of childbearing potential at the Visit 1a (predose) only.
a Two of the 20 samples are optional as indicated in Table 4.
During this study, it is expected that maximum volume of blood to be drawn from all subjects
will be 354 mL.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of 
blood drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 354 mL. When more than 1 blood assessment is done at 
the same time point/period, if they require the same type of tube, the assessments may be 
combined. 


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until 7 days after the last 
dose of investigational product. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE 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:
A type of AE that is usually alleviated with 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 subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product 
for each AE. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related.” The causality 
assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (angioedema attacks) should not be captured as AEs as 
long as they are within the normal day-to-day fluctuation or expected progression of the 
disease and are part of the efficacy data to be collected in the study; however, events 


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satisfying the serious criteria should be recorded as a SAE and reported to Shire 
Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range (either 
while continuing treatment or after the end of treatment with the investigational product), and 
the range of variation of the respective parameter within its reference range must be taken into 
consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department 
using the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Shire ViroPharma 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 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire 
Clinical Trial Serious Adverse Event Form. Note: An elective abortion is not considered an 
SAE.


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In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event 
Form as well as the Shire Investigational and Marketed Products Pregnancy Report Form. The 
test date of the first positive serum/urine -hCG test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: This includes a situation where the investigational product is not used 
as directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
higher than the protocol-specified dose.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Medication errors should be collected and reported to the sponsor for all products under 
investigation. The following should be considered as examples of reportable medication 
errors:

The administration and/or use of the unassigned treatment

The administration and/or use of an expired investigational product

Violation of storage or refrigeration requirements for the investigational product
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
All investigational products administered to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, 
or medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 
Trial Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to 
the contract research organization/Shire ViroPharma Medical Monitor using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as an SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 


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definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be 
reported to the Shire Pharmacovigilance Department and the contract research 
organization/Shire ViroPharma Medical Monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).


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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical contract research organization (CRO) are responsible for 
notifying the relevant regulatory authorities/US central Institutional Review Boards 
(IRBs)/EU central ethics committees (ECs) of related, unexpected SAEs.
In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to 
unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available. If applicable, unblinded data may be 
made available to quality assurance representatives for the purposes of conducting 
independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
All statistical analyses will be performed using SASVersion 9.1 or higher (SAS Institute, 
,
). 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
PPD PPD


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characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be 
addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee in this 
study.
9.6
Sample Size Calculation and Power Considerations
The enrollment goal for this study is to randomize at least 66 subjects to ensure 54 subjects 
complete both treatment periods (36 for the crossover sequences, 18 for the active/active 
sequence). This number will be sufficient to address all experimental efficacy and safety 
objectives.
For the primary efficacy endpoint, the NNA, a sample of 36 subjects will provide >95% 
power at an alpha level of 0.025 (1-sided) to detect a difference of 2.0 attacks per month 
between active treatment and placebo assuming a between-subject standard deviation of 3. 
This target is supported by the recently completed, dose-ranging, Phase 2 study with CINRYZE
(0624-206).
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR
relative to placebo, 36 subjects will provide 90% power to test the hypothesis H0: proportion 
≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided).
Previous communications have occurred between regulatory authorities and the sponsor 
regarding a Phase 3 study for the SC CINRYZE development program. The regulatory authority 
indicated that the Phase 3 study should be of sufficient size to have a 95% power for detection 
of safety signals occurring with an incidence of 5% or greater of subjects.
With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.
The sample size calculation was conducted using nQuery + nTerim 2.0.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have signed an informed consent and some 
study procedures have begun.


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The Randomized Set will consist of all subjects in the Screened Set for whom a 
randomization number has been assigned.
The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The Full Analysis Set will consist of all subjects in the Safety Set who have at least 
1 post-baseline (eg, randomization) primary efficacy assessment.
The Per-protocol Set will consist of all subjects in the Full Analysis Set who complete 
scheduled primary assessments for 6 study weeks and who do not have pre-defined protocol 
deviations that may affect the primary efficacy endpoint. 
The Completer Set will consist of all subjects in the Full Analysis Set who have completed 
the final scheduled primary assessment for the study.
The Pharmacokinetic and Pharmacodynamic Set will consist of all subjects in the Safety 
Set for whom the primary PK and PD data are considered sufficient and interpretable. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the NNA during a treatment period. The NNA is 
expressed as the number of attacks per month (ie, 30.4 days) of exposure:
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period)
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.
The primary efficacy analysis will be conducted for the subjects in the Full Analysis Set 
(Section 9.7) that are randomized to Treatment Sequence 1 (A/B) or 2 (B/A) to evaluate of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection compared 
to placebo. The null hypothesis to be tested is that the NNA of C1 esterase inhibitor [human] 
liquid for injection is greater than or equal to the NNA of placebo, and the alternative 
hypothesis is that the NNA of C1 esterase inhibitor [human] liquid for injection is less than 
the NNA of placebo as below:
H0: µ C1 INH - µ placebo >0 vs
H1: µ C1 INH - µ placebo <0
The primary efficacy endpoint will be analyzed by using a mixed effect linear model with 
period, sequence, and treatment as fixed effects, and subject nested within sequence as a 
random effect. The mean treatment difference (µ C1 INH - µ placebo) will be estimated with a 
95% CI.


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To assess any carryover effect, a sensitivity analysis will exclude from the evaluation of the 
NNA any attacks occurring within the first 2 weeks of Treatment Period 2 for both sequences 
when carryover is suspected to be maximal. Since carryover should occur only with the 
A/B treatment sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] 
liquid for injection efficacy into the placebo treatment period, thereby diluting the efficacy of 
C1 INH and favoring the null hypothesis of the primary efficacy analysis; it is not anticipated 
that any placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection 
within the B/A treatment sequence. The study is powered to demonstrate superior efficacy 
even in the presence of carryover effects. Additional sensitivity analyses may be developed 
and included in the SAP.
Adjustments for multiplicity: To control the overall type 1 error, the primary and key 
secondary endpoints will be tested hierarchically, so that the significance of the key secondary 
endpoint is contingent on whether the primary endpoint is significant. The determination of a 
successful study is based solely on the results of the primary endpoint analysis regardless of 
the results for the key secondary endpoint.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the clinical response to treatment relative to placebo. 
This is defined as achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase 
inhibitor [human] liquid for injection treatment period relative to the placebo period. 
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion 
PR. The null hypothesis is that PR is less than or equal to 0.2, and the alternative hypothesis is 
that PR is greater than 0.2. The proportion meeting criterion PR will be estimated with an exact 
95% CI. The lower limit of the 95% CI for the proportion will be compared with 0.2. This is 
equivalent to testing the null hypothesis against the alternative hypothesis at a 1-sided alpha 
level of 0.025 using the normal approximation to the binomial distribution.
9.8.2.2
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints to be evaluated in this study are:

To determine the proportions of subjects with a clinical response to treatment as defined 
by: 

Achieving at least a 50% reduction in the NNA during a treatment period relative 
to the pretreatment assessment. 

Achieving a NNA <2.0 during a treatment period.

Cumulative attack severity. This score is the sum of the maximum symptom severity 
recorded for each angioedema attack in a treatment period.


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
Cumulative daily severity. This score is the sum of the severity scores recorded for every 
day of reported symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment a treatment period.

Disease activity as measured by the 98-day AAS. This score is the sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day.

Results of the AE-QoL questionnaire.

Determine the response to icatibant when administered as treatment for an acute 
angioedema attack by:

Time to subject-assessed initial symptom improvement (TISI) 

Time to subject-assessed complete symptom resolution (TCSR) 
Subjects in the Full Analysis Set (Section 9.7) that are randomized to Treatment Sequence 1 
(A/B) or 2 (B/A) will be used to assess the secondary efficacy endpoints in the evaluation of 
the efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection
compared to placebo. The treatment differences in clinical responder rate, both of which are 
defined within treatments, will be analyzed using McNemar’s test for testing equality of 
proportions of responders within treatments. All other secondary endpoints will be analyzed 
using a linear mixed effect model with period, sequence, and treatment as fixed effects, and 
subject nested within sequence as a random effect. The results of all secondary efficacy 
analyses will be summarized by the point estimate of within-subject treatment differences or 
response rates and the corresponding 95% CI. Descriptive statistics (n, median, 25% and 75%
quartiles, and range) will be provided to summarize icatibant-related efficacy endpoints (TISI 
and TCSR) by treatment and icatibant-treated angioedema attack for all subjects in the Full 
Analysis Set. Where appropriate (for subjects ≥12 to <18 years of age), other rescue 
medications used to treat acute angioedema attacks will also be summarized using descriptive 
statistics. In addition, angioedema attacks will be summarized by the maximum symptom 
severity and treatment for all subjects in the Full Analysis Set. 
9.8.3
Exploratory Efficacy Endpoints
There are no exploratory efficacy endpoints in this study.
9.9
Safety Analyses
Adverse events will be coded using the MedDRA. The number of events, incidence, and 
percentage of TEAEs will be calculated overall, by system organ class, preferred term, and 
treatment. Treatment-emergent AEs will be further summarized by severity and relationship 
to investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.


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Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG 
findings will be summarized by treatment and visit. Potentially clinically important findings 
will also be summarized or listed.
The incidence and severity (mild, moderate, severe) of SC injection site reactions will be 
summarized by treatment and visit. 
Results of C1 INH antibody testing will be reported for individual subjects.
The tolerability of icatibant therapy for acute angioedema attacks will be summarized.
To assess the influence of any carryover effect on adverse reporting, a sensitivity analysis 
may be conducted by attributing TEAEs that occur during the first 2 weeks of Treatment 
Period 2 to Treatment Period 1 for the A/B (C1 INH to placebo) treatment sequence. In other 
words, C1 esterase inhibitor [human] liquid for injection may account for any TEAEs in the 
first 2 weeks of the placebo treatment, when the carryover effect (if present) is suspected to be 
maximal. 
9.10 Other Analyses
9.10.1
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, C1 INH functional, and complement C4 and C1q for 
individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics (number, geometric mean, coefficient of variation, 
mean, standard deviation, median, minimum, and maximum) for values at each time point.
C1q concentrations will only be assessed at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic parameters will be calculated using observed and baseline-corrected 
concentration-vs-time data using non-compartmental techniques for C1 INH antigen and 
functional activity. The following PK parameters will be calculated using both unadjusted and 
baseline-adjusted concentrations for SC administration: The Cmax, the tmax, the minimum 
observed concentration, and the AUClast. Additional PK parameters will be calculated using 
only baseline-adjusted concentrations, including t1/2, the λz, the AUC0-∞, the VZ/F, and the 
CL/F. Other PK parameters may be calculated as deemed appropriate. Pharmacokinetic 
parameters will be summarized using descriptive statistics.
Exploratory PK/PD analyses might be performed based on the correlation of plasma 
concentrations of C1 INH antigen, functional C1 INH, and C4 complement in conjunction 
with various safety parameters (eg, selected AEs, clinical laboratory results, antibodies 
generation, frequency, severity, or anatomic location of the angioedema attack, etc.). 
Correlations that will be analyzed will be determined based on observed data.
9.10.2
Health-related Quality of Life Analyses
Results of the EQ-5D-5L health status instrument will be presented in accordance with the 
EQ-5D-5L user guide (version 2.0) by treatment.


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Results of the WPAI-GH questionnaire will be summarized by treatment.
Results of the SDS will be summarized by treatment.
9.10.3
Surveys on SC Administration and Self-administration of Investigational 
Product
Results of the surveys for subject acceptability of SC administration and subject experience 
with self-administration of investigational product will be summarized.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. These regulations and 
guidelines also constitute compliance with the ethical principles described in the Declaration 
of Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ 
names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the Community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
studies as per guidance. The sponsor will provide the ECs with a copy of the same summary.


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10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason. If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification. Curriculum vitae for investigators and sub-investigators are 
provided to the study sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The


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investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective 
national, local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities 
and to have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc).


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These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written 
subject information and received an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent and assent documentation (ie, a complete 
set of subject information sheets and fully executed signature pages) must be given to the 
subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent 
form where applicable) which was reviewed by the IRB/EC and which received their 
favorable opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of


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these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible 
for this action. Additionally, if the IRB/EC requires modification of the sample subject 
information and consent document provided by the sponsor, the documentation supporting 
this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, 
or for multicenter studies the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor, the investigator, or for 
multicenter studies the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 


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register, or market C1 esterase inhibitor [human] liquid for injection; national or local 
regulatory authorities; and the IRBs/ECs which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present 
the study results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire ViroPharma will endeavor to publish the results of all qualifying, applicable, and 
covered studies according to external guidelines in a timely manner regardless of whether the 
outcomes are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma
adheres to external guidelines (eg, Good Publication Practices 2) when forming a publication 
steering committee, which is done for large, multicenter Phase 2-4 and certain other studies as 
determined by Shire ViroPharma. The purpose of the publication steering committee is to act 
as a non-commercial body that advises or decides on dissemination of scientific study data in 
accordance with the scope of this policy.
All publications relating to Shire ViroPharma products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma agreement to publish prior 
to release of information. The review is aimed at protecting the sponsor’s proprietary 
information existing either at the commencement of the study or generated during the study. 
To the extent permitted by the publisher and copyright law, the principal investigator will own 
(or share with other authors) the copyright on his/her publications. To the extent that the 
principal investigator has such sole, joint or shared rights, the principal investigator grants the 
sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 


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results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, the institution and 
principal investigator shall withhold submission of such publication for up to an additional 60 
days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the International Committee of Medical Journal 
Editors (ICMJE) current standards. Participation as an investigator does not confer any rights 
to authorship of publications.


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11.
REFERENCES
Agostoni A, Cicardi M 1992. Hereditary and acquired C1-inhibitor deficiency: biological and 
clinical characteristics in 235 patients. Medicine (Baltimore); 71(4): 206-15.
Aygören-Pürsün E, Bygum A, Beusterien K, et al. 2014. Socioeconomic burden of hereditary 
angioedema: results of the hereditary angioedema burden of illness study in Europe. Orphanet 
J Rare Dis;9:99.
Banerji A 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol; 111(5): 329-36. 
Bernstein
JA 2011. Update on angioedema: evaluation, diagnosis, and treatment. 
Allergy Asthma Proc; 32(6): 408-12.
Bork K, Barnstedt SE, Koch B, Traupe H 2000a. Hereditary angioedema with normal C1-
inhibitor activity in women. Lancet; 356(9225): 213-17.
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W 2000b. Asphyxiation by laryngeal edema 
in patients with hereditary angioedema. Mayo Clin Proc; 75(4): 349-54. 
Bork K, Gül D, Hardt J, Dewald G 2007. Hereditary angioedema with normal C1 inhibitor: 
clinical symptoms and course. Am J Med; 120(11):987-92.
Bowen T, Cicardi M, Farkas H, et al. 2010. 2010 International consensus algorithm for the 
diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol; 
6(1): 24.
Bygum A, Aygören-Pürsün E, Beusterien K, et al. 2015. Burden of illness in hereditary 
angioedema: a conceptual model. Acta Derm Venereol; [Epub ahead of print].
Caballero T, Aygören-Pürsün E, Bygum A, et al. 2014. The humanistic burden of hereditary 
angioedema: results from the burden of illness study in Europe. Allergy Asthma Proc; 35:47-
53.
Cicardi M, Igarashi T, Rosen FS, Davis AE 3rd 1987. Molecular basis for the deficiency of 
complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest; 79(3): 698-
702.
Cugno M, Nussberger J, Cicardi M, Agostoni A 2003. Bradykinin and the pathophysiology of 
angioedema. Int Immunopharmacol; 3: 311-7.
Cugno M, Nuijens J, Hack E, et al. 1990. Plasma levels of C1 inhibitor complexes and 
cleaved C1 inhibitor in patients with hereditary angioneurotic edema. J Clin Invest; 85:1215-
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Farkas H, Harmat G, Füst G, Varga L, Visy B 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol; 13(3): 153-61.
Farkas H, Jakab L, Temesszentandrási G, et al. 2007. Hereditary angioedema: a decade of 
human C1-inhibitor concentrate therapy. J Allergy Clin Immunol; 120(4): 941-7.


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Frank MM, Gelfand JA, Atkinson JP 1976. Hereditary angioedema: the clinical syndrome and 
its management. Ann Intern Med; 84(5): 580-93. 
Georgy MS, Pongracic JA 2012. Chapter 22: Hereditary and acquired angioedema. 
Allergy Asthma Proc; 33(Suppl 1): S73-6. 
Gompels MM, Lock RJ, Abinun M, et al. 2005. C1 inhibitor deficiency: consensus document. 
Clin Exp Immunol; 139(3): 379-94.
Kaplan AP 2010. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role 
of C1 inhibitor therapy. J Allergy Clin Immunol; 126(5): 918-25. 
Kaplan AP, Joseph K 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol; 104(3): 193-204. 
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT 2010. The 
humanistic burden of hereditary angioedema: Impact on health-related quality of life, 
productivity, and depression. Allergy Asthma Proc; 31(5): 407-14.
Ohela K 1977. Hereditary angioneurotic oedema in Finland. Clinical, immunological and 
genealogical studies. Acta Med Scand; 201(5): 415-27.
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65.
Sheehan DV 1983. The Anxiety Disease. New York, NY, USA: Charles Scribners Sons.
Weis M 2009. Clinical review of hereditary angioedema: diagnosis and management. 
Postgrad Med; 121(6): 113-20. 
Weller K, Groffik A, Magerl M, et al. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67(10): 1289-98.
Weller K, Groffik A, Magerl M, et al. 2013. Development, validation, and initial results of the 
angioedema activity score. Allergy; 68(9): 1185-92.
Zuraw BL 2003. Diagnosis and management of hereditary angioedema: an American 
approach. Transfus Apher Sci; 29(3): 239-45.
Zuraw BL 2008. Hereditary angioedema: a current state-of-the-art review, IV: short- and 
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Zuraw BL, Bork K, Binkley KE, et al. 2012. Hereditary angioedema with normal C1 inhibitor 
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12.
APPENDICES


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APPENDIX 1 HANDLING OF INVESTIGATIONAL PRODUCT FOR 
SUBCUTANEOUS INJECTION 
The procedures below are provided for the handling of the investigational product. Since 
treatment assignment to C1 esterase inhibitor [human] liquid for injection and placebo 
(Treatments A and B, respectively) is to be blinded, the following instructions apply for all 
SC administrations in Treatment Periods 1 and 2. Always work on a clean surface and wash 
hands before performing the following procedures.
Handling

Prior to administration, investigational product should be protected from light.

No reconstitution or additional dilution of investigational product is required.

A silicone-free syringe is to be used for withdrawal of the product from the vial 
and for administration.

Important Notes: (1) when withdrawing the product from the vial, and during 
administration, the plunger of the syringe should be moved back and forth 
carefully and slowly, avoid introducing any air bubbles, and pulling the plunger 
past the stop on the syringe; (2) there is no need for excessive shaking of either the 
vial or syringe during the preparation for the SC injection.

Investigational product should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. The 
product should be colorless and free from visible particles. Do not use if turbid or 
discolored.

Any vial that has been punctured should be used promptly.

Do not mix investigational product with other materials.

Do not freeze.

Do not use after expiration date.
NOTE: For this protocol, 2 vials of investigational product will be required for each SC 
injection (2x2 mL=4 mL total injection volume).
1. Aseptic technique should be used during handling.
2. Bring vials of investigational product to room temperature.
3. Remove caps from investigational product vials.
4. Cleanse stopper(s) with alcohol swab or germicidal solution, and allow them to dry prior 
to use.
5. Transfer the investigational product to a syringe for administration. Draw up the contents 
of 2 vials of investigational for a total volume of 4 mL.
Be sure to safely dispose of the used needle and syringe.


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Retain all used vials of investigational product for drug accountability purposes.


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APPENDIX 2 SUBCUTANEOUS INJECTION SITE SELECTION AND 
PREPARATION
Subcutaneous injections of investigational product will be administered in the abdominal area. 
Injection sites on the abdomen are depicted in the figure below. An abdominal site that is 
approximately at the level of the navel (as allowed by skin condition) and approximately 
15 cm (minimum 10 cm) away from the margin of the navel should be selected. The lateral 
portion of the abdomen is preferred over the midline area. The selected site should include 
fatty tissue. Administer the first injection in the right side (#1 in illustration) and the second 
injection in the left side (#2 in illustration). Keep alternating injection sites to the right side 
and then to the left side for all subsequent injections in Treatment Periods 1 and 2.
Illustration of Injection Sites on the Abdomen
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s 
position: 30-45º) and in a supine position immediately following injection for the evaluation 
of the injection site (ie, laying flat on back).
After the injection site for SC administration has been chosen, the investigational product will 
be administered as a single 4 mL SC injection as described briefly below.

Wipe skin with alcohol to cleanse. Allow to dry.

Gently pinch and lift the skin of the abdomen (ie, “tenting”).

Insert the needle with bevel up close to parallel to the skin or at an angle that is <20°. 
Once the needle is inserted, gently release the pinched and lifted skin (“untent the 
skin”). When the skin is in its normal state, the needle should have a slight upward 
angle of 20-30°. If the subject is obese, a steeper angle for needle insertion can be used 
but it is recommended keeping the angle <45°. In practical terms, the needle 
placement should resemble the angle of an IV needle placement in the arm. The 
purpose of pinching and lifting the skin is to make sure the needle is properly inserted 
in the SC space and is not intradermal.

Release the subcutaneous tissue. The needle will not back out during the injection if 
properly placed.

Care should be taken to avoid inadvertent IV or IM injection.
1
2


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It may be necessary to adjust the needle by pulling the needle slightly back if there appears to 
be a resistance to flow.


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APPENDIX 3 WELLS PREDICTION RULE FOR THE DIAGNOSIS OF 
VENOUS THROMBEMBOLISM
Table A.
Wells Prediction Rule for Diagnosing Deep Venous Thrombosis: Clinical 
Evaluation Table for Predicting Pretest Probability of Deep Venous 
Thrombosisa
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months, or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within 12 weeks requiring general anesthesia 
or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Alternative diagnosis at least as likely as deep venous thrombosis
−2
a Clinical probability of deep venous thrombosis: Low= ≤0; Intermediate=1 to 2; High= ≥3. In patients with symptoms in 
both legs, the more symptomatic leg is used.
Data source: Qaseem et al. 2007
Table B.
Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical 
Evaluation Table for Predicting Pretest Probability of Pulmonary 
Embolisma
Clinical Characteristic
Score
Previous pulmonary embolism or deep venous thrombosis
+1.5
Heart rate >100 beats per minute
+1.5
Recent surgery or immobilization
+1.5
Clinical signs of deep venous thrombosis
+3
Alternative diagnosis less likely than pulmonary embolism
+3
Hemoptysis
+1
Cancerb
+1
a Clinical probability of pulmonary embolism: Low=0 to 1; Intermediate=2 to 6; High= ≥7
b For the purposes of this study, cancer will include “treatment ongoing, within previous 6 months, or palliative.”
Data Source: Qaseem et al. 2007
References
Qaseem A, Snow V, Barry P, et al. 2007. Current diagnosis of venous thromboembolism in 
primary care: A clinical practice guideline from the American Academy of Family Physicians 
and the American College of Physicians. Ann Fam Med; 146(6):454-58.


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APPENDIX 4 ALGORITHM FOR SUSPECTED VENOUS
THROMBOEMBOLISM 
References
National 
Heart, 
Lung, 
and 
Blood 
Institute. 
Pulmonary 
embolism 
2011. 
http://www.nhlbi.nih.gov/book/export/html/4865. Accessed May 11, 2015. 
National 
Heart, 
Lung, 
and 
Blood 
Institute. 
Deep 
vein 
thrombosis
2011. 
http://www.nhlbi.nih.gov/book/export/html/4871. Accessed May 11, 2015.
Ozaki A, Bartholomew JR. Venous thromboembolism (deep venous thrombosis & pulmonary 
embolism). In: Carey WD, Rae-Grant A, Rimmerman C, ed. Disease Management Project. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous-
thromboembolism. Accessed May 11, 2015.


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APPENDIX 5 ALGORITHM FOR SUSPECTED ARTERIAL 
THROMBOEMBOLISM
References
National 
Library 
of 
Medicine. 
Arterial 
embolism
2014. 
http://www.nlm.nih.gov/medlineplus/ency/article/001102.htm. Accessed May 18, 2015.
Lyaker MR, Tulman DB, Dimitrova GT, Pin RH, Papadimos TJ 2013. Arterial embolism. Int 
J Crit Illn Inj Sci; 3(1): 77-87. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665125/?report=printable


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APPENDIX 6 PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
28 May 2015
Global

Prot_000.pdf: 
PROTOCOL: SHP616-300
TITLE:
A 
Phase 
3, 
Randomized, 
Double-blind, 
Placebo-controlled, 
Two-period, Three-sequence, Partial Crossover Study to Evaluate the 
Efficacy and Safety of Subcutaneous Administration of 2000 U of 
C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention 
of Angioedema Attacks in Adolescents and Adults with Hereditary 
Angioedema
DRUG:
SHP616, C1 esterase inhibitor [human] liquid for injection
IND:
16516
EUDRACT NO.:
2015-002478-19
SPONSOR: 
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
____________________
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Pending
PROTOCOL 
HISTORY:
Original Protocol: 28 May 2015, FINAL
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used solely for the 
purposes for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Shire ViroPharma, Inc.


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PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire ViroPharma, Inc.) Approval 
28 May 2015 
Page 2 of 103 
! Signature
______ l Dat
( 
·· ··· ·· · ·-·-· J 
Investigator's Acknowledgement 
I have read this protocol for Shire ViroPhatma Study SHP616-300. 
Title: A Phase 3, randomized, double-blind, placebo-controlled, two-period, tln·ee-sequence, 
patiial crossover study to evaluate the efficacy and safety of subcutaneous administration of 
2000 U of Cl esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks in adolescents and adults with hereditmy angioedema. 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ----------------------------- Date: 
PPD
PPD
PPD
PPD
PPD
PPD


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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover) and are 
provided below. 
US and Canadian Sites
Fax: 
Email: 
EU/ROW Sites
Fax: 
Email: 
For protocol- or safety-related issues, the investigator must contact the Shire
ViroPharma Medical Monitor:
, MD, 
, Clinical Development; Medical Monitor
Office phone: 
Fax: 
Mobile phone: 
Email: 
If the medical monitor is unavailable, please contact:
, MD, FRCP(C), 
, Clinical Development 
Office phone: 
Fax: 
Mobile phone: 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire
ViroPharma product (marketed or investigational) does not meet expectations (eg, inadequate 
or faulty closure, product contamination) or that the product did not meet the specifications 
defined in the application for the product (eg, wrong product such that the label and contents 
are different products). For instructions on reporting AEs related to product complaints, see 
Section 8.
Please report all Product Quality Complaints to:
PPD


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
EMERGENCY CONTACT INFORMATION ..........................................................................3
PRODUCT QUALITY COMPLAINTS ....................................................................................4
LIST OF TABLES......................................................................................................................9
LIST OF FIGURES....................................................................................................................9
LIST OF APPENDICES ..........................................................................................................10
ABBREVIATIONS..................................................................................................................11
STUDY SYNOPSIS.................................................................................................................13
STUDY SCHEDULES.............................................................................................................20
1.
BACKGROUND INFORMATION.............................................................................26
1.1
Indication and Current Treatment Options...................................................................26
1.2
Product Background and Clinical Information ............................................................27
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection ...............................29
1.2.1.1
Clinical Safety.............................................................................................30
1.2.1.2
Clinical Efficacy..........................................................................................32
1.2.2
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis............33
2.
STUDY OBJECTIVES AND PURPOSE....................................................................38
2.1
Rationale for the Study.................................................................................................38
2.2
Study Objectives...........................................................................................................38
2.2.1
Primary Objectives ................................................................................................38
2.2.2
Secondary Objectives ............................................................................................39
3.
STUDY DESIGN.........................................................................................................41
3.1
Study Design and Flow Chart ......................................................................................41
3.2
Duration and Study Completion Definition .................................................................42
3.3
Sites and Regions .........................................................................................................43
4.
STUDY POPULATION...............................................................................................44
4.1
Inclusion Criteria..........................................................................................................44
4.2
Exclusion Criteria.........................................................................................................45


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4.3
Reproductive Potential .................................................................................................45
4.3.1
Female Contraception............................................................................................45
4.3.2
Male Contraception................................................................................................46
4.4
Discontinuation of Subjects..........................................................................................46
4.4.1
Reasons for Discontinuation..................................................................................47
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit ..................................47
4.4.3
Anaphylactic Reaction...........................................................................................47
4.4.4
Thrombotic or Thromboembolic Event.................................................................47
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................49
5.1
Prior Treatment.............................................................................................................49
5.2
Concomitant Treatment and Medical/Surgical Procedures..........................................49
5.2.1
Management of Angioedema Attacks....................................................................49
5.2.2
Prohibited Treatment .............................................................................................50
6.
INVESTIGATIONAL PRODUCT..............................................................................51
6.1
Identity of Investigational Product...............................................................................51
6.2
Administration of Investigational Product ...................................................................51
6.3
Allocation of Subjects to Treatment Sequence ............................................................51
6.4
Blinding of Treatment ..................................................................................................52
6.4.1
Unblinding the Treatment Assignment..................................................................53
6.5
Treatment Compliance .................................................................................................53
6.6
Packaging and Labeling ...............................................................................................53
6.7
Storage and Accountability ..........................................................................................53
6.8
Investigational Product Retention at Study Site...........................................................54
7.
STUDY PROCEDURES..............................................................................................55
7.1
Study Schedule.............................................................................................................55
7.1.1
Screening Period....................................................................................................55
7.1.2
Treatment Period 1.................................................................................................56
7.1.2.1
Visit 1a (predose) ........................................................................................56
7.1.2.2
Visit 1a (postdose).......................................................................................56
7.1.2.3
Visit 2a through Visit 28a ...........................................................................57
7.1.3
Treatment Period 2.................................................................................................57
7.1.3.1
Visit 1b (predose) ........................................................................................57
7.1.3.2
Visit 1b (postdose).......................................................................................58
7.1.3.3
Visit 2b through Visit 28b...........................................................................58
7.1.4
Early Discontinuation Visit ...................................................................................59


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7.1.5
Follow-up Period ...................................................................................................60
7.2
Study Evaluations and Procedures ...............................................................................61
7.2.1
Demographic and Other Baseline Characteristics .................................................61
7.2.2
Efficacy..................................................................................................................61
7.2.2.1
Definition of an Angioedema Attack ..........................................................61
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary...........61
7.2.2.3
Angioedema Activity Score ........................................................................62
7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks .........63
7.2.3
Safety .....................................................................................................................63
7.2.3.1
Medical and Medication History.................................................................63
7.2.3.2
Physical Examination (Including Height and Weight)................................64
7.2.3.3
Adverse Event Collection............................................................................64
7.2.3.4
Vital Signs ...................................................................................................64
7.2.3.5
Clinical Laboratory Evaluations..................................................................64
7.2.3.6
Pregnancy Test ............................................................................................66
7.2.3.7
Electrocardiogram .......................................................................................66
7.2.3.8
Nonpharmacologic Treatments and Procedures..........................................67
7.2.3.9
Thrombotic or Thromboembolic Events.....................................................67
7.2.3.10 Injection Site Reactions...............................................................................68
7.2.4
Others.....................................................................................................................69
7.2.4.1
Clinical Pharmacology Assessments...........................................................69
7.2.4.2
Health-related Quality of Life Assessments................................................69
7.2.4.3
Health Resource Utilization Assessment ....................................................70
7.2.4.4
Survey of Acceptability of SC Administration ...........................................70
7.2.4.5
Self-administration Survey Assessment......................................................71
7.2.5
Volume of Blood to be Drawn From Each Subject...............................................71
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................72
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................72
8.1.1
Severity Categorization..........................................................................................72
8.1.2
Relationship Categorization...................................................................................73
8.1.3
Outcome Categorization ........................................................................................73
8.1.4
Symptoms of the Disease Under Study .................................................................73
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................74
8.1.6
Pregnancy...............................................................................................................74
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................75
8.2
Serious Adverse Event Procedures...............................................................................76


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8.2.1
Reference Safety Information................................................................................76
8.2.2
Reporting Procedures.............................................................................................76
8.2.3
Serious Adverse Event Definition .........................................................................76
8.2.4
Serious Adverse Event Collection Time Frame ....................................................77
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................77
8.2.6
Fatal Outcome........................................................................................................77
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................78
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................79
9.1
Data Collection.............................................................................................................79
9.2
Clinical Data Management...........................................................................................79
9.3
Data Handling Considerations......................................................................................79
9.4
Statistical Analysis Process..........................................................................................79
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........80
9.6
Sample Size Calculation and Power Considerations....................................................80
9.7
Study Population ..........................................................................................................80
9.8
Efficacy Analyses.........................................................................................................81
9.8.1
Primary Efficacy Endpoint ....................................................................................81
9.8.2
Secondary Efficacy Endpoints...............................................................................82
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................82
9.8.2.2
Other Secondary Efficacy Endpoints ..........................................................82
9.8.3
Exploratory Efficacy Endpoints.............................................................................83
9.9
Safety Analyses ............................................................................................................83
9.10
Other Analyses .............................................................................................................84
9.10.1 Pharmacokinetic and Pharmacodynamic Analyses ...............................................84
9.10.2 Health-related Quality of Life Analyses................................................................84
9.10.3 Surveys on SC Administration and Self-administration of Investigational 
Product...................................................................................................................85
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................86
10.1
Sponsor’s Responsibilities ...........................................................................................86
10.1.1 Good Clinical Practice Compliance.......................................................................86
10.1.2 Public Posting of Study Information .....................................................................86
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................86
10.1.4 Study Suspension, Termination, and Completion .................................................87
10.2
Investigator’s Responsibilities .....................................................................................87
10.2.1 Good Clinical Practice Compliance.......................................................................87


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10.2.2 Protocol Adherence and Investigator Agreement..................................................87
10.2.3 Documentation and Retention of Records.............................................................88
10.2.3.1 Case Report Forms......................................................................................88
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................88
10.2.3.3 Audit/Inspection..........................................................................................89
10.2.3.4 Financial Disclosure....................................................................................89
10.3
Ethical Considerations..................................................................................................89
10.3.1 Informed Consent ..................................................................................................89
10.3.2 Institutional Review Board or Ethics Committee..................................................90
10.4
Privacy and Confidentiality..........................................................................................90
10.5
Study Results / Publication Policy ...............................................................................91
11.
REFERENCES.............................................................................................................93
12.
APPENDICES..............................................................................................................96
LIST OF TABLES
Table 1:
Schedule of Assessments – Treatment Period 1....................................................20
Table 2:
Schedule of Assessments – Treatment Period 2....................................................22
Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits..............................................................................................24
Table 4:
Blood Sample Collection for PK/PD Analyses .....................................................25
Table 5:
Exposure to SC CINRYZE.......................................................................................30
Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)...................................................................................................33
Table 7:
Treatment Sequences.............................................................................................52
Table 8:
Severity Scoring for Injection Site Reactions........................................................68
Table 9:
Approximate Volume of Blood to be Drawn From Each Subject.........................71
LIST OF FIGURES
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity .....................................................34
Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)..................................................35


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Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice Weekly Dose Regimen ...................................................................36
Figure 4:
Study Design Flow Chart.......................................................................................41
LIST OF APPENDICES
Appendix 1 Handling of Investigational Product for Subcutaneous Injection.........................97
Appendix 2 Subcutaneous Injection Site Selection and Preparation........................................99
Appendix 3 Wells Prediction Rule for the Diagnosis of Venous Thrombembolism .............101
Appendix 4 Algorithm For Suspected Venous Thromboembolism .......................................102
Appendix 5 Algorithm For Suspected Arterial Thromboembolism.......................................103


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ABBREVIATIONS
AE
adverse event
AE-QoL
angioedema quality of life (questionnaire)
AAS
Angioedema Activity Score
ATE
arterial thromboembolism
AUC
area under the curve
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
C1 INH
C1 esterase inhibitor or C1 inhibitor
CI
confidence interval
CL
clearance
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval
Cmin
minimum concentration occurring at the time of maximum observed
concentration sampled during a dosing interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAE
hereditary angioedema
Β-hCG
beta human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRUA
health resource utilization assessment


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ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
λz
first order rate constant associated with the terminal (log-linear) portion of 
the curve
NNA
normalized number of attacks
PD
pharmacodynamics
PE
pulmonary embolism
PK
pharmacokinetics
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDS
Sheehan Disability Scale
t1/2
terminal half-life
T/TE
thrombotic/thromboembolic
TCSR
time-to-subject-assessed-complete-symptom resolution
TEAE
treatment-emergent adverse event
TISI
time-to-subject-assessed-initial-symptom improvement
tmax
time of maximum observed concentration sampled during a dosing 
interval
US
United States
VAS
Visual Analogue Scale
VTE
venous thromboembolism
WPAI-GH
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire)


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STUDY SYNOPSIS
Protocol number: SHP616-300
Drug: C1 esterase inhibitor [human] liquid for injection
Title of the study: A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, 
Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 U of C1 
Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and 
Adults with Hereditary Angioedema.
Number of subjects (total and for each treatment arm):
Approximately 75 subjects will be screened
At least 66 subjects will be enrolled and randomized to ensure that 54 subjects complete both treatment periods
At least 22 subjects will be randomized to each of the 3 treatment sequences 
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites globally (North America and Europe)
Study period (planned):
2015-2017
Clinical phase:
3
Objectives:
Primary:  
To demonstrate the superior efficacy of subcutaneous (SC) administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
normalized number of attacks (NNA) during a treatment period.
Key Secondary:  
To demonstrate the superior efficacy of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection for the prevention of angioedema attacks relative to placebo as measured by the proportion of subjects 
meeting the criterion of at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] 
liquid for injection treatment period relative to the placebo period.
Other Secondary:

To assess the proportion of responders during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo, where the proportion of responders is defined as:
-
Achieving at least a 50% reduction in the NNA during a treatment period relative to the 
pretreatment assessment (ie, the subject’s attack rate without prophylactic treatment)
-
Achieving a NNA <2.0 during a treatment period

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase inhibitor [human] 
liquid for injection relative to treatment with placebo

To assess the number of attack-free days during treatment with 2000 U C1 esterase inhibitor [human] liquid 
for injection relative to treatment with placebo

To assess the number of angioedema attacks requiring acute treatment during treatment with 2000 U C1 
esterase inhibitor [human] liquid for injection relative to treatment with placebo

To assess the safety and tolerability of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor [human] liquid for 
injection

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SC administration of 2000 U 


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28 May 2015
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C1 esterase inhibitor [human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the treatment of acute 
angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS)

To evaluate subject experience with self-administration of SC 2000 U C1 esterase inhibitor [human] liquid 
for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient population
Rationale:
Shire ViroPharma has developed a new, ready-to-use liquid formulation of CINRYZE® for SC administration. 
This product, C1 esterase inhibitor [human] liquid for injection, obviates the need for reconstitution by the 
patient or health care provider and, owing to its higher concentration, affords the opportunity for more rapid 
administration of the drug and may improve tolerability, without an expected change or compromise in efficacy.
Subcutaneous administration represents a convenient alternative method of administering prophylaxis to 
hereditary angioedema (HAE) patients overall and for whom accessing peripheral veins is difficult or in patients 
where placement of central venous catheters are contraindicated, as well as a means to minimize the potential 
adverse effects of intravenous (IV) administration.
Investigational product, dose, and mode of administration:

C1 esterase inhibitor [human] liquid for injection is supplied in clear glass vials containing 1000 U of 
C1 INH in 2 mL of sterile liquid. The solution also contains the following inactive ingredients: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.

Placebo is supplied in the identical 2 mL presentation as the active investigational product minus the 
C1 INH protein. The inactive ingredients in the 2 mL solution are the same as the active product: sodium 
phosphate, sorbitol, glycine, and water for injection. No reconstitution or dilution is required. Vials must 
be stored at 2–8oC (36–46oF) and protected from light.
Blinded investigational product (Treatments A or B: 2000 U C1 esterase inhibitor [human] liquid for injection 
or placebo) will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate treatment 
periods. Each dose of investigational product will be administered in the subject’s abdomen as a single 4 mL SC 
injection.
Methodology:
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial crossover study. 
This design was chosen as the best way to jointly address the protocol objectives of establishing efficacy 
(relative to placebo) and safety (ie, enrolling an adequate number of subjects for precision of estimation in 
detecting potential safety signals). Additionally, this design maximizes the number of subjects exposed to 
C1 esterase inhibitor [human] liquid for injection and minimizes subject exposure to placebo, while having 
adequate subject exposure to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. At least 66 eligible subjects will be randomized 
to 1 of 3 treatment sequences prior to the first dose of investigational product in Treatment Period 1 using 
interactive response technology (see table below). Randomization of subjects will be stratified by use of 
prophylactic therapy with C1 INH at the time enrollment.
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects Randomized
1
A/B
22
2
B/A
22
3
A/A
22
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 
3 or 4 days) for 14 weeks.
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.


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28 May 2015
Protocol SHP616-300
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Each treatment period will be 14 weeks, without a washout between the 2 periods. The omission of a washout 
period is to minimize the duration that subjects will be without active treatment. It is recommended that the 
twice weekly dosing schedule (every 3 or 4 days) be maintained between the last dose of investigational product 
in Treatment Period 1 and the first dose of investigational product in Treatment Period 2.
All study site personnel, subjects, qualified home health professionals, and the sponsor will be blinded to 
treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be administered at the 
investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both treatment periods. Other doses may be 
administered by qualified blinded personnel at the investigational site or at the subject’s home or other agreed 
upon location. During Treatment Period 2, after having received appropriate training, subjects will be allowed to 
self-administer the investigational product with direct supervision by study site personnel or a qualified home 
health professional. 
Throughout the study, an electronic subject diary will be used to record specific information regarding the 
subject’s symptoms of HAE. This will include signs and symptoms of angioedema attacks, location (including 
whether mucosal or non-mucosal), triggers for angioedema attacks, medications used for the acute treatment of 
angioedema attacks, elective procedures, and interruptions in activities of daily living due to an angioedema 
attack. Additionally, quality of life questionnaires and surveys on SC administration of the investigational 
product will be also subject evaluated. 
Adverse events will be recorded from the time the informed consent is signed through 7 days after the last dose 
of investigational product. This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product is administered. In addition, the investigator will report all SAEs that 
occur through 30 days after the last dose of investigational product to Shire Pharmacovigilance and the 
respective Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last dose of 
investigational product in Treatment Period 2 for follow-up safety assessments. In addition, subjects will have 
blood samples collected for PK/PD and C1 INH antibody testing at 1 month (±2 days) after the last dose of 
investigational product.
If a subject prematurely discontinues investigational product, early discontinuation visit procedures (Table 3) 
are to be performed as completely as possible. Whenever possible, all discontinued subjects should also 
complete the 1-week and 1-month post-treatment visits.  
The schedules of study procedures are provided immediately following the study synopsis:

Table 1: Clinical study assessments – Treatment Period 1 (Visits 1a to 24a).

Table 2: Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Table 3: Clinical study assessments – Early discontinuation visit, 1-week post-treatment and 1-month 
post-treatment visits.

Table 4: Blood sample collection schedule – PK/PD assessments


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Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 inhibitor (C1 INH) level less than 50% of 
normal.
3.
Meet one of the following criteria:

If currently receiving prophylactic therapy with C1 INH, have a history of ≥4.0 angioedema 
attacks per month (average)1 during the 3 consecutive months prior to starting prevention therapy. 
OR

If not receiving prophylactic therapy with C1 INH, have a history of ≥4.0 angioedema attacks per 
month (average)1 during the 3 consecutive months prior to the screening visit.
OR

If currently receiving a stable dose of attenuated androgens, have a history of ≥4.0 angioedema 
attacks per month (average)1 during the 3 consecutive months prior to the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any angioedema attacks 
that occur during the study that, in the opinion of the healthcare care provider, requires medical 
intervention. Note: For subjects ≥12 to <18 years of age, standard of care therapy per local protocols 
should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) pregnancy test at 
the screening visit and must have a negative urine pregnancy test prior to the first dose of 
investigational product (Visit 1a), and agree to comply with any applicable contraceptive requirements 
of the protocol.
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, 
barrier control) from the screening visit through 2 months after the last dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide written informed 
consent before any study-specific procedures. 
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study 
provide written informed consent for the child to participate in the study before any study-specific 
procedures are performed (with assent from the child when appropriate). Alternatively, certain 
sites/Independent Reviewing Authorities may permit adolescents who are <18 years of age to be 
informed of the nature of the study and provide written informed consent without consent from a 
parent(s)/legal guardian.
Exclusion Criteria:
1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 1000 U every 3 or 
4 days (receiving a weekly dose >2000 U).
2.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first dose of 
investigational product in Treatment Period 1.
3.
Have received any C1 INH therapy or any blood product for the treatment or prevention of angioedema 
attacks within 3 calendar days prior to the first dose of investigational product in Treatment Period 1.
4.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism.
5.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies.
                                                
1
The attack rate may be estimated based on subject recall in conjunction with the subject’s medical records.


Shire ViroPharma, Inc.
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28 May 2015
Protocol SHP616-300
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6.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of 
CINRYZE), or other blood products.
7.
Be pregnant or breastfeeding.
8.
Have received an investigational drug within 30 days prior to the first dose of investigational product in 
Treatment Period 1.
9.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any surgical or medical 
condition that could interfere with the administration of investigational product or interpretation of 
study results.
Maximum duration of subject involvement in the study:
Individual participation from the screening visit through the 1-month post-treatment visit will be approximately 
9 months.

Planned duration of screening period: Up to 21 days

Planned duration of enrollment period: 6 months

Planned duration of treatment period: Treatment Periods 1 and 2 are 14 weeks each (total 28 weeks) with 
no washout between periods

Planned duration of follow-up: 1 month follow-up in total, with safety assessments at both 1-week and 
1-month post-treatment
Endpoints and statistical analysis:
Primary Efficacy Endpoint: The NNA recorded during each treatment period. The NNA is computed as the 
number of attacks per month (ie, 30.4 days) of exposure (NNA = 30.4 x [number of attacks during treatment 
period]/[days of treatment period]). If a subject discontinues during the treatment period, the denominator of the 
NNA will be the days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation. 
The primary analysis of the primary efficacy endpoint will test against the null hypothesis that the NNA of C1 
esterase inhibitor [human] liquid for injection is greater than or equal to the NNA of placebo 
(H0: µ C1 INH - µ placebo >0; H1: µ C1 INH - µ placebo <0). The primary efficacy endpoint will be analyzed by using a 
mixed effect linear model with period, sequence, and treatment as fixed effects, and subject nested within 
sequence as a random effect. The mean treatment difference (µ C1 INH - µ Placebo) will be estimated with a 
95% confidence interval (CI).
To control the overall type 1 error, the primary and key secondary endpoints will be tested hierarchically, so that 
the significance of the key secondary endpoint is contingent on whether the primary endpoint is significant.
Key Secondary Efficacy Endpoint: The clinical response to treatment relative to placebo. This is defined as 
achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion PR. The null 
hypothesis is that PR is less than or equal to 0.2 and the alternative hypothesis is that PR is greater than 0.2. The 
proportion meeting criterion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. 
Other Secondary Efficacy Endpoints:

To determine the proportions of subjects with a clinical response to treatment as defined by: 
-
Achieving at least a 50% reduction in the NNA during a treatment period relative to the pretreatment 
assessment
-
Achieving a NNA <2.0 during a treatment period 

Cumulative attack severity. This score is the sum of the maximum symptom severity recorded for each 
angioedema attack in a treatment period.


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28 May 2015
Protocol SHP616-300
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
Cumulative daily severity. This score is the sum of the severity scores recorded for every day of reported 
symptoms in a treatment period.

Number of attack-free days during a treatment period.

Number of angioedema attacks requiring acute treatment during a treatment period.

Disease activity as measured by the 196-day AAS. This score is the sum of the daily AAS during a 
treatment period, where the daily AAS is the sum of AAS items per day.

Results of the Angioedema Quality of Life (AE-QoL) questionnaire.

Determine the response to icatibant when administered as treatment for an acute angioedema attack by:
-
Time to subject-assessed initial symptom improvement (TISI).
-
Time to subject-assessed complete symptom resolution (TCSR). 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC administration of C1 
esterase inhibitor [human] liquid for injection. The treatment differences in clinical responder rate, both of 
which are defined within treatments, will be analyzed using McNemar’s test for testing equality of proportions 
of responders within treatments. All other secondary endpoints will be analyzed using a linear mixed effect 
model with period, sequence, and treatment as fixed effects, and subject nested within sequence as a random 
effect. The results of all secondary efficacy analyses will be summarized by the point estimate of within-subject 
treatment differences or response rates and the corresponding 95% CI. Descriptive statistics (n, median, 25% 
and 75% quartiles, and range) will be provided to summarize icatibant-related efficacy endpoints (TISI and 
TCSR) by treatment and icatibant-treated angioedema attack for all subjects in the Full Analysis Set. Where 
appropriate (for subjects ≥12 to <18 years of age) other rescue medications used to treat acute angioedema 
attacks will also be summarized using descriptive statistics. In addition, angioedema attacks will be summarized 
by the maximum symptom severity and treatment for all subjects in the Full Analysis Set.
Safety Endpoints:

Number of subjects experiencing AEs, including severity and causality. AEs will also be assessed by time 
of onset (eg, during administration of investigational product or within 24 hours after the end of injection of 
investigational product). 

Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG findings will be 
summarized by treatment and visit. Potentially clinically important findings will also be summarized or 
listed. 

Incidence and severity (mild, moderate, severe) of SC injection site reactions. 

Results of C1 INH antibody testing will be reported for individual subjects and summarized. 

Tolerability of icatibant therapy for acute angioedema attacks will be summarized.
PK/PD Endpoints: Plasma concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
and C1q for individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics for values at each time point. C1q concentrations will only be assessed 
at baseline (ie, pre-injection, Dosing Visit 1a).
PK parameters will be calculated using observed and baseline-corrected concentration-vs-time data using non-
compartmental techniques for C1 INH antigen and functional activity, and results will be summarized using 
descriptive statistics.
Other Endpoints:

Results of the EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) health status instrument will 
be presented in accordance with the EQ-5D-5L user guide (Version 2.0). 

Results of the Work Productivity and Activity Impairment−General Health (WPAI-GH) questionnaire will 
be summarized. 

Results of the Sheehan Disability Scale (SDS) will be summarized.


Shire ViroPharma, Inc.
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28 May 2015
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
Results of the survey of subject acceptability of SC administration of investigational product will be 
summarized.

Results of the survey of subject experience with self-administration of investigational product will be 
summarized. 


Shire ViroPharma, Inc.
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28 May 2015
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STUDY SCHEDULES
Table 1:
Schedule of Assessments – Treatment Period 1
Procedures
Screena
TREATMENT PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a 26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj




























Acceptability surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m,
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c,n
c,n
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4


Shire ViroPharma, Inc.
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28 May 2015
Protocol SHP616-300
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Page 21 of 103
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report 
form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; HRUA=health 
resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; 
PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the 
injection.
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
g HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection.
k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see Table 
4).


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28 May 2015
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Page 22 of 103
Table 2:
Schedule of Assessments – Treatment Period 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b 18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg




























Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 4
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; 
INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan 
Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site.
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing 
days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.


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d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection.
h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.


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Table 3:
Schedule of Assessments – Early Discontinuation, 1-week and 1-month 
Post-treatment Visits
Procedures
Early Discontinuation 
Visita
[If Applicable]
1-Week (±1 day)
Post-treatment 
Visit
[All Subjects]
1-Month (±2 days)
Post-treatment
Visit
[All Subjects]
Concomitant medications


Physical examination


Vital signs (BP, pulse)b


Safety labsc


UA with microscopy


Pregnancy testingd


Adverse events


Angioedema attack monitoringe, f


AASe


Acceptability surveye

Self-administration surveye

AE-QoL questionnairee


EQ-5D-5Le


WPAI-GH and SDSe


HRUA-HAE

Immunogenicity (anti-C1 INH antibodies)



PK/PD



AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; 
BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level 
descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs 
that occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department.
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits. 
b Vital signs will be measured using standard methods at each investigational site. 
c Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer).  
d A urine pregnancy test will be performed for all female subjects of childbearing potential.
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation or at the 
1-week post-treatment visit.
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary.


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Table 4:
Blood Sample Collection for PK/PD Analyses
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Pointsa
C1 INH Antigen, C1 INH Functional, C4
1a / Dose 1b
Predose 1 (within 15 min) 
2a / Dose 2
Predose 2 (within 15 min)
8a / Dose 8
Predose 8 (within 15 min)
16a / Dose 16
Predose 16 (within 15 min) 
24a / Dose 24
Predose 24 (within 15 min)
Either 27a or 28a / Dose 27 or 28c
Predose 27 or 28 (within 15 min) 
48 hours postdose 27 or 28 (±3 hours)
TREATMENT PERIOD 2
1b / Dose 1
Predose 1 (within 15 min)
2b / Dose 2
Predose 2 (within 15 min)
8b / Dose 8
Predose 8 (within 15 min)
16b / Dose 16
Predose 16 (within 15 min)
24b / Dose 24
Predose 24 (within 15 min)
28b / Dose 28
Predose 28 (within 15 min)
24 hours postdose 28 (±3 hours) – optional sampling time point
48 hours postdose 28 (±3 hours) 
72 hours postdose 28 (±6 hours) – optional sampling time point
96 hours postdose 28 (±6 hours)
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT
Early discontinuation
1-week (± 1 day)
1-month (± 2 days)
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for 
guidance is as an approximate value.
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a).
c To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose
sample to be collected at either Visit 27a or 28a. 


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Hereditary angioedema (HAE) is an autosomal dominant disease caused by a gene mutation 
on chromosome 11 that results in a quantitative or functional deficiency of C1 esterase 
inhibitor (C1 INH) protein (Bernstein 2011). C1 INH is produced mainly by hepatocytes and 
acts as a “suicide inhibitor” by forming complexes with target serine proteases that result in 
their inactivation and the consumption of C1 INH. C1 INH regulates the activity of several 
components of the complement, contact (bradykinin-forming), and fibrinolytic systems 
(Kaplan 2010). Dysregulation of these cascades (particularly the contact system) due to 
C1 INH deficiency causes the uninhibited production of bradykinin, which promotes 
inflammation through increased vascular permeability and excessive accumulation of fluid in 
body tissues (Kaplan and Joseph 2010). Thus, patients with HAE are susceptible to recurrent 
episodes of debilitating swelling throughout the body. During acute angioedema attacks, the 
plasma levels of bradykinin in HAE patients can increase from 2 to 12 times (18.0–90.0 pM) 
the upper limit of normal (0.2-7.1 pM; Cugno et al. 2003). Serum concentrations of C1 INH 
in patients with HAE are 5% to 30% of normal (Cicardi et al. 1987), thus necessitating C1 
INH replacement therapy to prevent manifestations of the disease.
The diagnosis of a C1 INH deficiency is suggested by a history that includes recurrent attacks 
of angioedema, characterized by non-itching swelling of the skin or mucosa. Serum C4, 
C1 INH antigen, and functional C1 INH levels can be measured to assist with the diagnosis of 
HAE. There are 2 main types of HAE: Type I HAE (85% of cases), characterized by a low 
level of C1 INH antigen, and Type II HAE (15% of cases), characterized by “normal” levels 
of functionally deficient C1 INH protein (Frank et al. 1976). There is no clinical difference 
between Type I and Type II HAE. A third form of HAE, where patients have normal C1 INH 
levels, was initially described and referred to as Type III (Bork et al. 2000a). Patients with this 
type of HAE, more frequently women, have normal complement levels (including normal 
C1 INH), but a well-defined history of angioedema in the absence of concurrent urticaria 
(Zuraw and Christiansen 2009; Bernstein 2011). Mutations in the gene for coagulation factor 
XII (F12) have been identified in a minority of affected families (Bork et al. 2007). There are 
subtle phenotypic differences between patients with HAE due to C1 INH deficiency and those 
with normal C1 INH levels, including age at symptom onset, attack location(s), period of 
disease-free intervals, and inheritance pattern (Zuraw et al. 2012). The pathogenesis of HAE 
with normal C1 INH remains to be fully elucidated.  
Hereditary angioedema with C1 INH deficiency can present as early as the first year of life 
(Ohela 1977; Farkas et al. 2002), however, the median age at onset of initial symptoms is 
between 9 and 12 years (Farkas et al. 2007). Nearly all affected individuals experience 
symptoms of the disease; however, the symptoms vary in both their frequency and severity 
throughout a patient’s lifetime (Gompels et al. 2005; Zuraw 2003). Angioedema attacks may 
or may not have a triggering event. Trauma, medical or dental procedures, psychological 
stress, menstruation, infections, oral contraceptive use, and the use of other medications, such 
as angiotensin-converting enzyme inhibitors have been identified as possible triggers (Georgy 
and Pongracic 2012; Bowen et al. 2010). Angioedema attacks can affect the face, tongue, 


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larynx, gastrointestinal tract, genitourinary system, and extremities (Zuraw 2008). Laryngeal 
swelling can occlude the airway and cause death by asphyxiation, and these attacks primarily 
account for the mortality risk associated with C1 INH deficiency (Agostoni and Cicardi 1992; 
Bork et al. 2000b). Gastrointestinal involvement can mimic an acute surgical emergency, and 
misdiagnosis often results in unnecessary procedures to remove normal appendices and 
gallbladders (Weis 2009). Hence, angioedema attacks require prompt treatment, often in an 
emergency room.  
In addition to the impact on physical and mental health, the burden of illness in patients with 
HAE is considerable with respect to missed educational and career opportunities, work 
productivity, and a substantial economic burden for the cost of treatment (Lumry et al. 2010; 
Aygören-Pürsün et al. 2014). Hereditary angioedema not only causes short-term disability 
associated with attacks, but patients endure long-term effects on their daily lifestyle, 
emotional health, family life, and it may also affect caregivers’ quality of life (Bygum et al. 
2015). Effective management of HAE, including optimization of therapy, may reduce the 
clinical burden and have an overall favorable impact on the quality of life for individual HAE 
patients and their families (Banerji 2013; Caballero et al. 2014).
1.2
Product Background and Clinical Information
CINRYZE® (C1 esterase inhibitor [human]) was developed by the sponsor for the management 
of HAE. CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of C1 INH 
produced 
from 
human 
plasma. 
The 
manufacturing 
process 
includes 
3 
virus 
inactivation/removal 
steps: 
polyethylene 
glycol 
precipitation, 
pasteurization, 
and 
nanofiltration. CINRYZE is a normal human plasma protein that is not subject to cytochrome 
P450 metabolism, excretion, or pharmacokinetic (PK) drug-drug interactions exhibited by low 
molecular weight compounds. 
Intravenous administration of 1000 U of CINRYZE every 3 or 4 days is approved for routine 
prevention (prophylaxis) of angioedema attacks in patients with HAE in the United States 
(2008), European Union (2011), Australia (2012), Canada (2012), and Switzerland (2013). In 
several of these countries, CINRYZE is also approved for the acute treatment and preprocedure 
prevention of angioedema attacks.
The clinical efficacy of CINRYZE for the prevention of angioedema attacks in patients with 
HAE was demonstrated in 1
randomized, double-blind, placebo-controlled study 
(LEVP 2005-1/B) and 1
open-label study (LEVP 2006-4). Study LEVP 2005-1/B 
demonstrated that preventive therapy with CINRYZE resulted in both a statistically significant 
and clinically meaningful decrease in the rate, severity, and duration of acute attacks 
compared to placebo/on-demand therapy. Therapy with CINRYZE also increased antigenic 
C1 INH and functional C1 INH levels. These results were supported by Study LEVP 2006-4 
(that provided data for longer periods of preventive therapy across a wider age range of 
subjects), which demonstrated a reduction in the frequency of attacks while on CINRYZE
compared to a historical baseline. The open-label study also demonstrated that the efficacy of 
CINRYZE for the prevention of angioedema attacks did not diminish over time periods of at 
least 1 year. 


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The sponsor initiated a clinical development program for subcutaneous (SC) administration of 
CINRYZE for prevention of angioedema attacks using the same lyophilized formulation as that 
approved for IV injection. The initial program focused on safety, tolerability, and relative 
bioavailability of SC administration of CINRYZE (Studies 0624-100 and 0624-200). 
Preliminary assessments confirmed that CINRYZE can be absorbed after SC administration. 
However, because the exposure profile differed from that following IV administration, it was 
not known whether or to what extent SC administration would confer efficacy for the 
management of HAE.  
Based on results from nonsponsor studies conducted with recombinant human hyaluronidase 
(rHuPH20) and other injectable protein products, it was hypothesized that co-administration 
with rHuPH20 would increase dispersion and absorption of subcutaneously injected CINRYZE. 
Subsequently, 
the 
development 
program 
evaluated 
the 
safety, 
tolerability, 
PK/pharmacodynamics (PD), and efficacy of SC administration of CINRYZE with rHuPH20 
(Studies 0624-101, 0624-102, 0624-204, and 0624-206). However, in August 2013, the FDA 
directed the sponsor to stop administration of rHuPH20 in the ongoing Phase 2 study (0624-
206) of CINRYZE with rHuPH20 due to the development of anti-rHuPH20 antibodies in some 
patients. Dosing was also terminated in an ongoing Phase 1 healthy volunteer study (0624-
102) of CINRYZE with rHuPH20. Because the combination product (CINRYZE with rHuPH20) 
was being studied in these 2 trials, administration of CINRYZE was also discontinued. The 
FDA encouraged the sponsor to further the clinical development of CINRYZE alone 
administered via SC injection. Hence the evolution of the clinical development program with 
the new low volume, ready-to-use liquid formulation (C1 esterase inhibitor [human] liquid for 
injection) for SC administration. 
C1 esterase inhibitor [human] liquid for injection has been evaluated in an in vitro 
hemocompatibilitiy assay using human blood and plasma, a tissue irritation study in New 
Zealand White rabbits, and a 14-day repeat-dose toxicity study in Sprague Dawley rats. 
Incubation with whole blood at a concentration of 225 U/mL C1 esterase inhibitor [human] 
liquid for injection did not elicit hemolysis nor did the same concentration induce 
flocculation, precipitation, or coagulation. In the tissue irritation study in rabbits, microscopic 
examination of the injection sites showed minimal to mild inflammation that was most 
pronounced for perivascular injection route, followed by SC and then IV injection routes. In 
the 14-day repeat-dose study in rats, doses of 0 (sodium phosphate, glycine, and sorbitol), 
200, 400, and 1000 U/kg/day were administered subcutaneously once a day, while a fifth 
group of rats received 1000 U/kg/day intravenously. The only signs of toxicity were related to 
the expected immunogenic response to a human protein. Therefore, the no observed adverse
effect level is considered to be 1000 U/kg/day of C1 esterase inhibitor [human] liquid for 
injection for both the SC and IV routes of administration. Therefore, the toxicity profile for 
this ready-to-use liquid formulation is generally comparable to the lyophilized product even 
when a higher dose of the new formulation was tested. 
An initial clinical assessment of the new liquid formulation was conducted in a Phase 1 study 
in healthy volunteers (SHP616-103). This study evaluated the safety, tolerability, and relative 
bioavailability of the SC administration of 1000 U and 2000 U C1 esterase inhibitor [human] 
liquid for injection compared with the marketed formulation of CINRYZE (1000 U IV). This 


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single-center, open-label study consisted of a single-dose IV administration of CINRYZE
(lyophilized formulation) in Treatment Period 1 followed by a randomized, open-label, 2x2 
crossover design (Treatment Periods 2 and 3) to evaluate SC C1 esterase inhibitor [human] 
liquid for injection. Preliminary safety data from Protocol SHP616-103 regarding SC 
administration of C1 esterase inhibitor [human] liquid for injection is presented in 
Section 1.2.1.1.
High-level summaries of the clinical experience with SC administration of both CINRYZE
(CINRYZE alone and CINRYZE + rHuPH20) and C1 esterase inhibitor [human] liquid for 
injection are provided below. Always refer to the latest version of the CINRYZE investigator’s 
brochure for the overall risk/benefit assessment and the most accurate and current information 
regarding the drug metabolism, pharmacokinetics, efficacy, and safety of CINRYZE and C1 
esterase inhibitor [human] liquid for injection. 
1.2.1
Safety and Efficacy Data From Clinical Studies with SC CINRYZE and 
with SC C1 Esterase Inhibitor [Human] Liquid for Injection
Studies that evaluated SC administration of CINRYZE alone and CINRYZE with rHuPH20 
provided valuable data that informed key elements of this Phase 3 study of C1 esterase 
inhibitor [human] liquid for injection. Both programs enrolled healthy volunteers and subjects 
with HAE; 86 healthy volunteers (215 doses administered) and 72 subjects with HAE 
(1321 doses administered) have received 1 or more doses of SC CINRYZE in the development 
program to date (Table 5).


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Table 5:
Exposure to SC CINRYZE
Program
Study Number
Total Number of 
Subjects Exposed 
Number of SC Doses Administered
500 U
1000 U
2000 U
Total Doses
Healthy Volunteers
CINRYZE Alone
Study 0624-100a
9
1
0
14
15
Study 0624-102b
37 
0
37
0
37
CINRYZE with rHuPH20
Study 0624-101
24
0
0
47
47
Study 0624-102b
51 
0
116
0
116
Healthy Volunteers Total
86
1
153
61
215
Subjects with HAE
CINRYZE Alone
Study 0624-200
25
0
52
48
100
CINRYZE with rHuPH20
Study 0624-204
12 d
0
24
24
48
Study 0624-206
47
0
578
595
1173
Subjects with HAE Total
72
0
654
667
1321
OVERALL TOTAL
158
1
807
728
1536
HAE=hereditary angioedema; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
a CINRYZE via SC infusion and SC injection.
b A total of 53 subjects were enrolled in Study 0624-102 and received SC CINRYZE either alone (N=37) or co-administered 
with rHuPH20 (N=51).
c These 12 subjects received SC CINRYZE alone in Study 0624-200 and SC CINRYZE with rHuPH20 in Study 0624-204.
1.2.1.1
Clinical Safety 
Across the 2 studies of SC CINRYZE alone (Studies 0624-100 and 0624-200), 9 healthy adults 
and 25 subjects with HAE received CINRYZE doses of 1000 U and/or 2000 U. In healthy adult 
subjects, a single dose of 2000 U CINRYZE administered via the SC route was associated with 
mild injection/infusion site discomfort; however, no subjects were discontinued from study 
drug due to an AE. In HAE subjects, multiple doses of CINRYZE (1000 U or 2000 U) 
administered via the SC route were associated with generally mild to moderate injection site 
reactions, most notably pain, which was commonly characterized as burning or stinging. No 
subjects were discontinued from study drug due to an injection site reaction. No SAEs 
occurred during either SC study, and no subjects experienced a TEAE that was thrombotic or 
thromboembolic in nature. In addition, in both studies of SC CINRYZE, results of clinical 
laboratory evaluations and vital signs measurements were generally unremarkable and did not 
suggest any treatment-emergent abnormalities related to the administration of CINRYZE.
Across the 4 studies of SC CINRYZE + rHuPH20 (Studies 0624-101 0624-102, 0624-204 and 
0624-206), 77 healthy adults and 59 subjects with HAE received CINRYZE doses of 1000 U 


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and/or 2000 U. No SAEs occurred, no subjects were discontinued due to an AE, and no 
subjects experienced a TEAE that was thrombotic or thromboembolic in nature. The most 
commonly reported AEs were mild-moderate injection site reactions (eg, erythema, swelling, 
pain). Other safety parameters (clinical laboratory evaluations and vital signs measurements) 
were generally unremarkable and did not suggest any treatment-emergent abnormalities 
related to the administration of SC CINRYZE + rHuPH20. 
In Study 0624-206, a total of 21 (45%) subjects had detectable anti-rHuPH20 antibodies 
during the study, with 15 (32%) of the 21 subjects having a post-baseline titer of >1:20. All 
samples from these subjects were determined to be negative for rHuPH20-neutralizing 
activity. As requested by the FDA, the sponsor followed subjects who had treatment-emergent 
titers of ≥1:20 for 1 year post-treatment. There were no clinical sequelae observed in any 
subject and all titers declined during longitudinal follow-up. Three subjects in Study 0624-102 
had reportable anti-rHuPH20 antibodies at a titer ≥1:20; however, in all 3 cases, subjects had 
antibodies to rHuPH20 present at baseline (prior to the first dose of study drug). Subjects 
were not asked to participate in longitudinal follow-up, as anti-rHuPH20 antibody titers 
remained at or below the baseline level for each subject by the end of the study. 
In Protocol SHP616-103, a total of 26 healthy volunteers were enrolled in the study, of which 
23 subjects received 2 single SC doses of C1 esterase inhibitor [human] liquid for injection, 
while 1 subject received only a single SC dose (ie, 24 subjects received a total of 47 doses of 
C1 esterase inhibitor [human] liquid for injection). In preliminary data from 
Treatment Period 1 (IV administration) and approximately 50% of the SC administrations 
(Treatment Period 2) in this study, SC administration of C1 esterase inhibitor [human] liquid 
for injection was generally well tolerated, with no related SAEs or discontinuations resulting 
from an AE associated with its use. During the first 2 treatment periods, a total of 49 AEs 
were reported by 21 subjects; only 5 of these AEs (4 mild and 1 severe) were considered 
related to the study drug. One subject discontinued investigational product after Treatment 
Period 1 (where a single dose of 1000 U IV CINRYZE was administered on 26 Jan 2015) due 
to severe back pain. This AE was later reported as an SAE because of hospital admission
(04 Mar 2015) and the subject was subsequently diagnosed as having discitis between L5/S1 
vertebrae. This SAE was initially reported as related to investigational product by the 
investigator but was later considered not to be related after further information became 
available. Preliminary data indicates that there were no clinically important findings or 
clinically important changes from baseline in the vital signs, and there were also no apparent 
treatment-related trends or any clinically significant findings in the serum biochemistry, 
hematology and urinalysis parameters measured during these 2
treatment periods. 
Furthermore, no anti-C1 INH antibodies were detected in any subject through 30 days post-
treatment. With regard to the local tolerability of the SC administration of 1000 U and 2000 U 
C1 esterase inhibitor [human] liquid for injection in Treatment Period 2, the injection was 
generally well tolerated. Twenty-three of the total 24 subjects who received study treatment 
reported injection site reactions in Treatment Period 2. The most frequently reported reactions 
were mild erythema, followed by local warmth, all mostly resolved within 1-2 hours postdose. 


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1.2.1.2
Clinical Efficacy
The Phase 2 dose-ranging, crossover Study 0624-206 was designed to determine if there was 
a difference in efficacy between 2 SC doses of CINRYZE (1000 U and 2000 U co-administered 
with rHuPH20). The study was terminated before enrollment was complete (at the request of 
FDA due to the detection of anti-rHuPH20 antibodies in some subjects). Of the 47 subjects 
enrolled, 22 completed both treatment periods. Thus, due to the early termination of the study, 
the final sample size of the intent-to-treat efficacy population was smaller than planned 
(22/47, 47%). Regardless, the statistical advantage of a crossover study is that patients serve 
as their own control and the relative effect of the experimental treatments can be determined 
most efficiently with respect to within-patient differences.
The experimental results favored twice weekly SC administration of CINRYZE 2000 U + 
48,000 U rHuPH20 compared with CINRYZE 1000 U + 24,000 U rHuPH20 for the primary 
and all secondary efficacy endpoints during treatment, most notably in the within-subject 
treatment comparison.
An analysis of primary and secondary efficacy endpoints during treatment was performed for 
the mean difference between treatments (2000 U – 1000 U SC CINRYZE), within subjects in a 
treatment sequence and overall, as shown below in Table 6.
For the primary endpoint of normalized number of angioedema attacks during treatment, a 
treatment effect favoring the 2000 U compared with the 1000 U SC CINRYZE dose was 
observed for the within-subject treatment comparison; the overall mean difference (95% 
confidence interval [CI]) between treatments was -0.61 (-1.23, 0.01) and achieved borderline 
significance (p=0.0523).
With regard to secondary efficacy endpoints, statistically significant (p<0.05) treatment 
effects favoring the 2000 U compared with the 1000 U SC CINRYZE dose were observed for 
the within-subject treatment comparisons for both cumulative attack severity and for the 
number of attacks requiring acute treatment, with overall mean differences between 
treatments of -1.33 (p=0.0277) and -0.56 (p=0.0315), respectively.
No sequence effect was observed for the mean difference between the 2000 U and 1000 U SC 
CINRYZE doses within subjects in Sequences A/B or B/A for the primary or for any secondary 
endpoint (p-value for sequence effect across endpoints: ≥0.6290).
These findings indicated that CINRYZE at a dose of 2000 U SC was superior to a dose of 
1000 U in terms of clinical efficacy improvement. The results are more compelling in light of 
their arising from truncated enrollment and consequently, an underpowered study.


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Table 6:
Primary and Secondary Efficacy Endpoints During Treatment by Sequence 
(Within-Subject Treatment Comparison) – ITT-E Population 
(Study 0624-206)
Endpoints (Normalized)
Sequence A/B
Difference: B-A
N=12
Sequence B/A
Difference: B-A
N=10
Overall
Difference: B-A
N=22
Treatment
Comparison
p-valuea
Primary
Number of angioedema attacks
-0.72
(-1.71, 0.27)
-0.48
(-1.36, 0.40)
-0.61
(-1.23, 0.01)
0.0523
Secondary
Cumulative attack severity
-1.53
(-3.41, 0.35)
-1.09
(-2.74, 0.57)
-1.33
(-2.49, -0.16)
0.0277
Cumulative daily severity
-1.53
(-4.42, 1.36)
-2.19
(-6.06, 1.69)
-1.83
(-3.98, 0.32)
0.0912
Cumulative symptomatic days
-0.95
(-2.64, 0.74)
-0.87
(-3.35, 1.62)
-0.91
(-2.23, 0.41)
0.1660
Number of attacks requiring acute 
treatment
-0.67
(-1.20, -0.14)
-0.43
(-1.47, 0.62)
-0.56
(-1.06, -0.05)
0.0315
CI=confidence interval; ITT-E=intent-to-treat efficacy; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
Note: Data are presented as the mean (95% CI). Treatment A=1000 U SC CINRYZE + 24,000 U rHuPH20; 
Treatment B=2000 U SC CINRYZE + 48,000 U rHuPH20. Subjects who were dosed but did not have any attacks in the 
period were assigned a value of zero for each of the efficacy parameters.
a p-value for paired t-test.
b Only subjects who completed both treatment periods are included in the ITT-E population.
1.2.2
Population PK/PD Modeling and a PK/PD Exposure-Response Analysis
Population PK and PK/PD modeling of C1 INH and C4 were developed based on data 
collected in 10 clinical studies with healthy volunteers and HAE patients who received IV or 
SC administrations of CINRYZE. Exposure-response analyses were performed based on 
2 studies for the use of CINRYZE for the prophylactic treatment to prevent HAE. 
The final population PK model of C1 INH was a 1-compartment model with endogenous C1 
INH levels. The absorption of CINRYZE following SC dosing was characterized with a 
first-order rate and relative absorption fraction (Frel). Based on the population PK model, the 
relative bioavailability of CINRYZE following SC dosing without rHuPH20 was 38.8%. 
Typical CL of C1 INH was 0.0864 L/h (1.44 mL/min) in HAE patients with a typical body 
weight of 70 kg. The t1/2 of C1 INH in a typical 18.0, 36.6, and 80.0-year-old patient weighing 
70 kg were 32.0, 29.0, and 26.0 hours, respectively.
The effect of rHuPH20 on the rate and extent of absorption of C1 INH was included in the 
model. The use of rHuPH20 with SC administration appears to have little to no improvement 
on C1 INH exposure. This was illustrated in the Phase 1 study with healthy volunteers 
(Study 0624-102) where CINRYZE 1000 U SC administered with 200, 2000, or 20,000 U 
rHuPH20 was not statistically different in Cmax and AUClast compared with CINRYZE alone. In 


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addition, the population PK model estimated only a 10% increase in bioavailability with 
rHuPH20, which reached saturation with increasing rHuPH20 concentrations as presented in
Figure 1.
Figure 1:
The Effect of Increasing rHuPH20 Concentration on Relative SC 
Bioavailability of C1 INH Functional Activity
C1 INH=C1 esterase inhibitor; rHuPH20=recombinant human hyaluronidase; SC=subcutaneous
The population PK model was used to support the assessment of the exposure-response 
relationship of CINRYZE during prophylactic treatment of angioedema attacks for C1 INH and 
C4. The response criterion originally used in Study 0624-400 was used to define responder 
status, whereby a response was defined as ≤1 angioedema attack/month, since this criterion 
has been deemed clinically meaningful by both expert clinicians and patients with HAE. A 
logistic regression model was used to link Cmin values of C1 INH (continuous) with the 
probability of response (binary) following IV dosing of 1000 U of CINRYZE in studies LEVP 
2005-1/B and LEVP 2006-4 (Section 1.2). The exposure-response relationship of Cmin values 
of C1 INH following IV dosing of CINRYZE is presented in Figure 2.


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Figure 2:
Exposure-response Relationship Following IV Dosing of CINRYZE
(Probability of ≤1.0 Angioedema Attack/Month)
C1 INH=C1 esterase inhibitor; ROC=receiver-operating characteristic
Higher Cmin values of C1 INH were associated with a higher probability of response in 
patients with HAE (p<0.001). The above exposure-response relationship was to be used to 
predict the probability of response for any Cmin values of C1 INH in subjects with HAE. For 
example, typical Cmin values of 0.207, 0.289, 0.380, and 0.556 U/mL (corresponding to first, 
second, third, and fourth quartiles of Cmin of C1 INH, respectively) would be expected to 
result in response probabilities of 54.4%, 61.5%, 68.8%, and 80.5%, respectively. Typical C1 
INH plasma functional activity levels in HAE patients range from 5–30% of normal 
(0.05-0.3 U/mL) (Cugno et al. 1990).
Receiver-operating characteristic analysis was used to identify an optimal Cmin cutoff of C1 
INH that would optimize the probability of avoiding an angioedema attack. Based on data 
from study LEVP 2006-4 with IV administration of 1000 U CINRYZE approximately twice 
weekly, the optimal Cmin cutoff was 0.479 U/mL. When considering a 2-week period of delay, 
the optimal Cmin cutoff was 0.433 U/mL. Based on the above ROC analyses, a targeted C1 
INH Cmin value of 0.45 U/mL was used to determine the expected response following SC 
dosing of 2000 U of CINRYZE. Based on the exposure-response model, a C1 INH Cmin value 
of >0.45 U/mL would achieve at least a 70% probability of success (≤1 angioedema 
attack/month).
No statistically significant relationship was observed between minimum C4 concentrations 
and the probability of response.


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The combination of the population PK model and exposure-response relationship model was 
used to simulate C1 INH Cmin following SC dosing of CINRYZE to support the dosing rationale 
and improve the likelihood of success at achieving an efficacious dose in patients with HAE 
(Figure 3).
Figure 3:
Simulated Concentration-time Profiles of C1 INH in Adult Patients with 
HAE – Twice Weekly Dose Regimen
C1 INH=C1 esterase inhibitor; HAE=hereditary angioedema
From these simulations, results show that a dose of 2000 U would maintain mean (blue line) 
functional C1 INH Cmin values above the targeted level of 0.45 U/mL (red horizontal line).
In studies LEVP 2005-1/B and LEVP 2006-4, in which subjects with HAE received IV doses 
of 1000 U CINRYZE approximately twice weekly, mean pre-infusion functional C1 INH 
concentrations ranged from 0.38-0.41 U/mL and 0.37-0.52 U/mL, respectively, during the 
treatment period. In the recent Phase 2 clinical study 0624-206, in which subjects with HAE 
received twice weekly SC doses of 1000 U CINRYZE with 24,000 U rHuPH20 or 2000 U 
CINRYZE with 48,000 U rHuPH20 in two 8-week crossover periods, the mean (± standard 
error) steady-state functional C1 INH Cmin for 2000 U CINRYZE was 0.41 (±0.11) U/mL.
The approach for preventative therapy in HAE patients is to provide enough CINRYZE to 
achieve or exceed a threshold C1 INH functional activity concentration in plasma that has a 
>70% likelihood of preventing an angioedema attack. Under the assumption that, after final 
analysis, the data regarding C1 esterase inhibitor [human] liquid for injection from Protocol 


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SHP616-103 are consistent with previous data with respect to CINRYZE in the HAE program, 
the data support a SC dose of 2000 U of C1 esterase inhibitor [human] liquid for injection 
twice weekly to be effective in patients with HAE. Consistency of the data from Protocol 
SHP616-103 will be confirmed after final analysis.


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The sponsor has developed a new, ready-to-use liquid formulation of CINRYZE (C1 esterase 
inhibitor [human]). The CINRYZE liquid product (C1 esterase inhibitor [human] liquid for 
injection) is intended for the same indication as the licensed, lyophilized powder formulation 
of CINRYZE: routine prophylaxis against angioedema attacks in adolescent and adult patients 
with HAE. The route of administration will be SC injection, and the dosing regimen will be 
2000 U every 3 or 4 days. Shire ViroPharma anticipates that patients will benefit from the 
inherent advantages of SC administration, as well as the ready-to-use liquid, lower volume 
product compared with one requiring reconstitution. In addition, the CINRYZE liquid product 
is more concentrated than the licensed CINRYZE product (500 vs 100 U/mL), which should 
enable more rapid administration of the drug and may improve tolerability, without an 
expected change or compromise in efficacy.
The sponsor has selected 2000 U of C1 esterase inhibitor [human] liquid for injection as the 
appropriate active dose for this Phase 3 study. This dose is based on the results of a recently 
completed Phase 2, randomized, double-blind, dose-ranging, crossover study that evaluated 
SC administration of CINRYZE with rHuPH20 (a dispersing agent) for the prevention of 
angioedema attacks in adolescents and adults with HAE (Study 0624-206). Results revealed 
greater clinical benefit with 2000 U of CINRYZE compared with 1000 U. In addition, the 
2000 U dose is supported by PK results from Study 0624-206, by the results of population PK 
and exposure-response modeling, and by PK data from a Phase 1 study (0624-102) that 
demonstrated the minimal influence of rHuPH20 on functional C1 INH activity when co-
administered with CINRYZE (Section 1.2.2). Additionally, support for the 2000 U dose based 
on the PK and bioavailability data from the Phase 1 study of C1 esterase inhibitor [human] 
liquid for injection (Protocol SHP616-103) will be confirmed after the final data analysis.
The study design was chosen as the best way to jointly address the protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, adequate numbers of subjects for 
precision of estimation in detecting potential safety signals). Additionally, this design 
maximizes the number of patients exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes patient exposure to placebo while having adequate patient exposure 
to placebo to assess efficacy. Thus, the proposed study is described as a “partial” crossover 
because 2 treatment sequences involve crossing over to the other experimental agent and the 
third sequence does not. All subjects will receive active treatment during this study and will 
have a two-thirds probability to be randomized to active drug in any treatment period.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to demonstrate superior efficacy of SC administration 
of 2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 


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attacks relative to placebo based on the normalized number of attacks (NNA) during a 
treatment period.
2.2.2
Secondary Objectives
The key secondary objective is to demonstrate the superior efficacy of SC administration of 
2000 U C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by the proportion of subjects meeting the criterion of 
at least 50% reduction in the NNA during the 2000 U C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period.
Other secondary objectives are:

To assess the proportion of responders during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo, where the 
proportion of responders is defined as:
-
Achieving at least a 50% reduction in the NNA during a treatment period relative 
to the pretreatment assessment (ie, the subject’s attack rate without prophylactic 
therapy)
-
Achieving a NNA <2.0 during a treatment period

To assess the severity of angioedema attacks during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of attack-free days during treatment with 2000 U C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo 

To assess the number of angioedema attacks requiring acute treatment during treatment 
with 2000 U C1 esterase inhibitor [human] liquid for injection relative to treatment 
with placebo 

To assess the safety and tolerability of SC administration of 2000 U C1 esterase 
inhibitor [human] liquid for injection

To assess the immunogenicity of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection 

To characterize the PK and PD of SC administration of 2000 U C1 esterase inhibitor 
[human] liquid for injection

To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the 
treatment of acute angioedema attacks (applicable for subjects ≥18 years of age)

To assess disease activity as measured by the Angioedema Activity Score (AAS) 


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
To evaluate subject experience with self-administration of SC 2000 U C1 esterase 
inhibitor [human] liquid for injection 

To evaluate the impact of treatment on health status (quality of life) in this patient 
population


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, double-blind, placebo-controlled, two-period, three-sequence, partial 
crossover study. The design was chosen to optimally address the joint protocol objectives of 
establishing efficacy (relative to placebo) and safety (ie, enrolling an adequate number of 
subjects to have precision of estimation to detect or rule out safety signals). Additionally, this 
design maximizes the number of subjects exposed to C1 esterase inhibitor [human] liquid for 
injection and minimizes subject exposure to placebo, while having adequate subject exposure 
to placebo to assess efficacy. 
Subjects will be screened within 21 days prior to randomization. At least 66 eligible subjects 
will be randomized to 1 of 3 treatment sequences prior to the first dose of investigational 
product in Treatment Period 1 (ie, Dosing Day 1a) using interactive response technology 
(IRT). Randomization of subjects will be stratified by use of prophylactic therapy with 
C1 INH at the time enrollment. 
Figure 4:
Study Design Flow Chart
Each treatment period will be 14 weeks, without a washout between the 2 periods. The 
omission of a washout period is to minimize the duration that subjects will be without active 
treatment. It is recommended that the twice weekly dosing schedule (every 3 or 4 days) be 
maintained between the last dose of investigational product in Treatment Period 1 and the first
dose of investigational product in Treatment Period 2.


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All study site personnel, subjects, qualified home health professionals, and the sponsor will be 
blinded to treatment sequence. 
Subjects will remain outpatients throughout the study. Investigational product will be 
administered at the investigational site for Dosing Visits 1, 8, 16, 24, and 28 during both 
treatment periods. Other doses may be administered by qualified blinded personnel at the 
investigational site or at the subject’s home or other agreed upon location. During Treatment 
Period 2, after having received appropriate training, subjects will be allowed to 
self-administer the investigational product with direct supervision by the study site personnel 
or a qualified home health professional.
Throughout the study, an electronic subject diary will be used to record specific information 
regarding the subject’s symptoms of HAE. This will include signs and symptoms of 
angioedema attacks, triggers for angioedema attacks, location (including whether mucosal or 
non-mucosal), medications used for acute treatment of angioedema attacks, elective 
procedures, and interruptions in activities of daily living due to an angioedema attack. 
Additionally, quality of life questionnaires and surveys on SC administration of the 
investigational product will be also subject evaluated. 
Adverse events will be recorded from the time the informed consent is signed through 7 days 
after the last dose of investigational product. This includes events occurring during the 
screening phase of the study, regardless of whether or not the investigational product is 
administered. In addition, the investigator will report all SAEs that occur through 30 days 
after the last dose of investigational product to Shire Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of the investigational product in Treatment Period 2 for follow-up safety assessments. In 
addition, subjects will have blood samples collected for PK/PD and C1 INH antibody testing 
at 1 month (±2) days after the last dose of the investigational product.
If a subject prematurely discontinues investigational product, regardless of the reason, the 
early discontinuation visit safety procedures listed in Table 3 are to be performed as 
completely as possible. Whenever possible, all discontinued subjects should also complete the 
1-week and 1-month post-treatment visits. 
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 9 months. 
The study will be completed in approximately 15 months. 
The Study Completion Date is defined as the date the final subject, across all sites, completes
their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. The Study Completion Date is used to ascertain timing for study
results posting and reporting.


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3.3
Sites and Regions
Approximately 40 sites globally (North America and Europe) are expected to participate in 
this study.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria
below.
1.
Be ≥12 years of age.
2.
Have a diagnosis of HAE (Type I or II) and a functional C1 INH level less than 50% 
of normal.
3.
Meet one of the following criteria:

If currently receiving prophylactic therapy with C1 INH, have a history of ≥4.0 
angioedema attacks per month (average)1 during the 3 consecutive months prior to 
starting prevention therapy. 
OR

If not receiving prophylactic therapy with C1 INH, have a history of ≥4.0 
angioedema attacks per month (average)1 during the 3 consecutive months 
prior to the screening visit.
OR

If currently receiving a stable dose of attenuated androgens, have a history of ≥4.0 
angioedema attacks per month (average)1 during the 3 consecutive months prior to 
the screening visit.
4.
For subjects ≥18 years of age, be willing to receive treatment with icatibant for any 
angioedema attacks that occur during the study that, in the opinion of the healthcare 
care provider, require medical intervention. Note: For subjects ≥12 to <18 years of 
age, standard of care therapy per local protocols should be provided.
5.
Agree to adhere to the protocol-defined schedule of assessments.
6.
If female, must have a negative serum beta human chorionic gonadotrophin (β-hCG) 
pregnancy test at the screening visit and must have a negative urine pregnancy test 
prior to the first dose of investigational product (Visit 1a), and agree to comply with 
any applicable contraceptive requirements of the protocol. 
7.
If male, be surgically sterile or agree to follow an acceptable method of birth control 
(eg, abstinence, barrier control) from the screening visit through 2 months after the last 
dose of investigational product.
8.
If an adult (≥18 years of age), be informed of the nature of the study and provide 
written informed consent before any study-specific procedures. 
                                                
1
The attack rate may be estimated based on subject recall in conjunction with the subject’s medical records.


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OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the 
nature of the study provide written informed consent for the child to participate in the 
study before any study-specific procedures are performed (with assent from the child 
when appropriate). Alternatively, certain sites/Independent Reviewing Authorities 
may permit adolescents who are <18 years of age to be informed of the nature of the 
study and provide written informed consent without consent from a parent(s)/legal 
guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 
1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first 
dose of the investigational product in Treatment Period 1.
3.
Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1.
4.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition 
for thromboembolism. 
5.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH 
antibodies. 
6.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), or other blood products. 
7.
Be pregnant or breastfeeding. 
8.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
9.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following 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 


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sexually active during the period of the study and 30 days following the last dose of 
investigational product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and aged
51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
Screening Visit and a negative urine pregnancy test prior to randomization (predose at 
Visit 1a). Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception 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 Screening Visit (Visit 1a), 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 a hormonal contraceptive for 30 days.
4.3.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 2 months after the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Early Discontinuation Visit are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also complete the 1-week and 1-month Post-
treatment visits. Comments (spontaneous or elicited) or complaints made by the subject must 
be recorded in the source documents. The reason for termination, date of stopping 
investigational product, and the total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.


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Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject

Lost to follow up

Lack of efficacy

Other (specify) 
4.4.2
Subjects ‘Lost to Follow up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.4.3
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, investigational product will be discontinued, 
and the subject will follow the schedule of assessments for early discontinuation (Table 3). 
Subjects already enrolled will continue with study drug administration and procedures. 
4.4.4
Thrombotic or Thromboembolic Event
If a thrombotic/thromboembolic (T/TE) event occurs in any subject, no further enrollment 
will occur pending a complete review of all available data. Already enrolled subjects will 
continue with investigational product administration and study procedures. Following a safety 
review of the T/TE event, study enrollment may be restarted if the medical monitor 
determines that the event was unrelated or unlikely to be related to investigational product or 
other C1 inhibitors, which may have been administered for an angioedema attack. Unblinding 
of the randomization code for that subject may be required (see below).
If a T/TE event occurs in any subject, investigational product administration for that subject 
will be interrupted; however, other study procedures will continue, as clinically appropriate. 


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Diagnosis and management of all suspected T/TE events should be per local standard of care; 
Appendix 4 and Appendix 5 present a suggested medical algorithm for diagnosis and 
management of such conditions. Investigators must also comply with all reporting and/or 
concerning procedures for AEs/SAEs as indicated in the suggested algorithm. Following a 
complete medical review by the sponsor in conjunction with the investigator, and if 
determined safe to do so, dosing with investigational product may be resumed to complete a 
total of 28 doses in the treatment period that was interrupted. Study procedures, including 
PK/PD testing, will resume relative to dosing. If investigational product cannot be restarted 
within 30 days of the temporary interruption, the subject will be discontinued from treatment 
and will follow the schedule of assessments for early discontinuation (Table 3). If unblinding 
is required, a physician external to the study will review relevant safety information, including 
the subject’s assigned treatment. The unblinded physician will relay his or her findings and 
recommendations to the medical monitor, exercising caution not to reveal the subject’s 
randomization to anyone associated with the conduct of the study.


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5.
PRIOR AND CONCOMITANT TREATMENT
Prior and concomitant medications that will be recorded on the appropriate CRF page include 
prescription medications, blood products (eg, albumin, packed red blood cells, whole blood, 
fresh frozen plasma, platelets), dietary supplements/vitamins, electrolyte supplementation, 
and over-the-counter medications. Topical medications (non-prescription) will be recorded 
only if used as treatment for an AE.
5.1
Prior Treatment
Any therapy received during the 12 months prior to randomization for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and 
the HAE indication (ie, acute treatment, long-term prevention, short-term [preprocedural] 
prevention).  
In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the CRF.
5.2
Concomitant Treatment and Medical/Surgical Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the 1-week post-treatment visit, inclusive. All prescription and 
over-the-counter medications being taken by subjects during this time period are regarded as 
concomitant treatments. For any medication that is administered, the investigator will 
document the drug name, amount, route of administration, frequency, and duration 
administered, as well as the reason for administering the medication on the appropriate CRF 
page.
Medical/surgical procedures performed during the study will be recorded on the CRF, along 
with the date, time, and reason for the procedure. 
5.2.1
Management of Angioedema Attacks 
If a subject (≥18 years of age) experiences an acute angioedema attack at any time during 
study that in the opinion of the healthcare care provider requires medical intervention, 
icatibant should be administered to treat the attack. For subjects ≥12 to <18 years of age
standard of care therapy per local protocols should be provided, such as (where approved for 
adolescents) C1 esterase inhibitor (human), C1 esterase inhibitor (recombinant), and 
ecallantide. The determination of the necessity for therapy to alleviate subject symptoms will 
be at the discretion of the investigator. Administration of investigational product and study 
procedures will continue without alteration to the protocol schedule, even if a subject receives 
any treatment for an angioedema attack.
For medications associated with management of acute angioedema attacks, study personnel 
will record start/stop dates, time of administration, dose, unit, frequency, and route of 
administration in the subject’s CRF page. Adverse events associated with medications used in 


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the treatment of acute angioedema attacks will be captured on the AE CRF and attributed to 
the concomitant medication administered.
Angioedema attacks will not be considered AEs; however, events satisfying the serious 
criteria should be recorded as a SAE and reported to Shire Pharmacovigilance (Section 8.1.4). 
Data on angioedema attacks will be collected separately from general reports of AEs and will 
be used in the evaluation of efficacy (Section 7.2.2). In addition, if applicable, subjects will 
record their response to icatibant therapy when used for treating an angioedema attack, as well 
as any associated side effects or tolerability issues. This information will be recorded in the 
electronic subject diary (Section 7.2.2.4).
5.2.2
Prohibited Treatment
Use of C1 INH therapy (other than study drug) for prophylaxis against angioedema attacks is 
prohibited during this study (from the first dose of investigational product through the 
1-month post-treatment visit).
The initiation of androgen therapy is prohibited during the study (from the first dose of 
investigational product through the 1-month post-treatment visit). 


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is C1 esterase inhibitor [human] liquid for injection, which is supplied in 
clear glass vials containing 1000 U of C1 INH in 2 mL of sterile liquid. The solution also 
contains the following inactive ingredients: sodium phosphate, sorbitol, glycine, and water for 
injection.
The reference product is placebo, which is supplied in an identical 2 mL presentation as the 
active investigational product minus the C1 INH protein. The inactive ingredients in the 
solution are the same as the active drug product: sodium phosphate, sorbitol, glycine, and 
water for injection.
No reconstitution or dilution is required for the test or reference product. Vials must be stored 
at 2–8oC (36–46oF) and protected from light.
Instructions for handling of investigational product and for SC injection site selection and 
preparation are provided in Appendix 1 and Appendix 2, respectively.
6.2
Administration of Investigational Product
Blinded investigational product (C1 esterase inhibitor [human] liquid for injection or placebo) 
will be administered twice weekly (every 3 or 4 days) for 14 weeks in each of 2 separate 
treatment periods. The contents of 2 vials of investigational products (a total volume of 4 mL) 
will be drawn into a silicone-free syringe for each SC injection. Following appropriate SC 
injection site selection and preparation (Appendix 2), the needle will be inserted in the 
subject’s abdominal area in order to administer the SC injection as quickly as tolerated by the 
subject. 
Investigational product will be administered at the investigational site for Dosing Visits 1, 8, 
16, 24, and 28 during both treatment periods. Other doses may be administered by qualified 
blinded personnel at the investigational site or at the subject’s home or other agreed upon 
location. During Treatment Period 2, after having received appropriate training, subjects will 
be allowed to self-administer the investigational product with direct supervision by study site 
personnel or a qualified home health professional.
6.3
Allocation of Subjects to Treatment Sequence
This is a double-blind, placebo-controlled, two-period, 3-sequence, partial crossover study. At 
least 66 eligible subjects will be randomized to 1 of 3 treatment sequences (Table 7) prior to 
the first dose of investigational product in Treatment Period 1. The actual treatment sequence 
given to individual subjects is determined by a randomization schedule automatically assigned 
by the IRT. 


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Table 7:
Treatment Sequences
Sequence
Treatment: Period 1/Period 2
Approximate Number of Subjects 
Randomized
1
A/B
22
2
B/A
22
3
A/A
22
Treatment A=2000 U (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC 
twice weekly (every 3 or 4 days) for 14 weeks. 
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each level of use of prophylactic therapy with C1 INH across sites, the subject number is 
assigned to subjects according to the sequence of presentation for study participation. Subject 
number is unique within a protocol.
The randomization number represents a unique number corresponding to treatment sequence 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IRT at the baseline visit (predose Visit 1a) after subject eligibility has been 
confirmed using the randomization criteria. The randomization schedule will be stratified for 
use of prophylactic therapy with C1 INH at the time of enrollment versus no prophylactic 
therapy with C1 INH at the time of enrollment. 
The subject’s treatment sequence will be held in strict confidence. The treatment sequence for 
an individual subject may be broken in cases of emergency or for reasons of subject safety, as 
described in Section 6.4.1.
6.4
Blinding of Treatment
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence. 
To maintain the blind, C1 esterase inhibitor [human] liquid for injection and placebo will have 
an identical presentation, including its packaging and labeling, such that the contents of the 
glass vials within the prepackaged study kits will be indistinguishable from each other. As 
described in Section 6.6, investigational product will be identified only by a unique study 
drug kit number. Each prepackaged study kit will contain 2x2 mL vials of investigational 
product (a total volume of 4 mL), which will be required to be drawn into a silicone-free 
syringe for each SC injection. If possible, a different individual should draw up the 
investigational product into the syringe than the individual administering the SC injection to 
the study subject. 
Knowledge of the PK/PD data would compromise the study blind. As such, the independent 
external laboratory performing the PK/PD analyses will keep the results in strict confidence 
until the study is unblinded.


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Additionally, a limited number of representatives of the sponsor responsible for the IRT and 
product labeling will be unblinded to treatment assignment in order to review drug 
accountability on an ongoing basis throughout the study (Section 6.7).
6.4.1
Unblinding the Treatment Assignment
The randomization code for an individual subject may only be broken by the investigator or 
the sponsor for reasons of subject safety or in an emergency when knowledge of the product 
administered would be important for the treatment of the subject. If the blind is broken by the 
investigator, he/she must notify the Shire ViroPharma Medical Monitor immediately and must 
document the date, time, and reason for the code break in a note to file.
6.5
Treatment Compliance
Investigational product will be administered either by study site personnel or a qualified home 
health professional or will occur under their direct supervision for subjects who elect to 
self-administer during Treatment Period 2 (Section 6.2). Therefore, full subject compliance 
with treatment is expected in this study. 
6.6
Packaging and Labeling
C1 esterase inhibitor [human] liquid for injection and placebo will be packaged and labeled 
such that the products will be indistinguishable from each other by the investigator, study site 
personnel, home health professionals, and subjects.
Investigational product will be supplied in a prepackaged study kit. Each study kit will 
contain 2 vials of investigational product (C1 esterase inhibitor [human] liquid for injection or 
placebo). Both the vials and carton (kit) will be appropriately labeled according to local 
regulations and bear the unique study drug kit number.  
The investigative site will also be provided with ancillary supplies, such as silicone-free 
syringes and needles. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection.
Refer to the Pharmacy Manual for additional details on the investigational product and its 
administration.
6.7
Storage and Accountability
Investigational product will shipped refrigerated to the study site at 2–8oC. Vials of 
investigational product must be stored at 2–8oC (36–46oF) and protected from light. Do not 
freeze investigational product.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log. The date and time of administration of the investigational product must be documented 
on the appropriate CRF.


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The principal investigator, study site personnel, or qualified home health professional must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.
The sites must ensure that the investigational product is available for the monitor to inventory
and prepare for return shipment to the sponsor or designee, if required.
6.8
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an investigational product 
returns process/policy, the sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the site regulatory binder.
If the investigational product is to be destroyed by the sites, sites must follow their own 
process/policy that describes such activities. Sites must retain copies of these documents 
within the site regulatory binder. Sites must ensure that the clinical trial material 
accountability and destruction log is complete, accurate, and ready for review and/or audit at 
each monitoring visit.
All manifests documenting shipments of investigational product must be retained, as well as 
copies of any investigational product return forms.
Refer to the Pharmacy Manual for additional details.


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7.
STUDY PROCEDURES
Subjects may be enrolled in the study after the nature and purpose of the protocol has been 
explained, written informed consent to participate has been voluntarily granted, and the 
eligibility criteria listed in Sections 4.1 and 4.2 have been met.
7.1
Study Schedule
Table 1 (Treatment Period 1), Table 2 (Treatment Period 2), Table 3 (early discontinuation 
visit, 1-week and 1-month post-treatment follow-up visits), and Table 4 (blood sample 
collection for PK/PD Analyses) provide the timing of all study procedures and assessments. 
7.1.1
Screening Period
Informed consent must be obtained before any study-specific procedures are performed. Note 
that AEs will be collected from the time of informed consent through 7 days after the last dose 
of investigational product.
Subjects will have all screening procedures completed with 21 days prior to the first dose of 
investigational product (Visit 1a=Dosing Day 1) according to Table 1. The following 
procedures will occur:
•
Informed consent/assent
•
Adverse events (collection begins from the time of informed consent through 7 days after 
the last dose of investigational product)
•
Inclusion/exclusion criteria
•
Medical history (includes HAE history with the documentation of attack rate for study 
entry criteria)
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Virology screening
•
Vital signs
•
ECG
•
Height and weight
•
Serum pregnancy test (in females of childbearing potential)
•
Recording of prior and concomitant medications
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 


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7.1.2
Treatment Period 1
7.1.2.1
Visit 1a (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Randomization
•
Physical examination
•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications (needed for confirmation of subject eligibility)
•
PK (C1 INH antigen, C1 INH functional, [includes measurement of C1q]) and PD (C4) 
sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody)
•
Angioedema quality of life (AE-QoL) questionnaire, EuroQol 5-dimensional 5-level 
descriptive system (EQ-5D-5L), Work Productivity and Activity Impairment-General 
Health (WPAI-GH) questionnaire, and Sheehan Disability Scare (SDS) assessments
recorded in the electronic subject diary
•
Health resource utilization assessment (HRUA)-HAE
7.1.2.2
Visit 1a (postdose)
The following procedures will be performed after the administration of the first dose of 
investigational product at Visit 1a:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack (and the subject diary is to be updated daily; Section 7.2.2.2).
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary


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7.1.2.3
Visit 2a through Visit 28a
The following procedures will be performed throughout Treatment Period 1 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2a-28a)
•
Recording in the electronic subject diary daily any symptoms or occurrences of an 
angioedema attack (Visits 2a-28a)
•
Recording the daily AAS in the electronic subject diary (Visits 2a-28a)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2a, 3a, 4a, 8a, 16a, 24a, 28a)
•
Physical examination (Visits 8a, 16a, 24a, 28a)
•
Investigational product will be administered at each visit (2a-28a); Visits 8a, 16a, 24a, and 
28a must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2a-28a)
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8a, 16a, 24a, 
and 28a
•
Urinalysis testing with microscopy at Visit 28a
•
Acceptability survey assessment at Visit 28a
•
Quality of life assessments recorded in the electronic subject diary: AE-QoL (Visits 9a, 
17a, 25a), EQ-5D-5L (Visit 24a and on each day that a subject experiences signs or 
symptoms of an angioedema attack), and WPAI-GH and SDS (Visits 3a, 5a, 7a, 9a, 11a, 
13a, 15a, 17a, 19a, 21a, 23a, 25a, 27a)
•
HRUA-HAE (Visits 8a, 16a, 24a)
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8a, 16a, 24a, 27a or 28a)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2a, 8a, 
16a, 24a, 27a or 28a [within ≈15 min], and 48 h postdose Visits 27a or 28a [±3 hours])
7.1.3
Treatment Period 2
7.1.3.1
Visit 1b (predose)
The following procedures will be performed at the investigative site prior to the first dose of 
investigational product in Treatment Period 2 at Visit 1b:
•
Collection of AEs
•
Physical examination


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•
Vital signs (≤30 min before the start of injection)
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications 
•
PK (C1 INH antigen, C1 INH functional) and PD (C4) sampling (within ≈15 min)
•
Immunogenicity (anti-C1 INH antibody) blood sample collection
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS assessments recorded in the electronic subject 
diary
•
HRUA-HAE
7.1.3.2
Visit 1b (postdose)
The following procedures will be performed after the administration of investigational 
product at Visit 1b:
•
Collection of AEs
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack
•
Vital signs (≤10 min after the end of the injection and between 30 min and 1 hour after the 
end of the injection)
•
Injection site reaction assessment (15 min, 30 min, and 1 hour after the end of the 
injection)
•
Recording the daily AAS in the electronic subject diary
7.1.3.3
Visit 2b through Visit 28b
The following procedures will be performed throughout Treatment Period 2 at the visits 
indicated below:
•
All concomitant medication and AEs will be recorded at each visit (2b-28b)
•
Recording in the subject diary daily any symptoms or occurrences of an angioedema 
attack (Visits 2b-28b)
•
Recording the daily AAS in the subject diary (Visits 2b-28b)
•
Vital signs ≤30 min predose; ≤10 min and between 30 min and 1 hour after the injection 
(Visits 2b, 3b, 4b, 8b, 16b, 24b, 28b)
•
Physical examination (Visits 8b, 16b, 24b, 28b)


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•
Investigational product will be administered at each visit (2b-28b); Visits 8b, 16b, 24b, 
and 28b must occur at the investigational site. 
•
Injection site reaction assessment will be performed 15 min, 30 min, and 1 hour after 
investigational product administration at each visit (2b-28b)
•
Clinical laboratory testing (biochemistry, hematology, coagulation) at Visits 8b, 16b, 24b, 
and 28b
•
Urinalysis testing with microscopy at Visit 28b
•
Quality of life assessments: AE-QoL (Visits 9b, 17b, 25b), EQ-5D-5L (Visit 24b and on 
each day that a subject experiences signs or symptoms of an angioedema attack), and 
WPAI-GH and SDS (Visits 3b, 5b, 7b, 9b, 11b, 13b, 15b, 17b, 19b, 21b, 23b, 25b, 27b)
recorded in the electronic subject diary
•
HRUA-HAE (Visits 8b, 16b, 24b)
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments at Visit 28b
•
Immunogenicity (anti-C1 INH antibody) (predose Visits 8b, 16b, 24b, 28b)
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4) (predose Visits 2b, 8b, 
16b, 24b, and 28b [within ≈15 min], and 24 hours (±3 hours) (optional time point), 
48 hours (±3 hours), 72 h (±6 hours) (optional time point), and 96 hours (±6 hours) 
postdose Visit 28b) 
7.1.4
Early Discontinuation Visit
If a subject prematurely discontinues from investigational product, the following procedures 
are to be performed as completely as possible:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
Acceptability survey and self-administration survey (recorded in the electronic subject 
diary) assessments


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•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
7.1.5
Follow-up Period
A post-treatment visit will be performed at the investigative site 1 week (±1 day) after the last 
dose of investigational product for follow-up safety assessments (Table 3). The following 
procedures will occur:
•
All concomitant medications and any new or ongoing AEs will be recorded
•
Recording in the electronic subject diary any symptoms or occurrences of an angioedema 
attack; if possible, subjects should complete the subject diary on the day of 
discontinuation or at the 1-week post-treatment Visit
•
Recording the daily AAS in the electronic subject diary
•
Vital signs
•
Physical examination
•
Clinical laboratory testing (biochemistry, hematology, coagulation)
•
Urinalysis testing with microscopy
•
Urine pregnancy testing
•
AE-QoL, EQ-5D-5L, WPAI-GH, and SDS (recorded in the electronic subject diary) 
assessments
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
A second post-treatment visit will occur at the investigative site 1 month (±2 days) after the 
last dose of investigational product. The following procedures will be performed at this visit:
•
HRUA-HAE
•
PK/PD sampling (C1 INH antigen, C1 INH functional, and C4)
•
Immunogenicity (anti-C1 INH antibody) 
Note: In the event that a subject has C1 INH antibodies detected, he/she be requested to 
participate in longitudinal follow-up to test C1 INH antibody titers for up to 1-year post-
treatment.


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All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to the Shire Pharmacovigilance Department.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic details, medical history (including HAE history), prior and concomitant 
medication data, vital signs, height, weight, physical examination, 12-lead ECG, 
biochemistry, hematology, coagulation, virology screening, and serum β-hCG pregnancy test 
will be collected at the time of enrollment at the Screening Visit. 
7.2.2
Efficacy
Analyses of the efficacy endpoints in this study require documentation of specific information 
regarding the subject’s symptoms of any angioedema attacks they may experience during the 
study. 
7.2.2.1
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported indication of swelling or pain at 
any location following a report of no swelling or pain on the previous day (ie, there must be a 
full symptom-free calendar day preceding the onset of symptoms for an attack to be 
considered a new attack). Therefore, 

Attacks that progress from 1 site to another will be considered a single attack 

Attacks that begin to regress and then worsen before complete resolution will be 
considered 1 attack 

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar 
day reported after the appearance of resolution will also be considered 1 attack 
Note: An angioedema attack does not include swelling due to trauma, arthritis, or symmetrical 
nonpainful swelling of the lower extremities.
7.2.2.2
Recording of Angioedema Attacks in the Electronic Subject Diary
During the study, subjects will use an electronic subject diary each day to record any 
symptoms or occurrences of an angioedema attack. The investigator will complete a separate 
angioedema attack CRF for each attack based upon their review of the data in the subject 
diary. Information will include the following:

Date and time of onset of angioedema attack symptoms

Characterization of whether swelling or pain is (indicate all that apply):


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Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)
Non-mucosal (truncal, extremity, facial)

Location (site) of the swelling or pain (indicate all that apply):
Upper airway (includes laryngeal or pharyngeal)
Note: Pharyngeal or oral swelling that results in airway compromise will be 
classified as a laryngeal attack.
Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)
Genitourinary (including scrotum or vulva)
Cutaneous (facial)
Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, 
trunk])

Severity (intensity) of the sign/symptom at each location listed:
Absent
Mild: the angioedema attack sign/symptom(s) is noticeable but is easily 
tolerated by the subject and does not interfere with routine activities.
Moderate: the angioedema attack sign/symptom(s) interferes with the subject’s 
ability to attend work/school or participate in family life and social/recreational 
activities.
Severe: the angioedema attack sign/symptom(s) significantly limits the 
subject’s ability to attend work/school or participate in family life and 
social/recreational activities.

Visual Analogue Scale (VAS) pain measurement score

Angioedema attack trigger(s)

Answer to the question, “Was treatment administered for the attack?” If yes, record the 
date, time, and name of treatment administered.
7.2.2.3
Angioedema Activity Score
Subject self-assessment of disease activity will be assessed daily by the AAS. Subjects will 
respond to questions in the electronic subject diary about any swelling episode that has 
occurred within the previous 24 hours. Each AAS item (or question) is scored between 0 and 
3 points, with the minimum and maximum daily AAS ranging between 0 and 15 points 
(Weller et al. 2013).


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7.2.2.4
Assessment of Icatibant as Therapy for Acute Angioedema Attacks
Efficacy endpoints are based on subject-assessed symptom improvement as a measure of 
response to icatibant therapy. When a subject receives treatment with icatibant for an acute 
angioedema attack, they will record the date and time of administration of the SC injection in 
the electronic subject diary and will monitor the following events:
Initial Symptom Improvement

Report date and time when you feel that your symptoms start to improve.
Complete Symptom Resolution

Report date and time when you feel that your symptoms have completely resolved.
Tolerability

Report any side effects associated with administration of icatibant therapy.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical and Medication History
A medical history will be taken at the screening visit. All medical history findings that have 
been present/active within the 5 years prior to enrollment will be entered into the CRF 
regardless of clinical relevance or presence at study start. Medical history findings that have 
not been present within the 5 years prior to enrollment will be recorded if deemed clinically 
relevant by the investigator to the conduct of the study. The medical history should include 
any history of allergic reactions to drugs. 
HAE History
The following information associated with HAE history will be recorded in the CRF at the 
screening visit (Note: the attack rate may be estimated based on subject or parent/caregiver 
recall as well as the subject’s medical records):  

HAE type (I or II)

Estimated date of last angioedema (swelling) attack prior to the screening visit

Any therapy received during the last 12 months for management of HAE (Section 5.1)

Total number, typical locations and average overall duration (days), and average overall 
severity of angioedema attacks experienced:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH os.


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
Typical VAS score for the subject’s angioedema attack pain:

during the 3 consecutive months prior to the screening visit (all subjects)
and (if applicable)

during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens.
7.2.3.2
Physical Examination (Including Height and Weight)
The investigator or designee will perform physical examinations at the time points specified 
in Table 1, Table 2, and Table 3. General physical examinations will be performed in 
accordance with standard practices at the study site. Physical examination abnormalities 
observed prior to the screening visit will be entered into the medical history section of the 
CRF. Any new or worsening of pre-existing abnormalities noted at post-screening 
examinations should be captured as an AE on the AE CRF page, per investigator’s judgment. 
Body weight and height will be measured at the time points specified in Table 1 and Table 2. 
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed (Section 8).
7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse and will be measured at the time points specified 
in Table 1, Table 2, and Table 3. During the study, additional vital signs measurements will 
be performed if clinically indicated. Vital signs performed on a dosing day should be obtained 
immediately (≤30 minutes) before the start of the injection of investigational product, 
immediately after completion of the injection of investigational product (≤10 minutes), and 
then between 30 minutes and 1 hour after completion of the injection of investigational 
product. Every effort should be made to measure vital signs prior to any blood sample 
collection. Blood pressure should be determined by cuff (using the same method, the same
arm, and in the same position throughout the study). Any clinically significant deviations 
from Baseline (predose Visit 1a) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. Reference ranges are to be supplied by the laboratory and will be used to assess 
the clinical laboratory data for clinical significance and out-of-range pathological changes. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 


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condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (approximately 6 mL) for biochemistry will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Aspartate aminotransferase (AST)
Albumin
Alanine aminotransferase (ALT)
Total protein
Alkaline phosphatase (ALP)
Glucose
Creatine phosphokinase (CPK)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Chloride
Carbon dioxide
Phosphorus
Hematology
Blood samples (approximately 2 mL) for hematology will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
Hemoglobin
Red blood cell count
Hematocrit
Platelet count
White blood cell count – total and differential


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Coagulation
Blood samples (approximately 3 mL) for coagulation will be taken according to Table 1, 
Table 2, and Table 3. The following parameters will be assessed:
International normalized ratio (INR)
Prothrombin time (PT)
D-dimer a
Activated partial thromboplastin time (aPTT)
a In addition, D-dimer should be evaluated in any subject who presents with signs and symptoms consistent with 
suspected venous thromboembolism.
Virology
Blood samples (approximately 6 mL) will be taken according to Table 1. The following 
parameters will be assessed:
Human immunodeficiency virus (HIV; single 
assay/Western blot)
Hepatitis (hepatitis B surface antigen and 
hepatitis C antibody)
Urinalysis with microscopy
Urine samples (approximately 10 mL) will be taken according to Table 1, Table 2, and Table 
3. The following parameters will be assessed:
pH
Specific gravity
Dipstick (protein, glucose, ketones, 
hemoglobin)
Microscopic evaluation (red blood cells, 
white blood cells, crystals, casts, bacteria)
7.2.3.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all females of childbearing potential at the 
screening visit and a urine pregnancy test is performed thereafter according to the time points 
specified in Table 1, Table 2, and Table 3. Pregnancy test results must be confirmed as 
negative before subjects proceed in the study. 
7.2.3.7
Electrocardiogram 
Subjects will have a 12-lead ECG recorded at the screening visit, as specified in Table 1. 
During the study, additional ECGs will be performed if clinically indicated. The following 
ECG data will be entered into the CRF: heart rate, PR interval, QRS duration, and QT 
interval. The PQ interval may be used if the PR interval is not reported on the 12-lead ECG. 


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The investigator will be responsible for providing the interpretation of all ECGs (clinically 
significant/not clinically significant). The subject's ECG(s) should be consistently recorded in 
the same position (supine).
7.2.3.8
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (eg, surgical, diagnostic, or dental) that occur 
from the first dose of investigational product through the 1-week post-treatment visit will be 
recorded in the CRF (Section 5.2).
7.2.3.9
Thrombotic or Thromboembolic Events
Monitoring for Venous Thromboembolism or Arterial Thromboembolism
Study personnel will actively monitor subjects for possible venous thromboembolism (VTE), 
encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), and 
arterial thromboembolism (ATE) with medical history, physical examinations, review of AEs, 
routine coagulation laboratory testing, and/or other diagnostic tests as applicable per local 
standard of care at the time points specified in Table 1, Table 2, and Table 3. 
Subjects will also receive instruction on how to recognize symptoms associated with potential 
thrombotic events and to seek medical attention for these symptoms in addition to informing 
their investigator. Treatment procedures, when applicable, will be provided per local standard 
of care.
Suspected Venous Thromboembolism or Arterial Thromboembolism
In subjects who present with signs and symptoms that are suspicious of a possible VTE (DVT 
or PE) based on clinical history and physical examination, the Wells Prediction Rules 
(Appendix 3) in conjunction with D-dimer assessment and/or other diagnostic tests, as 
applicable per local standard of care, are suggested to help guide the physician. Diagnostic 
and/or treatment procedures, when applicable, will be provided per local standard of care.
Based on the Wells Prediction Rule scores, the following procedures are recommended:

If the Wells Prediction DVT risk score is ≥1, coagulation studies and an imaging 
study (eg, lower extremity ultrasound or contrast venography) may be performed 
as described below. 

If the Wells Prediction PE risk score is ≥2, coagulation studies and 1 or more 
imaging studies (eg, ventilation-perfusion scan, multidetector helical computed 
axial tomography, or pulmonary angiography) may be performed as described 
below. 
In the setting of suspected VTE events, site personnel will the complete the Wells Prediction 
Rule CRF.
Diagnosis and management of all suspected VTE and ATE events should be per local 
standard of care; Appendix 4 and Appendix 5 also presents a suggested medical algorithm for 
diagnosis and management of such conditions. Investigators must also comply with all 


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reporting and/or concerning procedures for AEs/SAEs as indicated in the suggested 
algorithm. Confirmed diagnoses of T/TE events will be reported as SAEs (Section 8.2). 
However, superficial thrombophlebitis and catheter-related thrombosis will be reported as 
either a nonserious AE or an SAE based on investigator assessment and standard AE/SAE 
definitions.
7.2.3.10 Injection Site Reactions
Investigational product SC injection site reactions will be captured in the local tolerability 
CRF. Injection site reactions that do not meet the criteria of a SAE will not need to be 
reported as an AE.
Subcutaneous injection site reactions will be assessed at the following post-injection time 
points in each treatment period: 15 minutes, 30 minutes, and 1 hour post-injection. Study 
personnel will make every effort to obtain a digital photograph(s) of a representative severe 
injection site reaction. Study personnel will examine injection sites for erythema or swelling 
and will question the subject to collect information on cutaneous pain, burning sensation, 
itching/pruritus, and warm sensation. The diameter of any erythema or swelling should be 
measured to obtain the severity grading, but will not be recorded on the CRF. The injection 
site reactions will be graded as absent, mild, moderate, or severe using the scoring criteria 
shown in Table 8. The severity score is to be transcribed to the CRF.
Table 8:
Severity Scoring for Injection Site Reactions
Reaction
Severity
Mild
Moderate
Severe
Erythema
>0 to 5 cm
>5 to 10 cm
>10 cm
Swelling
>0 to 5 cm
>5 to 10 cm
>10 cm
Cutaneous pain
Mild discomfort to touch
Discomfort with movement
Significant discomfort at rest
Burning sensation
Mild burning sensation, 
which is easily tolerated
Moderate burning sensation, 
causing some discomfort
Severe burning sensation, 
causing significant discomfort
Itching/pruritus
Mild itching/pruritus, 
which is easily tolerated
Moderate itching/pruritus, 
causing some discomfort
Severe itching/pruritus, causing 
significant discomfort
Warm sensation
Mild warmth to touch
Moderate warmth to touch
Significant warmth to touch
Only blinded study personnel are to perform assessments of injection site reactions. The 
injection site reaction data will be recorded on the local tolerability page of the CRF. Site 
personnel will distinguish between injection site reactions related to the procedure (eg, will 
check for redness after needle is inserted and prior to investigational product administration) 
vs the actual investigational product.


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7.2.4
Others
7.2.4.1
Clinical Pharmacology Assessments
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Subjects will have blood samples (7 mL) collected for the determination of plasma 
concentrations of C1 INH antigen, functional C1 INH, complement C4, and C1q at time 
points specified in Table 4. Serum samples (5 mL) will be collected prior to the first dose of 
investigational product on Visit 1a (Dose 1 of Treatment Period 1), Visit 1b (Dose 1 of 
Treatment Period 2), and throughout both treatment periods for the analysis of anti-C1 INH 
antibodies (Table 1 and Table 2). Additional blood samples for PK/PD and C1 INH antibody 
testing will be collected at the early discontinuation visit (if applicable) and the 1-week and 1-
month post treatment visits (Table 3). In the event that a subject has C1 INH antibodies 
detected, he/she may be requested to participate in longitudinal follow-up to test C1 INH 
antibody titers for up to 1-year post-treatment (Section 7.1.5).
The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH activity, complement C4 and C1q 
concentrations, and serum samples for the evaluation of anti-C1 INH antibodies will be 
analyzed using validated methods. All PK/PD and immunogenicity samples will be processed 
according to the procedure outlined in the laboratory manual.
Selected samples may be analyzed to investigate incurred sample reproducibility of the 
bioanalytical methods. These analyses are only to investigate the reproducibility of the 
bioanalytical methods used to determine C1 INH antigen and functional C1 INH 
concentrations in study samples. All incurred sample reproducibility results will be reported 
in a separate table in the bioanalytical report. Details of disposal will be documented and 
maintained with the study file at the analytical laboratory.
7.2.4.2
Health-related Quality of Life Assessments
Angioedema Quality of Life Questionnaire
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema (Weller et al. 2012). It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and food. Subjects will be asked how often 
they were restricted by—as well as the difficulties and problems that could be associated 
with—recurrent swellings (angioedema) during the previous 4 weeks. The AE-QoL will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3. Details about the use of the AE-QoL instrument are provided in a separate study 
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Health-related Quality of Life Questionnaire
The EQ-5D-5L1 is a descriptive system of health-related quality of life states consisting of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
of which can take 1 of 5 responses. The responses record 5 levels of severity within a 
particular dimension. The EQ-5D-5L will be completed in the electronic subject diary at the 
time points specified in Table 1, Table 2, and Table 3, as well as on each day that a subject 
experiences signs or symptoms of an angioedema attack. Details about the use and 
administration of the EQ-5D-5L instrument are provided in a separate study manual. 
Work Productivity and Activity Impairment-General Health Questionnaire
The WPAI-GH questionnaire includes 6 questions about work and activity impairment due to 
health problems during the past 7 days (Reilly et al. 1993). Outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less work or 
productivity. The WPAI-GH will be completed in the electronic subject diary at the time 
points specified in Table 1, Table 2, and Table 3. Details about the use of the WPAI-GH 
instrument are provided in a separate study manual.
Sheehan Disability Scale
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a 
subject’s disability due to an illness or health problem interferes with work/school, social 
life/leisure activities, and family life/home responsibilities (Sheehan 1983). The SDS will be 
completed in the electronic subject diary at the time points specified in Table 1, Table 2, and 
Table 3.
7.2.4.3
Health Resource Utilization Assessment
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. The Health Resource Utilization 
Assessment (HRUA-HAE) will be completed at the time points specified in Table 1, Table 2, 
and Table 3. Study personnel will enter the survey responses into the appropriate CRF.
7.2.4.4
Survey of Acceptability of SC Administration
Study personnel will ask subjects to rate their overall experience in receiving twice weekly 
SC injections of investigational product at the time points specified in Table 1, Table 2, and 
Table 3. For subjects who have previously received C1 INH products via IV administration, 
they will be asked to indicate the preferred route for medication administration. Study 
personnel will enter the subject’s survey responses into the electronic subject diary.
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) 
on the route to administer medications to prevent angioedema attacks.
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.


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7.2.4.5
Self-administration Survey Assessment
After receiving appropriate training, subjects are allowed to self-administer investigational 
product during Treatment Period 2 under the supervision of study site personnel or a qualified 
home health professional. For those subjects who choose to self-administer the investigational 
product, study personnel will ask specific questions about their experience with 
self-administration of SC medication (Table 2 and Table 3). Study personnel will enter the 
subject’s survey responses into the electronic subject diary.
7.2.5
Volume of Blood to be Drawn From Each Subject
Table 9:
Approximate Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
PK/PD 
7
20b
140
Immunogenicity (anti-C1 INH antibodies)
5
13
65
Safety
Biochemistry and -hCGa
6
13
78
Hematology
2
13
26
Coagulation
3
13
39
Virology
6
1
6
All assessments (mL)
354
Β-hCG=beta human chorionic gonadotrophin; C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a -hCG testing for females of childbearing potential at the Visit 1a (predose) only.
a Two of the 20 samples are optional as indicated in Table 4.
During this study, it is expected that maximum volume of blood to be drawn from all subjects
will be 354 mL.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of 
blood drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 354 mL. When more than 1 blood assessment is done at 
the same time point/period, if they require the same type of tube, the assessments may be 
combined. 


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.5. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE 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:
A type of AE that is usually alleviated with 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 subject.


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Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product 
for each AE. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related.” The causality 
assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (angioedema attacks) should not be captured as AEs as 
long as they are within the normal day-to-day fluctuation or expected progression of the 
disease and are part of the efficacy data to be collected in the study; however, events 


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satisfying the serious criteria should be recorded as a SAE and reported to Shire 
Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range (either 
while continuing treatment or after the end of treatment with the investigational product), and 
the range of variation of the respective parameter within its reference range must be taken into 
consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department 
using the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Shire ViroPharma 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 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire 
Clinical Trial Serious Adverse Event Form. Note: An elective abortion is not considered an 
SAE.


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In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event 
Form as well as the Shire Investigational and Marketed Products Pregnancy Report Form. The 
test date of the first positive serum/urine -hCG test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: This includes a situation where the investigational product is not used 
as directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
higher than the protocol-specified dose.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Medication errors should be collected and reported to the sponsor for all products under 
investigation. The following should be considered as examples of reportable medication 
errors:

The administration and/or use of the unassigned treatment

The administration and/or use of an expired investigational product

Violation of storage or refrigeration requirements for the investigational product
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
All investigational products administered to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, 
or medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 
Trial Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to 
the contract research organization/Shire ViroPharma Medical Monitor using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as an SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 


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definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be 
reported to the Shire Pharmacovigilance Department and the contract research 
organization/Shire ViroPharma Medical Monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).


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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical contract research organization (CRO) are responsible for 
notifying the relevant regulatory authorities/US central Institutional Review Boards 
(IRBs)/EU central ethics committees (ECs) of related, unexpected SAEs.
In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to 
unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available. If applicable, unblinded data may be 
made available to quality assurance representatives for the purposes of conducting 
independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
All statistical analyses will be performed using SASVersion 9.1 or higher (SAS Institute, 
,
). 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
PPD
PPD


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characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be 
addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee in this 
study.
9.6
Sample Size Calculation and Power Considerations
The enrollment goal for this study is to randomize at least 66 subjects to ensure 54 subjects 
complete both treatment periods (36 for the crossover sequences, 18 for the active/active 
sequence). This number will be sufficient to address all experimental efficacy and safety 
objectives.
For the primary efficacy endpoint, the NNA, a sample of 36 subjects will provide >95% 
power at an alpha level of 0.025 (1-sided) to detect a difference of 2.0 attacks per month 
between active treatment and placebo assuming a between-subject standard deviation of 3. 
This target is supported by the recently completed, dose-ranging, Phase 2 study with CINRYZE
(0624-206).
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR
relative to placebo, 36 subjects will provide 90% power to test the hypothesis H0: proportion 
≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided).
Previous communications have occurred between regulatory authorities and the sponsor 
regarding a Phase 3 study for the SC CINRYZE development program. The regulatory authority 
indicated that the Phase 3 study should be of sufficient size to have a 95% power for detection 
of safety signals occurring with an incidence of 5% or greater of subjects.
With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.
The sample size calculation was conducted using nQuery + nTerim 2.0.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have signed an informed consent and some 
study procedures have begun.


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The Randomized Set will consist of all subjects in the Screened Set for whom a 
randomization number has been assigned.
The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The Full Analysis Set will consist of all subjects in the Safety Set who have at least 
1 post-baseline (eg, randomization) primary efficacy assessment.
The Per-protocol Set will consist of all subjects in the Full Analysis Set who complete 
scheduled primary assessments for 6 study weeks and who do not have pre-defined protocol 
deviations that may affect the primary efficacy endpoint. 
The Completer Set will consist of all subjects in the Full Analysis Set who have completed 
the final scheduled primary assessment for the study.
The Pharmacokinetic and Pharmacodynamic Set will consist of all subjects in the Safety 
Set for whom the primary PK and PD data are considered sufficient and interpretable. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the NNA during a treatment period. The NNA is 
expressed as the number of attacks per month (ie, 30.4 days) of exposure:
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period)
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.
The primary efficacy analysis will be conducted over the Full Analysis Set. The null 
hypothesis to be tested is that the NNA of C1 esterase inhibitor [human] liquid for injection is 
greater than or equal to the NNA of placebo, and the alternative hypothesis is that the NNA of 
C1 esterase inhibitor [human] liquid for injection is less than the NNA of placebo as below:
H0: µ C1 INH - µ placebo >0 vs
H1: µ C1 INH - µ placebo <0
The primary efficacy endpoint will be analyzed by using a mixed effect linear model with 
period, sequence, and treatment as fixed effects, and subject nested within sequence as a 
random effect. The mean treatment difference (µ C1 INH - µ placebo) will be estimated with a 
95% CI.
To assess any carryover effect, a sensitivity analysis will exclude from the evaluation of the 
NNA any attacks occurring within the first 2 weeks of Treatment Period 2 for both sequences 
when carryover is suspected to be maximal. Since carryover should occur only with the 


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A/B treatment sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] 
liquid for injection efficacy into the placebo treatment period, thereby diluting the efficacy of 
C1 INH and favoring the null hypothesis of the primary efficacy analysis; it is not anticipated 
that any placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection 
within the B/A treatment sequence. The study is powered to demonstrate superior efficacy 
even in the presence of carryover effects. Additional sensitivity analyses may be developed 
and included in the SAP.
Adjustments for multiplicity: To control the overall type 1 error, the primary and key 
secondary endpoints will be tested hierarchically, so that the significance of the key secondary 
endpoint is contingent on whether the primary endpoint is significant. The determination of a 
successful study is based solely on the results of the primary endpoint analysis regardless of 
the results for the key secondary endpoint.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the clinical response to treatment relative to placebo. 
This is defined as achieving a ≥50% reduction in the NNA (PR) during the 2000 U C1 esterase 
inhibitor [human] liquid for injection treatment period relative to the placebo period. 
The key secondary endpoint will be analyzed as the proportion of subjects meeting criterion 
PR. The null hypothesis is that PR is less than or equal to 0.2, and the alternative hypothesis is 
that PR is greater than 0.2. The proportion meeting criterion PR will be estimated with an exact 
95% CI. The lower limit of the 95% CI for the proportion will be compared with 0.2. This is 
equivalent to testing the null hypothesis against the alternative hypothesis at a 1-sided alpha 
level of 0.025 using the normal approximation to the binomial distribution.
9.8.2.2
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints to be evaluated in this study are:

To determine the proportions of subjects with a clinical response to treatment as defined 
by: 

Achieving at least a 50% reduction in the NNA during a treatment period relative 
to the pretreatment assessment. 

Achieving a NNA <2.0 during a treatment period.

Cumulative attack severity. This score is the sum of the maximum symptom severity 
recorded for each angioedema attack in a treatment period.

Cumulative daily severity. This score is the sum of the severity scores recorded for every 
day of reported symptoms in a treatment period.

Number of attack-free days during a treatment period.


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
Number of angioedema attacks requiring acute treatment a treatment period.

Disease activity as measured by the 196-day AAS. This score is the sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day.

Results of the AE-QoL questionnaire.

Determine the response to icatibant when administered as treatment for an acute 
angioedema attack by:

Time to subject-assessed initial symptom improvement (TISI) 

Time to subject-assessed complete symptom resolution (TCSR) 
Subjects in the Full Analysis Set (Section 9.7) will be used to evaluate the efficacy of SC 
administration of C1 esterase inhibitor [human] liquid for injection. The treatment differences 
in clinical responder rate, both of which are defined within treatments, will be analyzed using 
McNemar’s test for testing equality of proportions of responders within treatments. All other 
secondary endpoints will be analyzed using a linear mixed effect model with period, 
sequence, and treatment as fixed effects, and subject nested within sequence as a random 
effect. The results of all secondary efficacy analyses will be summarized by the point estimate 
of within-subject treatment differences or response rates and the corresponding 95% CI. 
Descriptive statistics (n, median, 25% and 75% quartiles, and range) will be provided to 
summarize icatibant-related efficacy endpoints (TISI and TCSR) by treatment and 
icatibant-treated angioedema attack for all subjects in the Full Analysis Set. Where 
appropriate (for subjects ≥12 to <18 years of age), other rescue medications used to treat acute 
angioedema attacks will also be summarized using descriptive statistics. In addition, 
angioedema attacks will be summarized by the maximum symptom severity and treatment for 
all subjects in the Full Analysis Set. 
9.8.3
Exploratory Efficacy Endpoints
There are no exploratory efficacy endpoints in this study.
9.9
Safety Analyses
Adverse events will be coded using the MedDRA. The number of events, incidence, and 
percentage of TEAEs will be calculated overall, by system organ class, preferred term, and 
treatment. Treatment-emergent AEs will be further summarized by severity and relationship 
to investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests (hematology, chemistry, and coagulation), vital signs, and ECG 
findings will be summarized by treatment and visit. Potentially clinically important findings 
will also be summarized or listed.
The incidence and severity (mild, moderate, severe) of SC injection site reactions will be 
summarized by treatment and visit. 


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Results of C1 INH antibody testing will be reported for individual subjects.
The tolerability of icatibant therapy for acute angioedema attacks will be summarized.
To assess the influence of any carryover effect on adverse reporting, a sensitivity analysis 
may be conducted by attributing TEAEs that occur during the first 2 weeks of Treatment 
Period 2 to Treatment Period 1 for the A/B (C1 INH to placebo) treatment sequence. In other 
words, C1 esterase inhibitor [human] liquid for injection may account for any TEAEs in the 
first 2 weeks of the placebo treatment, when the carryover effect (if present) is suspected to be 
maximal. 
9.10 Other Analyses
9.10.1
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, C1 INH functional, and complement C4 and C1q for 
individual subjects will be determined using validated bioanalytical methods. Results will be 
summarized using descriptive statistics (number, geometric mean, coefficient of variation, 
mean, standard deviation, median, minimum, and maximum) for values at each time point.
C1q concentrations will only be assessed at baseline (ie, pre-injection, Dosing Visit 1a).
Pharmacokinetic parameters will be calculated using observed and baseline-corrected 
concentration-vs-time data using non-compartmental techniques for C1 INH antigen and 
functional activity. The following PK parameters will be calculated using both unadjusted and 
baseline-adjusted concentrations for SC administration: The Cmax, the tmax, the minimum 
observed concentration, and the AUClast. Additional PK parameters will be calculated using 
only baseline-adjusted concentrations, including t1/2, the λz, the AUC0-∞, the VZ/F, and the 
CL/F. Other PK parameters may be calculated as deemed appropriate. Pharmacokinetic 
parameters will be summarized using descriptive statistics.
Exploratory PK/PD analyses might be performed based on the correlation of plasma 
concentrations of C1 INH antigen, functional C1 INH, and C4 complement in conjunction 
with various safety parameters (eg, selected AEs, clinical laboratory results, antibodies 
generation, frequency, severity, or anatomic location of the angioedema attack, etc.). 
Correlations that will be analyzed will be determined based on observed data.
9.10.2
Health-related Quality of Life Analyses
Results of the EQ-5D-5L health status instrument will be presented in accordance with the 
EQ-5D-5L user guide (version 2.0) by treatment.
Results of the WPAI-GH questionnaire will be summarized by treatment.
Results of the SDS will be summarized by treatment.


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9.10.3
Surveys on SC Administration and Self-administration of Investigational 
Product
Results of the surveys for subject acceptability of SC administration and subject experience 
with self-administration of investigational product will be summarized.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. These regulations and 
guidelines also constitute compliance with the ethical principles described in the Declaration 
of Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ 
names and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the Community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
studies as per guidance. The sponsor will provide the ECs with a copy of the same summary.


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10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason. If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification. Curriculum vitae for investigators and sub-investigators are 
provided to the study sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The


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investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective 
national, local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities 
and to have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc).


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These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written 
subject information and received an explanation of what the study involves, including but not 
limited to: the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent and assent documentation (ie, a complete 
set of subject information sheets and fully executed signature pages) must be given to the 
subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent 
form where applicable) which was reviewed by the IRB/EC and which received their 
favorable opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of


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these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible 
for this action. Additionally, if the IRB/EC requires modification of the sample subject 
information and consent document provided by the sponsor, the documentation supporting 
this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, 
or for multicenter studies the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor, the investigator, or for 
multicenter studies the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 


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register, or market C1 esterase inhibitor [human] liquid for injection; national or local 
regulatory authorities; and the IRBs/ECs which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present 
the study results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire ViroPharma will endeavor to publish the results of all qualifying, applicable, and 
covered studies according to external guidelines in a timely manner regardless of whether the 
outcomes are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma
adheres to external guidelines (eg, Good Publication Practices 2) when forming a publication 
steering committee, which is done for large, multicenter Phase 2-4 and certain other studies as 
determined by Shire ViroPharma. The purpose of the publication steering committee is to act 
as a non-commercial body that advises or decides on dissemination of scientific study data in 
accordance with the scope of this policy.
All publications relating to Shire ViroPharma products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma agreement to publish prior 
to release of information. The review is aimed at protecting the sponsor’s proprietary 
information existing either at the commencement of the study or generated during the study. 
To the extent permitted by the publisher and copyright law, the principal investigator will own 
(or share with other authors) the copyright on his/her publications. To the extent that the 
principal investigator has such sole, joint or shared rights, the principal investigator grants the 
sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 


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results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, the institution and 
principal investigator shall withhold submission of such publication for up to an additional 60 
days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the International Committee of Medical Journal 
Editors (ICMJE) current standards. Participation as an investigator does not confer any rights 
to authorship of publications.


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11.
REFERENCES
Agostoni A, Cicardi M 1992. Hereditary and acquired C1-inhibitor deficiency: biological and 
clinical characteristics in 235 patients. Medicine (Baltimore); 71(4): 206-15.
Aygören-Pürsün E, Bygum A, Beusterien K, et al. 2014. Socioeconomic burden of hereditary 
angioedema: results of the hereditary angioedema burden of illness study in Europe. Orphanet 
J Rare Dis;9:99.
Banerji A 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol; 111(5): 329-36. 
Bernstein
JA 2011. Update on angioedema: evaluation, diagnosis, and treatment. 
Allergy Asthma Proc; 32(6): 408-12.
Bork K, Barnstedt SE, Koch B, Traupe H 2000a. Hereditary angioedema with normal C1-
inhibitor activity in women. Lancet; 356(9225): 213-17.
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W 2000b. Asphyxiation by laryngeal edema 
in patients with hereditary angioedema. Mayo Clin Proc; 75(4): 349-54. 
Bork K, Gül D, Hardt J, Dewald G 2007. Hereditary angioedema with normal C1 inhibitor: 
clinical symptoms and course. Am J Med; 120(11):987-92.
Bowen T, Cicardi M, Farkas H, et al. 2010. 2010 International consensus algorithm for the 
diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol; 
6(1): 24.
Bygum A, Aygören-Pürsün E, Beusterien K, et al. 2015. Burden of illness in hereditary 
angioedema: a conceptual model. Acta Derm Venereol; [Epub ahead of print].
Caballero T, Aygören-Pürsün E, Bygum A, et al. 2014. The humanistic burden of hereditary 
angioedema: results from the burden of illness study in Europe. Allergy Asthma Proc; 35:47-
53.
Cicardi M, Igarashi T, Rosen FS, Davis AE 3rd 1987. Molecular basis for the deficiency of 
complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest; 79(3): 698-
702.
Cugno M, Nussberger J, Cicardi M, Agostoni A 2003. Bradykinin and the pathophysiology of 
angioedema. Int Immunopharmacol; 3: 311-7.
Cugno M, Nuijens J, Hack E, et al. 1990. Plasma levels of C1 inhibitor complexes and 
cleaved C1 inhibitor in patients with hereditary angioneurotic edema. J Clin Invest; 85:1215-
20.
Farkas H, Harmat G, Füst G, Varga L, Visy B 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol; 13(3): 153-61.
Farkas H, Jakab L, Temesszentandrási G, et al. 2007. Hereditary angioedema: a decade of 
human C1-inhibitor concentrate therapy. J Allergy Clin Immunol; 120(4): 941-7.


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Frank MM, Gelfand JA, Atkinson JP 1976. Hereditary angioedema: the clinical syndrome and 
its management. Ann Intern Med; 84(5): 580-93. 
Georgy MS, Pongracic JA 2012. Chapter 22: Hereditary and acquired angioedema. 
Allergy Asthma Proc; 33(Suppl 1): S73-6. 
Gompels MM, Lock RJ, Abinun M, et al. 2005. C1 inhibitor deficiency: consensus document. 
Clin Exp Immunol; 139(3): 379-94.
Kaplan AP 2010. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role 
of C1 inhibitor therapy. J Allergy Clin Immunol; 126(5): 918-25. 
Kaplan AP, Joseph K 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol; 104(3): 193-204. 
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT 2010. The 
humanistic burden of hereditary angioedema: Impact on health-related quality of life, 
productivity, and depression. Allergy Asthma Proc; 31(5): 407-14.
Ohela K 1977. Hereditary angioneurotic oedema in Finland. Clinical, immunological and 
genealogical studies. Acta Med Scand; 201(5): 415-27.
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65.
Sheehan DV 1983. The Anxiety Disease. New York, NY, USA: Charles Scribners Sons.
Weis M 2009. Clinical review of hereditary angioedema: diagnosis and management. 
Postgrad Med; 121(6): 113-20. 
Weller K, Groffik A, Magerl M, et al. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67(10): 1289-98.
Weller K, Groffik A, Magerl M, et al. 2013. Development, validation, and initial results of the 
angioedema activity score. Allergy; 68(9): 1185-92.
Zuraw BL 2003. Diagnosis and management of hereditary angioedema: an American 
approach. Transfus Apher Sci; 29(3): 239-45.
Zuraw BL 2008. Hereditary angioedema: a current state-of-the-art review, IV: short- and 
long-term treatment of hereditary angioedema: out with the old and in with the new? Ann 
Allergy Asthma Immunol; 100(1 Suppl 2): S13-18.
Zuraw BL, Christiansen SC 2009. Pathogenesis and laboratory diagnosis of hereditary 
angioedema. Allergy Asthma Proc; 30(5): 487-92.


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Zuraw BL, Bork K, Binkley KE, et al. 2012. Hereditary angioedema with normal C1 inhibitor 
function: Consensus of an international expert panel. Allergy Asthma Proc; 33(Suppl 1): 
S145-56.


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12.
APPENDICES


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APPENDIX 1 HANDLING OF INVESTIGATIONAL PRODUCT FOR 
SUBCUTANEOUS INJECTION 
The procedures below are provided for the handling of the investigational product. Since 
treatment assignment to C1 esterase inhibitor [human] liquid for injection and placebo 
(Treatments A and B, respectively) is to be blinded, the following instructions apply for all 
SC administrations in Treatment Periods 1 and 2. Always work on a clean surface and wash 
hands before performing the following procedures.
Handling

Prior to administration, investigational product should be protected from light.

No reconstitution or additional dilution of investigational product is required.

A silicone-free syringe is to be used for withdrawal of the product from the vial 
and for administration.

Important Notes: (1) when withdrawing the product from the vial, and during 
administration, the plunger of the syringe should be moved back and forth 
carefully and slowly, avoid introducing any air bubbles, and pulling the plunger 
past the stop on the syringe; (2) there is no need for excessive shaking of either the 
vial or syringe during the preparation for the SC injection.

Investigational product should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. The 
product should be colorless and free from visible particles. Do not use if turbid or 
discolored.

Any vial that has been punctured should be used promptly.

Do not mix investigational product with other materials.

Do not freeze.

Do not use after expiration date.
NOTE: For this protocol, 2 vials of investigational product will be required for each SC 
injection (2x2 mL=4 mL total injection volume).
1. Aseptic technique should be used during handling.
2. Bring vials of investigational product to room temperature.
3. Remove caps from investigational product vials.
4. Cleanse stopper(s) with alcohol swab or germicidal solution, and allow them to dry prior 
to use.
5. Transfer the investigational product to a syringe for administration. Draw up the contents 
of 2 vials of investigational for a total volume of 4 mL.
Be sure to safely dispose of the used needle and syringe.


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Retain all used vials of investigational product for drug accountability purposes.


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APPENDIX 2 SUBCUTANEOUS INJECTION SITE SELECTION AND 
PREPARATION
Subcutaneous injections of investigational product will be administered in the abdominal area. 
Injection sites on the abdomen are depicted in the figure below. An abdominal site that is 
approximately at the level of the navel (as allowed by skin condition) and approximately 
15 cm (minimum 10 cm) away from the margin of the navel should be selected. The lateral 
portion of the abdomen is preferred over the midline area. The selected site should include 
fatty tissue. Administer the first injection in the right side (#1 in illustration) and the second 
injection in the left side (#2 in illustration). Keep alternating injection sites to the right side 
and then to the left side for all subsequent injections in Treatment Periods 1 and 2.
Illustration of Injection Sites on the Abdomen
The subject should be in a semi-reclined position during the injection (ie, semi-Fowler’s 
position: 30-45º) and in a supine position immediately following injection for the evaluation 
of the injection site (ie, laying flat on back).
After the injection site for SC administration has been chosen, the investigational product will 
be administered as a single 4 mL SC injection as described briefly below.

Wipe skin with alcohol to cleanse. Allow to dry.

Gently pinch and lift the skin of the abdomen (ie, “tenting”).

Insert the needle with bevel up close to parallel to the skin or at an angle that is <20°. 
Once the needle is inserted, gently release the pinched and lifted skin (“untent the 
skin”). When the skin is in its normal state, the needle should have a slight upward 
angle of 20-30°. If the subject is obese, a steeper angle for needle insertion can be used 
but it is recommended keeping the angle <45°. In practical terms, the needle 
placement should resemble the angle of an IV needle placement in the arm. The 
purpose of pinching and lifting the skin is to make sure the needle is properly inserted 
in the SC space and is not intradermal.

Release the subcutaneous tissue. The needle will not back out during the injection if 
properly placed.

Care should be taken to avoid inadvertent IV or IM injection.
1
2


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It may be necessary to adjust the needle by pulling the needle slightly back if there appears to 
be a resistance to flow.


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APPENDIX 3 WELLS PREDICTION RULE FOR THE DIAGNOSIS OF 
VENOUS THROMBEMBOLISM
Table A.
Wells Prediction Rule for Diagnosing Deep Venous Thrombosis: Clinical 
Evaluation Table for Predicting Pretest Probability of Deep Venous 
Thrombosisa
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months, or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within 12 weeks requiring general anesthesia 
or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Alternative diagnosis at least as likely as deep venous thrombosis
−2
a Clinical probability of deep venous thrombosis: Low= ≤0; Intermediate=1 to 2; High= ≥3. In patients with symptoms in 
both legs, the more symptomatic leg is used.
Data source: Qaseem et al. 2007
Table B.
Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical 
Evaluation Table for Predicting Pretest Probability of Pulmonary 
Embolisma
Clinical Characteristic
Score
Previous pulmonary embolism or deep venous thrombosis
+1.5
Heart rate >100 beats per minute
+1.5
Recent surgery or immobilization
+1.5
Clinical signs of deep venous thrombosis
+3
Alternative diagnosis less likely than pulmonary embolism
+3
Hemoptysis
+1
Cancerb
+1
a Clinical probability of pulmonary embolism: Low=0 to 1; Intermediate=2 to 6; High= ≥7
b For the purposes of this study, cancer will include “treatment ongoing, within previous 6 months, or palliative.”
Data Source: Qaseem et al. 2007
References
Qaseem A, Snow V, Barry P, et al. 2007. Current diagnosis of venous thromboembolism in 
primary care: A clinical practice guideline from the American Academy of Family Physicians 
and the American College of Physicians. Ann Fam Med; 146(6):454-58.


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APPENDIX 4 ALGORITHM FOR SUSPECTED VENOUS
THROMBOEMBOLISM 
References
National 
Heart, 
Lung, 
and 
Blood 
Institute. 
Pulmonary 
embolism 
2011. 
http://www.nhlbi.nih.gov/book/export/html/4865. Accessed May 11, 2015. 
National 
Heart, 
Lung, 
and 
Blood 
Institute. 
Deep 
vein 
thrombosis
2011. 
http://www.nhlbi.nih.gov/book/export/html/4871. Accessed May 11, 2015. 
Ozaki A, Bartholomew JR. Venous thromboembolism (deep venous thrombosis & pulmonary 
embolism). In: Carey WD, Rae-Grant A, Rimmerman C, ed. Disease Management Project. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/venous -
thromboembolism. Accessed May 11, 2015.


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APPENDIX 5 ALGORITHM FOR SUSPECTED ARTERIAL 
THROMBOEMBOLISM
References
National 
Library 
of 
Medicine. 
Arterial 
embolism
2014. 
http://www.nlm.nih.gov/medlineplus/ency/article/001102.htm. Accessed May 18, 2015.
Lyaker MR, Tulman DB, Dimitrova GT, Pin RH, Papadimos TJ 2013. Arterial embolism. Int 
J Crit Illn Inj Sci; 3(1): 77-87. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665125/?report=printable

SAP_005.pdf: 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
SHP616-300 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Placebo-
controlled, Two-period, Three-sequence, Partial 
Crossover Study to Evaluate the Efficacy and 
Safety of Subcutaneous Administration of 2000 IU 
of C1 Esterase Inhibitor [Human] Liquid for 
Injection for the Prevention of Angioedema Attacks 
in Adolescents and Adults with Hereditary 
Angioedema 
Drug: 
SHP616, C1 esterase inhibitor [human] liquid for 
injection 
Sponsor:  
Shire Development LLC and International 
Affiliates 
300 Shire Way, Lexington, MA  02421 USA 
Version No. and Date: 
Final Version 1.0, Date  17AUG2017 
  
Version No: 
Document History 
Description of Update 
Author(s) 
 
Effective Date 
0.1 
Draft 0.1 for Shire BSP review 
 
(PPD) 
Aug. 27, 2015 
0.2 
Draft 0.2 for Shire study team review 
 
(PPD), modified by 
 (Shire) 
Sep. 01, 2015 
1.0 
Draft 1.0 for IND 
 
(Shire)/
 
(Shire) 
Sep. 14, 2015 
1.1 
Draft 1.1 for Shire internal review 
 (Shire)/ 
 
(PPD) 
Sep. 22, 2016 
1.2 
Draft 1.2 for Shire internal review 
 (Shire)/ 
 
17OCT2016 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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(PPD) 
1.3 
V1.3 for Shire internal review 
 (Shire)/ 
 
(PPD) 
07NOV2016 
1.4 
V1.4 for Shire internal review 
 
(PPD) 
20MAR2017 
2.1 
V2.1 for Shire review 
 (PPD) 
25APR2017 
2.2 
V2.2 for Shire review 
 (PPD) 
21JUN2017 
3.1 
V3.1 for Shire review 
 (PPD) 
11AUG2017 
3.2 
V3.2 for Shire review 
 (PPD) 
16AUG2017 
Final 1.0 
Final Version 1.0 
 (PPD) 
17AUG2017 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 3 
ABBREVIATIONS .................................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................................... 8 
2. 
STUDY DESIGN ................................................................................................................. 9 
2.1 
General Study Design ............................................................................................. 9 
2.2 
Randomization ..................................................................................................... 11 
2.3 
Blinding ............................................................................................................... 11 
2.4 
Schedule of Assessments ...................................................................................... 11 
2.5 
Determination of Sample Size .............................................................................. 17 
3. 
OBJECTIVES .................................................................................................................... 19 
3.1 
Primary Objective ................................................................................................ 19 
3.2 
Secondary Objectives ........................................................................................... 19 
4. 
SUBJECT POPULATION SETS ....................................................................................... 21 
4.1 
Screened Set ......................................................................................................... 21 
4.2 
Enrolled Set.......................................................................................................... 21 
4.3 
Randomized Set ................................................................................................... 21 
4.4 
Safety Set ............................................................................................................. 21 
4.5 
Full Analysis Set .................................................................................................. 21 
4.6 
Per-protocol Set .................................................................................................... 21 
4.7 
Completer Set ....................................................................................................... 21 
4.8 
Pharmacokinetic and Pharmacodynamic Set ......................................................... 21 
5. 
SUBJECT DISPOSITION .................................................................................................. 22 
6. 
PROTOCOL VIOLATIONS AND DEVIATIONS ............................................................ 23 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................ 24 
7.1 
Medical History .................................................................................................... 24 
7.2 
HAE History ........................................................................................................ 24 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ..................................... 26 
8.1 
Exposure to Investigational Product ..................................................................... 26 
8.2 
Measurement of Treatment Compliance ............................................................... 26 
9. 
PRIOR AND CONCOMITANT MEDICATION ............................................................... 27 
10. EFFICACY ANALYSES ................................................................................................... 28 
10.1 
Primary Efficacy Variable(s) and Analysis ........................................................... 28 
10.2 
Key Secondary Efficacy Variable(s) and Analysis ................................................ 29 
10.3 
Adjustments for Multiplicity ................................................................................ 29 
10.4 
Other Secondary Efficacy Variable(s) and Analysis .............................................. 30 
10.5 
Exploratory Efficacy Variable(s) and Analyses..................................................... 31 


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10.5.1 
Sensitivity Analyses ............................................................................................. 31 
10.5.2 
Multiple Imputation Analysis ............................................................................... 32 
11. SAFETY ANALYSES ....................................................................................................... 35 
11.1 
Adverse Events .................................................................................................... 35 
11.2 
Clinical Laboratory Variables ............................................................................... 36 
11.3 
Vital Signs ........................................................................................................... 38 
11.4 
Electrocardiogram ................................................................................................ 39 
11.5 
Injection Site Reaction ......................................................................................... 39 
11.6 
Tolerability of Icatibant Therapy .......................................................................... 39 
12. OTHER ANALYSES ......................................................................................................... 40 
12.1 
Pharmacokinetic and Pharmacodynamic analyses ................................................. 40 
12.2 
C1 INH Antibody ................................................................................................. 40 
12.3 
Health-related Quality of Life Analyses ................................................................ 40 
12.4 
Surveys on SC Administration and Self-administration of Investigational 
Product ................................................................................................................. 41 
12.5 
Subgroup Analyses ............................................................................................... 41 
12.5.1 
Age Group ........................................................................................................... 41 
12.5.2 
Sex ....................................................................................................................... 41 
12.5.3 
Race Group .......................................................................................................... 42 
12.5.4 
Use of Prophylactic therapy with C1 INH at Randomization ................................ 42 
12.5.5 
Use of Prophylactic Therapy with C1 INH or Androgens Prior to Screening ........ 42 
12.5.6 
Long-Term Prevention at Randomization ............................................................. 42 
12.5.7 
Region .................................................................................................................. 42 
12.5.8 
Location ............................................................................................................... 42 
12.5.9 
Mucosal and Non-Mucosal Location .................................................................... 43 
13. INTERIM ANALYSIS....................................................................................................... 44 
14. DATA MONITORING/REVIEW COMMITTEE .............................................................. 45 
15. COMPUTER METHODS .................................................................................................. 46 
16. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................... 47 
17. DATA HANDLING CONVENTIONS .............................................................................. 48 
17.1 
General Data Reporting Conventions.................................................................... 48 
17.2 
Derived Efficacy Variables ................................................................................... 49 
17.3 
Repeated or Unscheduled Assessments of Efficacy and Safety Parameters ........... 49 
17.4 
Termination visits for patients who discontinued investigational product or 
study early ............................................................................................................ 49 
17.5 
Missing Date of Investigational Product ............................................................... 50 
17.6 
Missing Date Information for Prior and Concomitant Medications ....................... 50 
17.6.1 Incomplete Start Date ......................................................................................... 50 


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17.6.2 Incomplete Stop Date ......................................................................................... 50 
17.7 
Missing Date Information for Adverse Events ...................................................... 51 
17.7.1 Incomplete Start Date ......................................................................................... 51 
17.7.2 Incomplete Stop Date ......................................................................................... 52 
17.8 
Missing Severity Assessment for Adverse Events ................................................. 52 
17.9 
Missing Relationship to Investigation Product for Adverse Events ....................... 52 
17.10 
Character Values of Clinical Laboratory Variables ............................................... 52 
17.11 
Handling Missing HAE Attack Data ..................................................................... 52 
18. TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS ............................. 54 
19. APPENDIX........................................................................................................................ 55 
19.1 
Derivations of efficacy endpoints related to angioedema attacks ........................... 55 
19.2 
Derivation of normalized efficacy endpoints......................................................... 56 
19.3 
Angioedema Quality of Life Questionnaire – American English Version 2012 ..... 56 
19.4 
Major Protocol Deviations .................................................................................... 58 


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ABBREVIATIONS 
AE 
adverse event 
AE-QoL 
angioedema quality of life (questionnaire) 
AAS 
Angioedema Activity Score 
ATE 
arterial thromboembolism 
AUC 
area under the curve 
AUClast 
area under the curve from the time of dosing to the last measurable 
concentration 
AUC0-∞ 
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration 
C1 INH 
C1 esterase inhibitor or C1 inhibitor 
CI 
confidence interval 
CL 
clearance 
CL/F 
total body clearance for extravascular administration divided by the 
fraction of dose absorbed 
Cmax 
maximum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval 
Cmin 
minimum concentration occurring at the time of maximum observed 
concentration sampled during a dosing interval 
CRF 
case report form 
CRO 
contract research organization 
EC 
ethics committee 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQol 5-dimensional 5-level descriptive system 
EU 
European Union 
FDA 
Food and Drug Administration 
HAE 
hereditary angioedema 
HIV 
human immunodeficiency virus 
HRUA 
health resource utilization assessment 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
intravenous 
NNA 
normalized number of attacks 
PD 
pharmacodynamics 
PE 
pulmonary embolism 


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PK 
pharmacokinetics 
PCI 
Potentially clinical important 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDS 
Sheehan Disability Scale 
t1/2 
terminal half-life 
TCSR 
time-to-subject-assessed-complete-symptom resolution 
TEAE 
treatment-emergent adverse event 
TISI 
time-to-subject-assessed-initial-symptom improvement 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
US 
United States 
VAS 
Visual Analogue Scale 
WPAI-GH 
Work 
Productivity 
and 
Activity 
Impairment-General 
Health 
(questionnaire) 


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1. 
INTRODUCTION 
This is the full analysis Statistical Analysis Plan (SAP) for Study SHP616-300. The SAP 
provides a technical and detailed elaboration of the statistical analyses of safety and efficacy data 
as described in the study protocol amendment 4.0 dated 08 February 2017. Specifications for 
tables, figures, and listings will be provided in a separate document.  


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2. 
STUDY DESIGN  
2.1 
General Study Design 
This is a phase 3, randomized, double-blind, placebo-controlled, two-period, three-sequence, 
partial crossover study to evaluate the efficacy and safety of subcutaneous (SC) administration of 
2000 IU of C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks in adolescents and adults with hereditary angioedema (HAE).  
Individual participation from the screening visit through the 1-month post-treatment visit will be 
approximately 9 months (up to 21-day screening period, two 14-week treatment periods [total 28 
weeks] with no washout between treatment periods, and 1-week and 1-month post-treatment 
follow-up visits).  A study flow chart is shown below (Figure 1).  
Participants are expected to receive blinded investigational product (C1 esterase inhibitor 
[human] liquid for injection or placebo) twice weekly (every 3 or 4 days) for 14 weeks in each 
treatment period. Eligible subjects will be randomized to one of the three treatment sequences, 
A/B, B/A, or A/A (Table 1). 


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Table 1: 
Treatment Sequences 
Sequence 
Treatment: Period 1/Period 
2 
Approximate Number of Subjects 
Randomized 
1 
A/B 
26 
2 
B/A 
26 
3 
A/A 
14 
Treatment A=2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection 
administered SC twice weekly (every 3 or 4 days) for 14 weeks.  
Treatment B=Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) 
for 14 weeks. 
 
Figure 1: Study Design Flow Chart 
 
 
 
 
 


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2.2 
Randomization 
The randomization schedule will be stratified for use of prophylactic therapy with C1 INH at the 
time of enrollment versus no prophylactic therapy with C1 INH at the time of enrollment. At 
least 66 eligible subjects will be randomized to 1 of 3 treatment sequences prior to the first dose 
of investigational product in Treatment Period 1. The actual treatment sequence given to 
individual subjects is determined by a randomization schedule automatically assigned by the 
IRT.  
2.3 
Blinding  
The study will be double-blinded. All study site personnel, subjects, qualified home health 
professionals, and the sponsor will be blinded to treatment sequence.  
2.4 
Schedule of Assessments 
 


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Table 2: 
Schedule of Assessments – Treatment Period 1 
Procedures 
Screena 
TREATMENT PERIOD 1 (BY STUDY WEEK) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
DOSING VISITS (1a to 28a) 
1a 
2a 
3a 
4a 
5a 
6a 
7a 
8a 
9a 
10a 11a 12a 13a 14a 15a 16a 17a 18a 19a 20a 21a 22a 23a 
24a 25a 26a 
27a 
28a 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsb 
 
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Randomization 
(predose) 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant meds 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Height and body weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, pulse)d, 
e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety labsf 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA with microscopy 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screeningg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testingh 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP injection 
 
i 
 
 
 
 
 
 
i 
 
 
 
 
 
 
 
i 
 
 
 
 
 
 
 
i 
  
 
i 
ISR assessmentj 
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
j 
Acceptability surveyk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-administration 
surveyk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Angioedema attack 
monitoringk, l 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ 
AASk 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ 
AE-QoL questionnairek 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5Lk, m, 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WPAI-GH and SDSk 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRUA-HAE 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-C1 INH antibodies 
 
c 
 
 
 
 
 
 
c 
 
 
 
 
 
 
 
c 
 
 
 
 
 
 
 
c 
 
 
c,n 
c,n 
PK/PD sampling 
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 5 


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Table 2: 
Schedule of Assessments – Treatment Period 1 
Procedures 
Screena 
TREATMENT PERIOD 1 (BY STUDY WEEK) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
DOSING VISITS (1a to 28a) 
1a 
2a 
3a 
4a 
5a 
6a 
7a 
8a 
9a 
10a 11a 12a 13a 14a 15a 16a 17a 18a 19a 20a 21a 22a 23a 
24a 25a 26a 
27a 
28a 
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPTT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case 
report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; 
HRUA=health resource utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; 
PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire 
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1). 
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product. 
c Specified procedures should be performed prior to investigational product administration. 
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically 
indicated. 
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of 
theinjection. Note: Vital sign measurements are not required at Visits 2a, 3a, and 4a for subjects self-administering investigational product without supervision (ie, assessment may 
not be possible). 
f Biochemistry, hematology, and coagulation (aPTT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism. 
g HIV (single assay antibody/INNO-LIA) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody). 
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points. 
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a. 
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28a the overall impact on daily living (yes/no) and  the  duration 
of  injection site reactions will be assessed for each subject. 
k In the electronic subject diary. 
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary. 
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.  
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see 
Table 5). 


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Table 3: 
Schedule of Assessments–Treatment Period 2 
Procedures 
TREATMENT PERIOD 2 (BY STUDY WEEK) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
DOSING VISITS (1b to 28b) 
1b 
2b 
3b 
4b 
5b 
6b 
7b 
8b 
9b 
10b 11b 12b 13b 14b 15b 
16b 17b 18b 19b 20b 21b 22b 23b 24b 
25b 26b 27b 28b 
Adverse eventsa 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Physical 
examination 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, 
pulse)c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety labsd 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA with 
microscopy 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testinge 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP injection 
f 
 
 
 
 
 
 
f 
 
 
 
 
 
 
 
f 
 
 
 
 
 
 
 
f 
 
 
 
f 
ISR assessmentg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
g 
Acceptability 
survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-administration 
surveyh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Angioedema attack 
monitoringh, i 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
AASh 
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
AE-QoL 
questionnaireh 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5Lh, j 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WPAI-GH and 
SDSh 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRUA-HAE 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-C1 INH 
antibodies 
b 
 
 
 
 
 
 
b 
 
 
 
 
 
 
 
b 
 
 
 
 
 
 
 
b 
 
 
 
b 
PK/PD sampling 
A detailed blood sample collection schedule for PK/PD assessments is provided in Table 5 


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Table 3: 
Schedule of Assessments–Treatment Period 2 
Procedures 
TREATMENT PERIOD 2 (BY STUDY WEEK) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
DOSING VISITS (1b to 28b) 
1b 
2b 
3b 
4b 
5b 
6b 
7b 
8b 
9b 
10b 11b 12b 13b 14b 15b 
16b 17b 18b 19b 20b 21b 22b 23b 24b 
25b 26b 27b 28b 
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPTT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; 
CRF=case report form; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource 
utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; 
PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire 
Note: ECGs may be performed during Treatment Period 2 if clinically indicated, using standard methods at each study site. 
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product. 
b Specified procedures should be performed prior to investigational product administration. 
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On 
dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end 
of the injection. Note: Vital sign measurements are not required at Visits 2b, 3b, and 4b for subjects self-administering investigational product without supervision (ie, 
assessment may not be possible). 
d Biochemistry, hematology, and coagulation (aPTT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and 
symptoms consistent with suspected venous thromboembolism. 
e Urine pregnancy test for female subjects of childbearing potential. 
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b. 
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visit 28b, the overall impact on daily living (yes/no) and the 
duration of  injection site reactions will be assessed for each subject. 
h In the electronic subject diary. 
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary. 
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack. 


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Table 4: 
Schedule of Assessments–Early Discontinuation, 1-week and 1-month 
Post-treatment Visits 
Procedures 
Early Discontinuation 
Visita 
[If Applicable] 
1-Week (±1 day) 
Post-treatment 
Visit 
[All Subjects] 
1-Month (±2 days) 
Post-treatment 
Visit 
[All Subjects] 
Concomitant medications 
 
 
 
Physical examination 
 
 
 
Vital signs (BP, pulse)b 
 
 
 
Safety labsc 
 
 
 
UA with microscopy 
 
 
 
Pregnancy testingd 
 
 
 
Adverse events/ SAEs g 
 
 
 
Angioedema attack monitoringe, f 
 
 
 
AASe 
 
 
 
Acceptability surveye 
 
 
 
Self-administration surveye 
 
 
 
AE-QoL questionnairee 
 
 
 
EQ-5D-5Le 
 
 
 
WPAI-GH and SDSe 
 
 
 
HRUA-HAE 
 
 
 
Immunogenicity (anti-C1 INH antibodies) 
 
 
 
PK/PD 
 
 
 
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPTT=activated partial thromboplastin time; 
BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; EQ-5D-5L=EuroQol 5-dimension 5-level 
descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; PT=prothrombin time; SAE=serious adverse event; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire 
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs 
that occur >30 days after the last dose of investigational product to Shire Pharmacovigilance Department. 
a If a subject prematurely discontinues investigational product, regardless of the reason, the early discontinuation visit 
procedures are to be performed as completely as possible. Whenever possible, all discontinued subjects should also complete 
the 1-week and 1-month post-treatment follow-up visits.  
b Vital signs will be measured using standard methods at each investigational site.  
c Biochemistry, hematology, and coagulation (aPTT, PT, INR, D-dimer).   
d A urine pregnancy test will be performed for all female subjects of childbearing potential. 
e In the electronic subject diary. If possible, subjects should complete the subject diary on the day of discontinuation or at the 
1-week post-treatment visit. 
f The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the 
subject diary. 
g Serious Adverse Events (SAEs) are to be followed until 1 month post-treatment visit. 


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Table 5: 
Blood Sample Collection for PK/PD Analyses 
TREATMENT PERIOD 1 
Visit / Dose # 
Blood Sampling Time Pointsa 
C1 INH Antigen, C1 INH Functional, C4 
1a / Dose 1b 
Predose 1 (within 15 min)  
2a / Dose 2c 
Predose 2 (within 15 min) 
8a / Dose 8 
Predose 8 (within 15 min) 
16a / Dose 16 
Predose 16 (within 15 min)  
24a / Dose 24 
Predose 24 (within 15 min) 
Either 27a or 28a / Dose 27 or 28d  
Predose 27 or 28 (within 15 min)  
48 hours postdose 27 or 28 (±3 hours) 
TREATMENT PERIOD 2 
1b / Dose 1 
Predose 1 (within 15 min) 
2b / Dose 2c 
Predose 2 (within 15 min) 
8b / Dose 8 
Predose 8 (within 15 min) 
16b / Dose 16 
Predose 16 (within 15 min) 
24b / Dose 24 
Predose 24 (within 15 min) 
28b / Dose 28 
Predose 28 (within 15 min) 
24 hours postdose 28 (±3 hours) – optional sampling time point 
48 hours postdose 28 (±3 hours)  
72 hours postdose 28 (±6 hours) – optional sampling time point 
96 hours postdose 28 (±6 hours) 
EARLY DISCONTINUATION (if applicable) and POST-TREATMENT 
Early discontinuation 
1-week (± 1 day) 
1-month (± 2 days) 
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics 
a The actual date and time of each sample collection will be recorded, therefore the sampling window is provided for guidance 
is as an approximate value. 
b C1q concentration will also be assessed using the baseline sample (predose at Dosing Visit 1a). 
c Subjects who self-administer investigational product without supervision are not required to have a blood sample collected at 
Visit 2a or 2b. 
d To avoid collecting a PK/PD blood sample during the weekend, subjects have the option for a predose and 48 h postdose 
sample to be collected at either Visit 27a or 28a.  
2.5 
Determination of Sample Size 
The enrollment goal for this study is to randomize at least 66 subjects to ensure 54 subjects 
complete both treatment periods (44 for the crossover sequences, 10 for the active/active 
sequence).  
For the primary efficacy endpoint, the normalized number of angioedema attacks (NNA), a 
sample of 44 subjects will provide 90% power at an alpha level of 0.025 (1-sided) to detect a 
difference of 1.0 attacks per month between active treatment and placebo assuming a standard 
deviation of the difference of 2.0. 
Regarding the analysis of the key secondary endpoint, the proportion meeting criterion PR 
relative to placebo, 44 subjects will provide 90% power to test the hypothesis H0: proportion 


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≤0.2 against H1: proportion >0.2, assuming the true proportion is 0.44 by using a 1-group 
Chi-square test at an alpha level of 0.025 (1-sided). 
With respect to safety, a Safety Analysis Set of 60 subjects ensures that if the true population 
event proportion of any subject with a particular event is at least 5%, then the probability of 
observing at least 1 such event in the Safety Analysis Set is >95%.  
The sample size calculation was conducted using nQuery + nTerim 2.0. 
 


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3. 
OBJECTIVES 
3.1 
Primary Objective 
To demonstrate superior efficacy of SC administration of 2000 IU C1 esterase inhibitor [human] 
liquid for injection for the prevention of angioedema attacks relative to placebo based on the 
NNA during a treatment period. 
3.2 
Secondary Objectives 
The key secondary objectives are to demonstrate the superior efficacy of SC administration of 
2000 IU C1 esterase inhibitor [human] liquid for injection for the prevention of angioedema 
attacks relative to placebo as measured by: 
1. The proportion of subjects meeting the criterion of at least 50% reduction in the NNA 
during the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo perio 
2. The NNA during each treatment period excluding the first 2 weeks 
3. The proportion of subjects meeting the criterion of at least a 50% reduction in the NNA 
for the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo period excluding the first 2 weeks of each treatment period.  
Other secondary objectives are: 
• 
To assess the proportion of responders during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo, where the 
proportion of responders is defined as achieving at least a 50% reduction, and/or 
achieving reduction to less than 1 NNA during a treatment period relative to the 
pretreatment assessment (ie, the subject’s attack rate without prophylactic treatment) 
• 
To assess the severity of angioedema attacks during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo  
• 
To assess the number of attack-free days during treatment with 2000 IU C1 esterase 
inhibitor [human] liquid for injection relative to treatment with placebo  
• 
To assess the number of angioedema attacks requiring acute treatment during treatment 
with 2000 IU C1 esterase inhibitor [human] liquid for injection relative to treatment with 
placebo  
• 
To assess the safety and tolerability of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection 
• 
To assess the immunogenicity of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection  


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• 
To characterize the PK and PD of SC administration of 2000 IU C1 esterase inhibitor 
[human] liquid for injection 
• 
To assess the clinical response and safety/tolerability of icatibant (Firazyr®) for the 
treatment of acute angioedema attacks (applicable for subjects ≥18 years of age) 
• 
To assess disease activity as measured by the Angioedema Activity Score (AAS)  
• 
To evaluate subject experience with self-administration of SC 2000 IU C1 esterase 
inhibitor [human] liquid for injection  
• 
To evaluate the impact of treatment on health status (quality of life) in this patient 
population 
 


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4. 
SUBJECT POPULATION SETS 
4.1 
Screened Set 
All subjects who have signed an informed consent will be included in the screened set. 
4.2 
Enrolled Set 
All subjects who have signed an informed consent and some study procedures have begun will 
be included in the enrolled set. 
4.3 
Randomized Set 
 All subjects in the Screened Set for whom a randomization number has been assigned will be 
included in the randomized set. 
4.4 
Safety Set 
All subjects who have taken at least 1 dose of investigational product will be included in the 
safety set. 
4.5 
Full Analysis Set 
All subjects in the Safety Set who have at least 1 post-baseline (i.e., randomization) primary 
efficacy assessment will be included in the full analysis set. 
4.6 
Per-protocol Set 
All subjects in the Full Analysis Set who complete scheduled primary assessments for 6 study 
weeks and who do not have pre-defined protocol deviations that may affect the primary efficacy 
endpoint will be included in the Per-protocol Set. Refer to Appendix 19.4 for the protocol 
deviations that exclude subjects from the Per-protocol Set. 
4.7 
Completer Set 
All subjects in the Full Analysis Set who have completed the final scheduled primary assessment 
for the study will be included in the completer set. 
4.8 
Pharmacokinetic and Pharmacodynamic Set  
All subjects in the Safety Set for whom the primary PK and PD data are considered sufficient 
and interpretable will be included in the pharmacokinetic and pharmacodynamic set. 


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5. 
SUBJECT DISPOSITION  
The number and percentage of subjects who have been randomized and included in each subject 
population set will be presented by treatment sequence and overall. The denominator for the 
percentage calculation will be the number of randomized subjects. 
The number and percentage of subjects who prematurely discontinued during the study will be 
presented for each treatment sequence, treatment at time of discontinuation and overall for the 
Safety Set and Full Analysis Set. Primary reasons for premature discontinuation from the study 
as recorded on the termination page of the eCRF will be summarized (number and percentage) 
by treatment sequence and by treatment received at time of discontinuation for the Safety Set and 
Full Analysis Set.  
Subject disposition, subjects completing and terminating the study, and study analysis sets will 
be listed by subject for all subjects in the Enrolled Set.  
Subjects who are excluded from the Per-protocol Set will be listed for the Full Analysis Set. 
Deviations from Inclusion/Exclusion criteria will be listed for the Screened Set. 
 


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6. 
PROTOCOL VIOLATIONS AND DEVIATIONS 
Protocol deviation is defined as a variation from processes or procedures defined in a protocol. 
Deviations usually do not preclude the overall evaluability of subject data for either efficacy or 
safety, and are often acknowledged and accepted in advance by the sponsor. 
Major Protocol deviation (violation) is defined as a significant departure from processes or 
procedures that were required by the protocol. Violations often result in data that are not deemed 
evaluable for a per-protocol analysis, and may require that the subject(s) who violate the protocol 
be discontinued from the study. 
A summary of the number and percentage of subjects in the Safety Set with major protocol 
deviations (violations) or minor deviations will be produced.  
All protocol violation and deviation data will be listed for the subjects in the Safety Set. 
 


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS  
Demographic and baseline characteristics will be determined using the screening visit or last 
observation prior to the first dose of investigational product, whichever is later. Descriptive 
summaries of demographic and baseline characteristics will be presented by treatment sequence 
for the Safety Set, Full Analysis Set and Per-protocol Set.  
Subject demographics including age, age group (<18 yrs, 18-<=64 yrs, and >=65 yrs), sex, race, 
ethnicity, weight, height, BMI, and use of prophylactic therapy with C1 INH at randomization 
use will be summarized by treatment sequence for the Safety Set,Full Analysis Set, and Per-
protocol Set. Continuous variables will be summarized by descriptive statistics including number 
of subjects, mean, standard deviation (SD), median, minimum, and maximum. Categorical 
variables will be summarized by the number of subjects in each category and the percentage of 
subjects out of the total in the respective analysis set. 
Height and weight will be used to calculate BMI using the formula below: 
 
 
 
BMI = 
2
[m])
 
(height
[kg]
 
weight
 
A listing will be created to show all the demographics and baseline characteristics for all subjects 
in the Enrolled Set. 
7.1 
Medical History  
A medical history will be taken at the screening visit. All medical history findings that have been 
present/active within the 5 years prior to enrollment or any relevant history beyond 5 years that is 
considered important by the investigator will be entered into the CRF regardless of clinical 
relevance or presence at study start.  The number and percentage of subjects in each primary 
system organ class (SOC) and each preferred term (PT) will be summarized by treatment 
sequence, a total of crossover sequences, and a total of all sequences on Safety set and Full 
Analysis Set. Medical history findings will also be listed for all subjects in the Enrolled Set. 
7.2 
HAE History  
The following information associated with HAE history will be recorded in the CRF at the 
screening visit (NOTE:  the attack rate may be estimated based on subject or parent/caregiver 
recall as well as the subject's medical records):   
• HAE Type (I or II) 
• Estimated date of last angioedema (swelling) attack prior to the screening visit 
• Any therapy received during the last 12 months for management of HAE  
• Any use of prophylactic therapy with C1 INH or Androgens prior to screening 
• Any long-term prevention at randomization 
• Total number, typical locations and average overall duration (days), and average 
overall severity of angioedema attacks experienced: 


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during the 3 consecutive months prior to the screening visit (all subjects) 
and (if applicable) 
during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens. 
• Typical Visual Analogue Scale (VAS) score for the subject’s angioedema attack pain: 
during the 3 consecutive months prior to the screening visit (all subjects) 
and (if applicable) 
during the 3 consecutive months prior to starting prophylactic therapy with 
C1 INH or androgens. 
HAE history will be summarized by treatment sequence for the Safety Set and Full Analysis Set, 
and also be listed for all the subjects in the Enrolled Set.  


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational Product  
For all treated subjects, including the ones who had early termination, treatment exposure is the 
duration between the first dose date and last dose date in each treatment period. Average daily 
dose, total dose, total number of doses, total exposure, length of exposure to investigational 
product (<=1 wk, >1 - <=2 wk, >2 - <=5 wks, >5 - <=10 wks, >10 - <=14 wks, >14 – <=18 wks, 
>18 - <=24 wks, >24 - <=28 wks, >28 wks), and treatment compliance will be summarized by 
treatment for the Safety Set and Full Analysis Set. 
A listing will be created by subject and treatment and will show the date and time of dose 
administration for each treatment given for the Safety Set. 
8.2 
Measurement of Treatment Compliance 
Investigational product dosing compliance for a specified period is defined as the total volume of 
investigational product actually taken by a subject during that period divided by the volume of 
investigational product expected to be taken during the same period, multiplied by 100. Each 
complete dose of investigational product will consist of a total volume of 4 mL. For doses where 
the drug administration was not complete, the dose is the total volume administered. The volume 
expected to be taken for a specified period is calculated as the number of weeks in that period 
multiplied by 4ml and multiplied by the number of doses to be taken per week (twice weekly) 
during that period.  
Descriptive statistics including the number of subjects, mean, standard deviation, median, 
minimum, and maximum will be presented for exposure to investigational product and 
compliance by treatment for the Safety Set and Full Analysis Set. The treatment compliance will 
be categorized and summarized as follow: < 85, >= 85 - < 100, >= 100 for the Safety Set and 
Full Analysis Set. 
 


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9. 
PRIOR AND CONCOMITANT MEDICATION  
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHODRUG) Version June 2017. 
Prior medications are defined as medications with start time prior to the time of investigational 
product administration.  
Concomitant medications are defined as medications with a start times after the time of 
investigational product administration or medications with a start time prior to investigational 
product administration but continuing after treatment, and with a start time before the 1-month 
post-treatment visit, inclusive.  
Medical/surgical procedures performed during the treatment (between the dates of the first dose 
and the 1-month post-treatment visit, inclusive) will be recorded on the CRF, along with the date, 
time, and reason for the procedure.  
Prior medication usage will be summarized using the number and percentage of subjects 
receiving each medication by treatment sequence, a total of crossover sequences and a total of all 
sequences, by indications, level 1 of the Anatomic Therapeutic Chemical (ATC) classification 
system and preferred term (PT) within the Safety Set and Full Analysis Set.  Multiple medication 
usage by a subject in the same preferred term category will be counted only once. Concomitant 
medications will be summarized by the number and percentage of subjects receiving each 
medication/procedure by treatment, indications, ATC level 1, and preferred term (PT) within the 
Safety Set and Full Analysis Set. For this summary, concomitant medications will be assigned to 
a treatment if they are recorded at least once within the period corresponding to that treatment. 
Medical/surgical procedures will be listed for the Safety Set. 
All non-study medications taken during the study will be listed and flagged with prior, 
concomitant and post treatment (taken after the 1-month post-treatment visit, exclusive) 
medications for Safety Set. Medical/surgical procedures performed during the treatment 
(between the dates of the first dose and the 1-month post-treatment visit, inclusive) will also be 
listed for the Safety Set.  


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10. EFFICACY ANALYSES    
10.1 
Primary Efficacy Variable(s) and Analysis  
The primary efficacy analysis will be conducted over the subjects in the Full Analysis Set that 
are randomized to Treatment Sequence 1 (A/B) or 2 (B/A) to evaluate of the efficacy of SC 
administration of C1 esterase inhibitor [human] liquid for injection compared to placebo. 
The primary efficacy endpoint is defined as the normalized number of angioedema attacks 
during a treatment period. The NNA is expressed as the number of attacks per month (ie, 30.4 
days) of exposure: 
NNA = 30.4 x (number of attacks during treatment period)/(days of treatment period) 
If a subject discontinues during the treatment period, the denominator of the NNA will be the 
days on treatment for that subject; this is equivalent to the last observation carried forward 
imputation method to impute the missing information following the subject’s discontinuation.  
To test the hypothesis that the NNA of C1 esterase inhibitor [human] liquid for injection is 
greater than or equal to the NNA of placebo, and the alternative hypothesis that the NNA of 
C1 esterase inhibitor [human] liquid for injection is less than the NNA of placebo as below: 
  
H0: µ C1 INH - µ placebo >0  
                    vs 
H1: µ C1 INH - µ placebo <0 
A linear mixed effect model will be performed to analyze the primary efficacy endpoint with 
period, sequence, use of prophylactic therapy with C1 INH, which is derived by long-term 
prevention with C1 INH at randomization, and treatment as fixed effects, and subject nested 
within sequence as a random effect.  If the variance-covariance matrix of random effects is not 
positive definite, a mixed effect model with the same fixed effects and subject nested within 
sequence as repeated measurements will be performed instead; the repeated measurement is 
equivalent to the random effect in terms of statistical testing and point estimates of coefficients 
of fixed effects, however, the variance covariance matrix of random effects will not be estimated. 
The mean treatment difference (µ C1 INH - µ placebo) will be estimated with a 95% CI provided. The 
upper confidence bound of 95% CI must be less than 0 in order for C1 INH to be considered 
superior to the placebo. 
A summary of NNA during each treatment period by treatment sequences will be provided for 
the Full Analysis Set. 
In addition, the NNA will be presented graphically for subjects randomized to the first 2 
treatment sequences (A/B or B/A) in the Full Analysis Set, with the observed NNA on the 
vertical axis and the treatment periods (with assigned treatments) on the horizontal axis.  
 


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10.2 
Key Secondary Efficacy Variable(s) and Analysis  
The key secondary efficacy variables are listed as following: 
1. The proportion of subjects meeting the criterion of at least a 50%, 70%, 90% and 100% 
reduction in the NNA during the 2000 IU C1 esterase inhibitor [human] liquid for 
injection treatment period relative to the placebo period. 
2. The NNA excluding the first 2 weeks of each treatment period. 
3. The proportion of subjects meeting the criterion of at least a 50%, 70%, 90% and 100% 
reduction in the NNA for the 2000 IU C1 esterase inhibitor [human] liquid for injection 
treatment period relative to the placebo period excluding the first 2 weeks of each 
treatment period. 
Key secondary efficacy endpoints 1 and 3 are defined as achieving a ≥50% reduction in the 
NNA (PR) during the 2000 IU C1 esterase inhibitor [human] liquid for injection treatment period 
relative to the placebo period.  
The Key secondary endpoints 1 and 3 will be analyzed as the proportion of subjects meeting the 
above clinical response criterion (PR). The analysis will be conducted over the Full Analysis Set 
from the first two treatment sequences. The null hypothesis is that PR is less than or equal to 0.2, 
and the alternative hypothesis is that PR is greater than 0.2 as below: 
          H0: PR ≤ 0.2 
                    vs 
H1: PR > 0.2 
The proportion PR will be estimated with an exact 95% CI. The lower limit of the 95% CI for the 
proportion will be compared with 0.2. This is equivalent to testing the null hypothesis against the 
alternative hypothesis at a 1-sided alpha level of 0.05 using the binomial distribution.  
Analysis of key secondary endpoint 2 will follow the same methods (ie, the linear mixed effect 
model) used for the primary efficacy endpoint. 
The key secondary analyses will be performed using the Full Analysis Set and the Per-protocol 
Set. 
10.3 
Adjustments for Multiplicity 
To control the overall type 1 error, the primary and key secondary endpoints will be tested at the 
0.05 significance level in the pre-specified order of the primary endpoint, key secondary 
endpoint 1, key secondary endpoint 2, and key secondary endpoint 3. Once one hypothesis test is 
not significant, the significance of all subsequent tests will not be assessed. The determination of 
a successful study is based solely on the results of the primary endpoint analysis regardless of the 
results for the key secondary endpoints.  


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10.4 
Other Secondary Efficacy Variable(s) and Analysis 
Data from subjects in the Full Analysis Set that are randomized to Treatment Sequence 1 (A/B) 
or 2 (B/A) will be used to assess the secondary efficacy endpoints in the evaluation of the 
efficacy of SC administration of C1 esterase inhibitor [human] liquid for injection compared to 
placebo. If a subject discontinues during the treatment period, the days of the treatment period 
will be the days on treatment for that subject; this is equivalent to the last observation carried 
forward imputation method to impute the missing information following the subject’s 
discontinuation. 
Other secondary efficacy variables are listed as following:   
• To determine the proportions of subjects with a clinical response to treatment as defined 
by: Achieving at least a 50%, 70%, 90% and 100% reduction as well as subjects 
achieving reduction to less than 1 NNA during a treatment period relative to the 
pretreatment assessment. 
• The summary of clinical response to treatment will be repeated using the Per-protocol Set 
• Cumulative attack severity: the normalized sum (per month) of the maximum symptom 
severity recorded for each angioedema attack in a treatment period. 
• Cumulative daily severity: the normalized sum (per month) of the severity scores 
recorded for every day of reported symptoms in a treatment period. 
• Number of attack-free days during a treatment period: the normalized number (per 
month) of attack-free days. 
• Number of angioedema attacks requiring acute treatment during a treatment period: the 
normalized number of angioedema attacks requiring acute treatment. 
• Disease activity as measured by the 98-day AAS: the normalized sum of the daily AAS 
during a treatment period, where the daily AAS is the sum of AAS items per day. Each 
AAS item is scored between 0 and 3 points, with the minimum and maximum daily AAS 
ranging between 0 and 15 points.  
• Results of the AE-QoL questionnaire: the questionnaire consists of 17 specific questions 
that are associated with work, physical activity, free time, social relations, and food. 
• Number of angioedema attacks requiring icatibant by the number of icatibant injections 
during the first three attacks of the treatment period. 
• Kaplan-Meier estimate of time to initial improvement and time to complete resolution 
since acute treatment administration by attack order during the treatment period.  
• Kaplan-Meier estimate of time to initial improvement and time to complete resolution 
since onset of attack by attack order during the treatment period. 
The treatment differences in clinical responder rates, both of which are defined within 
treatments, i.e., the difference in the proportions of subjects with a clinical response to C1 INH 


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or placebo, each of them will be analyzed using McNemar’s test for testing equality of 
proportions of responders within treatments. 
Cumulative attack severity, cumulative daily severity, number of attack-free days during a 
treatment period and the 98-day AAS will be analyzed using a linear mixed effect model with 
period, sequence, use of prophylactic therapy with C1 INH, which is derived by long-term 
prevention with C1 INH at randomization, and treatment as fixed effects, and subject nested 
within sequence as a random effect. If the variance-covariance matrix of random effects is not 
positive definite, a mixed effect model with the same fixed effects and subject nested within 
sequence as repeated measurements will be performed instead. The results will be summarized 
by the point estimate of within-subject treatment differences or response rates and the 
corresponding 95% CI.  
Kaplan-Meier analysis will be performed on all subjects in the Full Analysis Set without 
censoring. Median, 25%, 75% quartiles and their CI’s will be estimated for time to initial 
improvement / complete resolustion since acute treatment administration / onset of attack. 
Summary statistics (n, mean, SD, median, minimum and maximum) will be provided on each 
dimension and total score of AE-QoL by treatment and visit. A table will be provided 
summarizing the change from baseline to each visit and the last observation recorded within the 
treatment period for a subject's response to each dimension and the total score of AE-QoL.  
In addition, angioedema attacks will be summarized by the maximum symptom severity of the 
attack and treatment for all subjects in the Full Analysis Set. Acute angioedema attacks will be 
summarized by acute therapy, the maximum symptom severity of the attack and treatment for all 
subjects in the Full Analysis Set. 
Cumulative attack severity, cumulative daily severity and number of attack-free days will be 
plotted by treatment for the subjects who are randomized to the first two treatment sequences 
(A/B or B/A) in the Full Analysis Set.  
Details on derivation of normalized efficacy variables are provided in the Appendix. 
10.5 
Exploratory Efficacy Variable(s) and Analyses  
10.5.1 
Sensitivity Analyses  
The following sensitivity analyses will be performed on the primary and key secondary efficacy 
endpoint 1 to evaluate the robustness of the results. Data summaries will parallel those described 
for the primary analysis of the primary and key secondary efficacy endpoint 1. If not otherwise 
specified, the sensitivity analyses will be performed in the Full Analysis Set. 
• To assess any carryover effect, a sensitivity analysis will be conducted by excluding any 
angioedema attacks occurring within the first 2 weeks of Treatment Period 2 for sequence 
A/B, when carryover is suspected to be maximal.  
• To assess carryover effect with an assumption that it exists for both A/B and B/A 
treatment sequences, a sensitivity analysis will be conducted by excluding any 


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angioedema attacks occurring within the first 2 weeks of Treatment Period 2, when 
carryover is suspected to be maximal. 
• The analyses for the primary and key secondary endpoint 1 will be repeated using Per-
protocol Set. 
• The analyses for the primary and key secondary endpoint 1 will be repeated using 
Completer Set. 
• One subject (
) reported atypical clinical presentation, an extensive number 
of HAE attacks, and very few symptom-free days between attacks throughout the study 
duration. During the study the subject underwent abdominal computer tomography 
imaging to identify potential for alternative diagnosis. Sensitivity analyses are planned 
prior to study data unblinding in order to assess the robustness of the study results by 
considering this subject’s attacks differerently.  
- 
Exclude this subject from the full analysis set  
• The primary efficacy endpoint will be compared for the active treatment to the placebo 
treatment using a generalized estimating equation (GEE) for count data assuming a 
negative binomial distribution with a log-link function. The model will include fixed 
effects for treatment, sequence, period, and use of prophylactic therapy with C1 INH, 
which is derived by long-term prevention with C1 INH at randomization, and the 
logarithm of time in days each subject was observed during a treatment period will be 
used as an offset variable in the model. 
• The primary efficacy endpoint will be compared for the active treatment to the placebo in 
the Full Analysis Set, including subjects in the A/A treatment sequence. In this analysis, 
the same method used in the analysis for the primary efficacy endpoint will be applied. 
• The primary efficacy analysis will be repeated with exclusion of data after any major 
protocol deviation. 
10.5.2 
Multiple Imputation Analysis   
Analysis based on imputing missing values by drop out reason (Protocol Section 4.4.1) are added 
as sensitivity analysis to the primary efficacy analysis. The primary imputation method within 
the sensitivity analysis will be the multiple imputation method for the Full Analysis Set 
described below in this section. 
A subject is considered to have missing values in case he/she leaves the study prematurely. The 
fraction of non-missing data (f) and normalized number of HAE attacks (NNAobserved) will be 
determined per treatment period and subject as follows: 
PPD


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Category 
Level of Participation 
per Treatment Period 
Fraction of non-missing 
data (f) per Treatment 
Period 
Observed normalized 
number of HAE attacks 
(NNAobserved) 
A 
Subject is not 
discontinued from the 
study 
1 
As outlined in Section 8.1 
B 
Subject is discontinued 
from the study in a 
treatment period 
Days of participation / 
scheduled length of 
treatment period (days) 
As outlined in Section 8.1 
C 
Treatment period 2 
among subjects who 
discontinued during 
treatment period 1 
0 
 
Days of participation will be calculated as defined in Section 8.1 and scheduled length of 
treatment period is the intended length, i.e., 14 weeks for analysis equals 14×7=98 days. 
The missing data will be imputed with NNA according to the sensitivity analysis by drop out 
reason. The normalized number of HAE attacks to be used for the sensitivity analysis 
(NNAanalyzed) will be calculated based on the observed number (NNAobserved) and the imputed 
number (NNAimputed) taking into account the fraction of non-missing data (f) as: 
NNAanalyzed = f × NNAobserved + (1 – f) × NNAimputed.   
(Equation 10.1) 
Values for NNAobserved will be determined as outlined in the above table; values for NNAimputed 
will be determined for each subject and period with missing data depending on the sensitivity 
analysis as described below. 
If a subject discontinues prematurely in treatment period 1, his/her NNAanalyzed value during 
treatment period 2 will be imputed by the median of the non-missing NNAobserved from all 
subjects who have complete data within the same treatment as that the subject is expected to take 
in treatment period 2. 
If a subject discontinues prematurely from a treatment period, the remaining part of this period 
(NNAimputed) will be imputed using the bootstrap method. The same imputation method used for 
treatment period 1 missing data will be used for treatment period 2 missing data 
1. Draw a bootstrap sample with replacement from all Full Analysis Set subjects of the 
same treatment sequence with no missing values using PROC SURVEYSELECT with a 
seed of 300. 
2. Use the following rules to calculate NNAimputed for the missing data for each bootstrap 
sample. 


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a) Missing data are considered as missing at random (MAR) if the dropout reasons are 
not related to the investigational product and study termination by sponsor (subjectdid 
not want to be in this study, site was closing, other personal reasons). For subjects 
with MAR data, the value of NNAimputed will be the median of NNAobserved of all 
subjects who have complete data within the same treatment. 
b) Data which are missing due to dropout for the following reasons are considered 
missing not at random (MNAR): discontinued due to AEs, death or lack of efficacy. 
For subjects with MNAR data, the median of the worst 25% observed data of the 
bootstrap sample from subjects who have complete data within the same treatment (xѺ) 
will be determined. The value of NNAimputed equals the maximum NNAobserved among 
all these subjects if NNAobserved > xѺ, and xѺ otherwise. 
c) Data which are missing because of protocol violations, other, withdrawal by subjects, 
or physician decision will be reviewed, and a decision of classifying them into the 
categories as described in a) or b) will be made and documented prior to unblinding. 
3. After NNAimputed is calculated, use Equation 10.1 to calculate NNAanalyzed. The complete 
bootstrap sample with imputed values (NNAanalyzed) will be analyzed by fitting the 
primary analysis model 
4. Repeat the above 3 steps for 1000 times. 
5. The model adjusted summaries will be combined from the 1000 imputed bootstrap 
samples using Rubin’s formulae from PROC MIANALYZE. These estimates include: the 
model adjusted NNA, the overall difference of NNA between the study drug and the 
placebo, and the type III tests p-values of fixed effects. 
 
 


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11. SAFETY ANALYSES 
The safety analyses will be performed by treatment using the Safety Set. Safety endpoints 
include adverse events (AE), clinical laboratory assessments, vital signs, ECG findings, SC 
injection site reactions, C1 INH antibody status and patient-reported tolerability of icatibant 
therapy for acute angioedema attacks. The last assessment prior to the first dose of 
investigational product in treatment period 1 will be used as baseline for all safety analyses. 
11.1 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 19.0 adverse events dictionary. 
Adverse events will be collected from the time of informed consent through 7 days after the last 
dose date of investigational product. All serious adverse events (SAE) that occur ≤30 days after 
the last dose date of investigational product and related SAEs that occur >30 days after the last 
dose date of investigational product will be collected.  
An adverse event that increases in severity will be captured as a new event. An AE that develops 
into a SAE will be captured as a new event from the date it met the seriousness criteria. 
Worsening of pre-treatment events, after initiation of investigational product, will be recorded as 
new AE. An AE (classified by preferred term) that occurs during the study will be considered a 
treatment emergent adverse event (TEAE) if the start date and time of the AE is on or after the 
first dose date of investigational product and up to 7 days after the last dose of investigational 
product, or if the start date of the SAE is on or after the first dose date of investigational product 
and up to 30 days after the last dose of investigational product, or with an increase in severity on 
or after the date and time of the first dose.  
In addition, angioedema attacks and ISRs will not be considered AEs unless they satisfy serious 
criteria according to the protocol. 
The number and percentage of subjects reporting any TEAEs, SAEs, and TEAEs related to 
investigational product, TEAEs leading to withdrawal, Severe TEAEs and absolute count of 
events will be summarized. Angioedema attacks and ISRs will not be considered AEs unless 
they satisfy serious criteria according to the protocol. 
The number and percentage of subjects reporting any TEAEs, and absolute count of events will 
also be summarized in the following ways: 
• By SOC, preferred term and treatment  
• By SOC, preferred term, treatment and maximum severity  
• By SOC, preferred term, treatment and relationship to investigational product in the 
opinion of the investigator 
• By preferred term 
TEAEs leading to withdrawal, SAEs, and deaths will be similarly summarized as TEAEs. 


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TEAEs related to investigational product, serious TEAEs related to investigational product and 
TEAEs related to investigational product leading to withdrawal will be similarly summarized as 
TEAEs. Summaries of TEAE or TEAE related to investigational product within 24 hours after 
the end of injection of investigational product will be provided by treatment. 
A sensitivity analysis will be conducted by attributing TEAEs that occur during the first 2 weeks 
of Treatment Period 2 to Treatment Period 1 for the A/B (C1 INH to placebo treatment sequence. 
To assess carryover effect with an assumption that it exists for both A/B and B/A treatment 
sequences, a sensitivity analysis will be conducted by excluding any TEAEs occurring within the 
first 2 weeks of Treatment Period 2, when carryover is suspected to be maximal. 
All information about AEs collected on the eCRF will be listed alongside the treatment, 
preferred term, and SOC. Listings will also be provided on TEAEs related to investigational 
product, TEAEs leading to withdrawal, SAEs, and deaths. 
11.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point (baseline, 8a, 16a, 24a, 28a, 8b, 16b, 24b and 28b) will be presented 
by treatment for the following clinical laboratory variables:  
Hematology: WBC count (total and differential), RBC count, hemoglobin, hematocrit, and 
platelet count. 
Biochemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), creatine phosphokinase (CPK), Blood urea nitrogen (BUN), creatinine, 
carbon dioxide (CO2), albumin, total protein, glucose, potassium, sodium, chloride, and 
phosphorus 
Coagulation: Prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin time (aPTT) and D-dimer. 
Urinalysis with microscopy: pH, Dipstick (protein, glucose, ketones, hemoglobin), Specific 
gravity, Microscopic evaluation (red blood cells, white blood cells, crystals, casts, bacteria). 
Clinical laboratory test values are potentially clinical important (PCI) if they meet either the low 
or high PCI criteria listed in Table 6 and fall outside the laboratory's normal range in the same 
direction (high or low) as their PCI criteria.  Subjects with post-dose PCI values will be 
summarized by treatment and also listed.  In addition, The number of subjects with a non-
missing result, and the number and percentage of subjects with a clinically significant result less 
than the lower limit of normal, non-clinically significant result less than the lower limit of 
normal, within the normal range, non-clinically significant result more than the upper limit of 
normal, and clinically significant result more than the upper limit of normal will be summarized 
by visit and treatment. 


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Table 6: 
Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Age Range 
Gender 
Criteria for Clinically Significant Laboratory 
Abnormalities1 
Low 
High 
Hematology 
 
 
 
 
Eosinophils (%) 
All 
Male, 
Female 
NA  
>4 x ULN 
Hematocrit 
All 
Male, 
Female 
<0.6 x LLN 
>1.3 x ULN 
Hemoglobin 
All 
Male, 
Female 
<0.6 x LLN 
>1.3 x ULN 
Neutrophils (%) 
All 
Male, 
Female 
<0.5 x LLN 
NA 
Platelets 
All 
Male, 
Female 
<0.4 x LLN 
>2 x ULN 
Leukocytes (WBC)  
All 
Male, 
Female 
<0.5 x LLN 
>2 x ULN 
Coagulation 
Intl. Normalized Ratio 
(INR) 
All 
Male, 
Female 
NA 
>1.5 x ULN 
Activated 
Partial 
Thromboplastin 
Time 
(aPTT) 
All 
Male, 
Female 
NA 
>2.0 x ULN 
Chemistry 
Albumin 
All 
Male, 
Female 
<0.6 x LLN 
NA 
Alkaline Phosphatase 
All 
Male, 
Female 
ΝΑ  
>3.0 x ULN 
Alanine 
Aminotransferase 
(ALT) 
All 
Male, 
Female 
ΝΑ 
>3.0 x ULN 
Aspartate 
Aminotransferase 
(AST) 
All 
Male, 
Female 
ΝΑ 
>3.0 x ULN 
Blood Urea Nitrogen 
(BUN) 
All 
Male, 
Female 
ΝΑ 
>3.0 x ULN 
Chloride 
All 
Male, 
Female 
<0.8 x LLN 
>1.2 x ULN 
Creatinine 
All 
Male, 
Female 
NA 
>1.5 x ULN 
Potassium 
All 
Male, 
Female 
<0.85 x LLN 
>1.2 x ULN 


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Table 6: 
Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Age Range 
Gender 
Criteria for Clinically Significant Laboratory 
Abnormalities1 
Low 
High 
Glucose 
All 
Male, 
Female 
<0.6 x LLN 
>3.5 x ULN 
Sodium 
All 
Male, 
Female 
<0.9 x LLN 
>1.1 x ULN 
NA=Not Applicable; LLN=Lower Limit of Normal; ULN=Upper Limit of Normal; Intl.=International. 
1 
If criteria in both directions are shown for a single parameter, then abnormalities in each direction are 
summarized separately. 
11.3 
Vital Signs 
Descriptive statistics for vital signs (e.g. systolic and diastolic blood pressure and pulse) and their 
changes from baseline at each post-dose visit will be presented by treatment. 
Vital sign values will be considered PCI if they meet the observed value criteria or the change 
from baseline criteria listed in Table 7. Subjects with post-baseline PCI values will be 
summarized by treatment and a supportive listing of subjects with post-baseline PCI values will 
also be provided.  All vital signs results will be listed for the Safety Set.  
Table 7: 
Criteria for Potentially Clinically Important Vital Signs 
Vital Sign Parameter 
Flag 
Criteria 
Observed Value 
Systolic blood pressure (mmHg) 
High 
Increase of ≥ 20  from 
baseline value and ≥ 140  
Low 
Decrease of ≥ 20 from 
baseline value and ≤ 90  
Diastolic blood pressure (mmHg) 
High 
Increase of ≥ 15 from baseline 
value and ≥ 90  
Low 
Decrease of ≥ 15 from 
baseline value and ≤ 50  
Pulse rate 
(beats per minute) 
High 
Increase of > 15 from baseline 
value and ≥ 100  


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Table 7: 
Criteria for Potentially Clinically Important Vital Signs 
Vital Sign Parameter 
Flag 
Criteria 
Observed Value 
Low 
Decrease of > 15 from 
baseline value and ≤ 45  
Temperature (˚C)   
High 
> 38.3 
Low 
< 35 
11.4 
Electrocardiogram 
All 12-lead ECG collected at the screening visit will be listed for the Safety Set.  
11.5 
Injection Site Reaction 
A summary of SC injection site reactions will be summarized by treatment. The categories in this 
summary include: any injection site reaction, any severe reaction, any mild reaction, and any 
moderate reaction. Subjects will be counted in each category only once, the worst reaction 
among 15 assessments will be counted. The percentage will be calculated from the total number 
of subjects in each treatment. The incidence of SC injection site reactions will be summarized by 
treatment, time points post-injection, reaction, and severity (absent, mild, moderate, and severe). 
Injection site reaction will also be summarized by maximum severity and visit at 15 minutes, 30 
minutes and 1 hour post injection. The proportion of the most extreme reactions among 
injections throughout all 5 visits will be calculated. In addition, the overall impact on daily living 
(severity and duration) of subject's injection site reactions will also be summarized by treatment. 
A listing will also be provided. 
11.6 
Tolerability of Icatibant Therapy  
TEAEs considered related to icatibant therapy will be summarized by treatment according to 
system organ class (SOC) and preferred terms (PT).  


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12. OTHER ANALYSES 
12.1 
Pharmacokinetic and Pharmacodynamic analyses 
 Plasma concentrations will be used to perform non-compartmental analysis (NCA) as 
appropriate. Further details of the pharmacokinetic modeling and simulation will be documented 
in a PK population analysis plan (PAP). Statistical Analysis of Pharmacokinetic and 
Pharmacodynamic Data 
 All of the PK/PD analyses will be performed using the PK/PD Set. 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all PK/PD parameters 
derived by NCA, as appropriate.   
Plasma concentrations of C1 INH antigen, C1 INH functional activity, C4 and C1 q at each 
nominal sampling time with and without baseline-adjustment will also be summarized using 
descriptive statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean). 
12.2 
C1 INH Antibody 
Results of C1 INH antibody testing will be summarized by treatment and visits, and listed by 
individual subjects for the Safety Set. 
12.3 
Health-related Quality of Life Analyses 
Details of the health-related quality of life analyses will be documented in a quality of life SAP. 
The health-related quality of life analyses will be summarized using the Full Analysis Set. 
The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent 
angioedema. It consists of 17 specific questions that are associated with work, physical activity, 
free time, social relations, and food. Subjects will be asked how often they were restricted by—
as well as the difficulties and problems that could be associated with—recurrent swellings 
(angioedema) during the previous 4 weeks. The result of the AE-QoL questionnaire is specified 
as a secondary efficacy endpoint (see Section 10.3). 
The EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L) is a descriptive system of 
health-related quality of life states consisting of 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression), each of which can take 1 of 5 responses. The 
responses record 5 levels of severity within a particular dimension. Results of the EQ-5D-5L 
health status instrument will be summarized on each question using descriptive statistics in 
accordance with the EQ-5D-5L user guide (version 2.0) by treatment and visit.  
The Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire 
includes 6 questions about work and activity impairment due to health problems during the past 
7 days. Outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less work or productivity. Results of the WPAI-GH questionnaire will be 
summarized on each question using descriptive statistics by treatment and visit. 


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The Sheehan Disability Scale (SDS) is a 5-item, self-rated questionnaire designed to measure the 
extent to which a subject’s disability due to an illness or health problem interferes with 
work/school, social life/leisure activities, and family life/home responsibilities. Results of the 
SDS will be summarized on each question using descriptive statistics by treatment and visit. 
Study personnel will ask subjects specific questions regarding their utilization of health care 
resources for the management of their HAE disease. Assessment (HRUA-HAE) will be 
completed at the time points specified protocol. Study personnel will enter the survey response 
into the eCRF. Results of the HRUA-HAE will be summarized on each question using 
descriptive statistics by treatment and visit.  
12.4 
Surveys on SC Administration and Self-administration of Investigational 
Product 
Subjects will be asked to rate their overall experience in receiving twice weekly SC injections of 
investigational product. Subjects who have previously received C1 INH products via IV 
administration will be asked to indicate the preferred route for medication administration.  
Those subjects, who choose to self-administer the investigational product during Treatment 
Period 1 or 2 under supervision, will be asked specific questions about their experience with 
self-administration of SC administration of C1 INH. 
Results of the surveys for subject acceptability of SC administration and subject experience with 
self-administration of investigational product will be summarized by treatment and period using 
the Full Analysis Set. 
12.5 
Subgroup Analyses 
Subgroup analyses are planned for exploratory purposes; p-values will be presented as 
descriptive statistics. Subgroup analyses will be performed for the primary and key secondary 
efficacy endpoint 1 using the Full Analysis Set, and for the analysis of safety endpoints (AEs) 
using the Safety Set. Data will be summarized by treatment within subgroup.  
12.5.1 
Age Group 
A subgroup analysis of age will be conducted using 18 years and 64 years as cut points to 
examine the treatment effect in adolescent vs. adult subjects. 
• <18 years 
• 18-64 years 
• >= 65 years 
12.5.2 
Sex 
A subgroup analysis will be conducted to examine the treatment effect in male vs. female 
subjects. 
• Male 
• Female 


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12.5.3 
Race Group 
Subgroup analyses will be conducted by race to examine the treatment effect in White vs. those 
subjects of other races. 
• White 
• Other Races 
12.5.4 
Use of Prophylactic therapy with C1 INH at Randomization 
Subgroup analyses will be conducted by prophylactic therapy with C1 INH at randomization 
(defined as taken within 5 days prior to randomization). 
• Use of prophylactic therapy with C1 INH at randomization: Yes 
• Use of prophylactic therapy with C1 INH at randomization: No 
12.5.5 
Use of Prophylactic Therapy with C1 INH or Androgens Prior to 
Screening 
Subgroup analyses will be conducted by prophylactic therapy with C1 INH or androgens prior to 
screening for the primary endpoint only. 
• Use of prophylactic therapy with C1 INH or androgens prior to screening: Yes 
• Use of prophylactic therapy with C1 INH or androgens prior to screening: No 
12.5.6 
Long-Term Prevention at Randomization 
Subgroup analyses will be conducted by long-term prevention at randomization. 
• Any long-term prevention 
• C1 INH prophylaxis 
• Oral Androgen 
• Oral other 
• No long-term prevention 
12.5.7 
Region 
Subgroup analyses will be conducted by region. 
• North America 
• Europe 
12.5.8 
Location 
Subgroup analyses will be conducted by location. 
• Upper airway (includes laryngeal or pharyngeal) 
• Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, swelling, 
and/or change in bowel habits) 


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• Genitourinary (including scrotum or vulva) 
• Cutaneous (facial) 
• Cutaneous (extremity, peripheral, or torso [eg, buttocks, external head/neck, trunk])   
• Non upper airway 
12.5.9 
Mucosal and Non-Mucosal Location 
Subgroup analyses will be conducted by mucosal and non-mucosal location. 
• Mucosal 
• Non-mucosal 
• Both mucosal and non-mucosal 


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13. INTERIM ANALYSIS 
There is no planned interim analysis in this study. 
 


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14. DATA MONITORING/REVIEW COMMITTEE 
There is no planned data monitoring committee in this study. 
 


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15. COMPUTER METHODS  
All statistical analyses will be performed using SAS Version 9.2 or higher (SAS Institute, 
, 
) on a suitably qualified environment. 
 
PPD
PPD


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16. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Not applicable. 
 
 
 


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17. DATA HANDLING CONVENTIONS 
17.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, SD, 
median, minimum, and maximum. Categorical and count variables will be summarized by the 
number of subjects (n) and the percent of subjects in each category.   
Unless specified otherwise, min/max will be presented to the same decimal places as the raw 
data. Percentage, mean and median will be presented to 1 more decimal places than the raw data. 
Standard deviation and standard error will be presented to 2 more decimal places than the raw 
data. 
In addition, p-values will generally be presented to 4 decimal places; values less than 0.0001 will 
be presented as <0.0001. 
Treatment Columns Displayed in Summary Tables 
The treatment columns displayed will differ between summary tables. Tables that summarize 
information only from the prior treatment or post-treatment periods will generally have the 
following treatment columns displayed:   
Sequence A/B 
Sequence B/A 
Sequence A/A 
Total 
Tables that summarize efficacy and safety information only from the treatment period will 
generally have the following treatment columns displayed: 
Treatment A: 2000 IU C1 INH 
Treatment B:  Placebo 
Total (if needed) 
Tables that summarize efficacy and safety information from the treatment period and treatment 
sequence will generally have the following treatment columns displayed: 
Sequence A/B: Period 1: 2000 IU C1 INH 
Sequence A/B: Period 2: Placebo 
Sequence B/A: Period 1:  Placebo  
Sequence B/A: Period 2: 2000 IU C1 INH 
Sequence A/A: Period 1: 2000 IU C1 INH  
Sequence A/A: Period 2: 2000 IU C1 INH 


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Tables that summarize efficacy and safety information from the treatment period with different 
treatment sequence combinations will generally have the following treatment columns displayed: 
Treatment A from Sequence A/B and B/A: 2000 IU C1 INH 
Treatment A from Sequence A/A: 2000 IU C1 INH 
Treatment A Overall: 2000 IU C1 INH 
Treatment B: Placebo 
17.2 
Derived Efficacy Variables  
Details on normalized efficacy variables: cumulative attack severity, cumulative daily severity, 
number of attack-free days, number of angioedema attacks requiring acute treatment and 98-day 
AAS are provided in the Appendix. 
17.3 
Repeated or Unscheduled Assessments of Efficacy and Safety Parameters 
If a subject has repeated assessments before the date and time of the first dose of investigational 
product, then last assessment prior to or on the date and time of the first dose of treatment period 
1 will be used as baseline. If clinical discharge assessments are repeated or unscheduled, the last 
assessment will be used as the clinical discharge assessment for generating descriptive statistics. 
However, all post-baseline assessments will be used for post-baseline overall PCI value 
determination, and all assessments will be presented in the data listings.  
For repeated and/or unscheduled assessments, the assessment that is following the rules in the 
next section will be used for efficacy and safety analysis. However, all visit data (including 
repeated and unscheduled) will be included in subject data listings. 
17.4 
Termination visits for patients who discontinued investigational product or 
study early 
For assessments collected by visits (laboratory parameters, ECG variables, vital signs 
parameters, scheduled questionnaire, etc), the nominal visits (CRF visits) will be used in the by-
visit summaries. Only laboratory data from available visits for these assessments will be used in 
the analysis according to the following order:  
• First, if the scheduled visit assessments exist, they will be used in the analysis; 
• Second, if the scheduled visit assessments do not exist but the remapped visit assessments 
from TERMINATION visit exist, these assessments will be used in the analysis; 
• Third, if both the scheduled visit assessments and the remapped visit assessments from 
termination visit do not exist but unscheduled visit assessments exist, then these assessments 
will be used in the analysis.  
The termination visits for patients who discontinue the investigational product prematurely, are 
not time point specific visits. In addition to serve as the last on study assessment, they will also 
be remapped to nominal visits based on the following rules: 


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• If these visits fall into a specific visit window and the corresponding scheduled visit is 
missing, then these visits will be remapped to be that scheduled visit. The visit windows are 
defined relative to study day (if visit exists) or target day (if visit does not exist) as follows 
• ± 3 days for visits that occur every week 
• ± 7 days for visits that occur every other week 
• ± 14 days for monthly visits 
• ± 45 days for all quarterly visits 
17.5 
Missing Date of Investigational Product 
If the date of the last dose of investigational product is missing for a subject in the Safety Set, all 
efforts should be made to obtain the date from the investigator. If it is still missing after all 
efforts, then the last visit date when investigational product was returned will be used in the 
calculation of treatment duration.  
17.6 
Missing Date Information for Prior and Concomitant Medications  
For prior and concomitant medications, incomplete (i.e., partially missing) start dates and/or stop 
dates will be imputed. When the start date and the stop date are both incomplete for a subject, the 
start date will be imputed first.  
17.6.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
• Missing day, month and year 
- 
The start date will be set to null. 
• Missing day and month 
- 
01 January will be assigned to the missing fields. 
• Missing day only 
- 
The first day of the month will be assigned to the missing day. 
17.6.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date. 
• Missing day, month and year 
- 
The day, month and year of the last date on study will be assigned to the missing fields. 


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• Missing day and month 
- 
If the year of the incomplete stop date is the same as the year of the last date on study, 
then the day and month of the last date on study will be assigned to the missing fields. 
- 
If the year of the incomplete stop date is not the same as the year of the last date on study, 
then 31 December will be assigned to the missing fields. 
• Missing day only 
- 
If the month and year of the incomplete stop date are the same as the month and year of 
the last date on study, then the day of the last date on study will be assigned to the 
missing day. 
- 
If the month and year of the incomplete stop date are not the same as the month and year 
of the last date on study, then the last day of the month will be assigned to the missing 
day. 
17.7 
Missing Date Information for Adverse Events  
17.7.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
• Missing day, month and year 
- 
The day, month and year of the date of the first dose of investigational product will be 
assigned to the missing fields. 
• Missing day and month 
- 
If the year of the incomplete start date is the same as the year of the date of the first dose 
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields. 
- 
If the year of the incomplete start date is not the same as the year of the date of the first 
dose of investigational product, then 01 January will be assigned to the missing fields. 
• Missing day only 
- 
If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day.If the month and year 
of the incomplete start date are not the same as the month and year of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day. 


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17.7.2 
Incomplete Stop Date  
No imputation is needed for AE stop dates. 
17.8 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting before the date of the first dose of the investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
on or after the date of the first dose of the investigational product, then a severity of “Severe” 
will be assigned.  The imputed values for severity assessment will be used for incidence 
summaries, while the actual values will be used in data listings.  
17.9 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date of 
the dose of the investigational product, a causality of “Related” will be assigned.  The imputed 
values for relationship to the investigational product will be used for incidence summaries, while 
the actual values will be presented in data listings. 
17.10 
Character Values of Clinical Laboratory Variables  
If a character value collected from the CRF contains “>” sign, the numeric value used in the 
analysis will be calculated from the numeric part of the collected value times 2. For example, 
given a collected clinical laboratory result of “> 75”, the numeric value used in the analysis will 
be 150. 
If a character value collected from the CRF contains “<” sign, the numeric value used in the 
analysis will be calculated from the numeric part of the collected value divided by 2. For 
example, given a collected clinical laboratory result of “< 120”, the numeric value used in the 
analysis will be 60. 
17.11 
Handling Missing HAE Attack Data 
If there are incomplete attack start/end dates in the collected data, the following imputations will 
be performed in a sequential order of the incomplete dates within each subject. This is to ensure 
that multiple identical incomplete dates will be imputed as separate attacks. 
• Imputation of start date for an attack: 
- 
If the attack start day is unknown and there is no previous attack in the same month, the 
first day of the month will be assigned to the missing field. 
- 
If the attack start day is unknown and there is at least one previous attack in the same 
month, the previous attack end date + 1 will be assigned to the missing field. 
• Imputation of end date for an attack: 
The imputation of end date for an attack will follow one of the following 3 rules, 
whichever is the earliest: 


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- 
The start date of the current attack + 6 if attack end date is partially or completely 
missing. 
- 
The start date of the next attack – 2 if attack end date is partially or completely missing. 
- 
The last day of the month if attack end date is partially missing with missing day only. 


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18. TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS 
The Mock TFLs will be provided in a separate document. 


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19. APPENDIX 
19.1 
Derivations of efficacy endpoints related to angioedema attacks 
The derivations of efficacy endpoints are demonstrated using the following hypothetical 
example.  
Study 
Day 
Symptoms 
Present 
Maximuma 
Symptom 
Severity  
Symptom 
Severity 
Score 
Attack 
Number 
Maximumb 
Attack 
Severity  
Daily 
Severity  
1 
Yes 
Moderate 
2 
1 
- 
2 
2 
Yes 
Moderate 
2 
 
2 
2 
3 
No 
 
 
 
 
 
4 
Yes 
Mild 
1 
2 
- 
1 
5 
Yes 
Severe 
3 
 
- 
3 
6 
Yes 
Moderate 
2 
 
3 
2 
7 
No 
 
 
 
 
 
8 
Yes 
Moderate 
2 
3 
- 
2 
9 
Yes 
Severe 
3 
 
- 
3 
10 
Yes 
Moderate 
2 
 
- 
2 
11 
Yes 
Moderate 
2 
 
3 
2 
a: 
Maximum Severity across all anatomic locations on the corresponding study day. 
b: 
Maximum Severity across all anatomic locations and days with symptoms for the corresponding attack. 
In this hypothetical example, a patient recorded 9 days of symptoms in an 11-day study period.  
Because individual attacks require at least one symptom-free calendar day between episodes, this 
diary fragment identifies 3 angioedema attacks.  The maximum severity of each attack is 
determined on the last day of symptoms and is derived as Mild, Moderate, or Severe.  Coding 
these categories as Mild=1, Moderate=2, and Severe=3 and summing over the three unique 
attacks, yields a Cumulative Attack Severity of 8.  Finally, summing the reported severity scores 
over the 9 days with symptoms yields a Cumulative Daily Severity of 19.  With respect to these 
defined endpoints, this hypothetical eleven-day symptom diary would be quantitatively described 
by: 
 


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Endpoint 
Value 
Number of Angioedema Attacks 
3 
Cumulative Attack Severity 
8 
Cumulative Daily Severity 
19 
For the secondary efficacy variables of Cumulative Attack Severity, Cumulative Daily Severity, 
Number of attack-free days during a treatment period, Number of angioedema attacks requiring 
acute treatment during a treatment period and 98-day AAS, the normalized numbers (per month) 
calculated by following steps will be used in the analyses. 
19.2 
Derivation of normalized efficacy endpoints  
Any subject who completes a treatment period should provide data with which to derive efficacy 
scores. Thus, for each individual treatment period, the normalized efficacy scores are calculated as 
below: 
Xi = Number of days of participation in that treatment period for Subject i, 
 
Yi = RAW Efficacy Score expressing the cumulative period score for Subject i,  
Y*i = NORMALIZED Efficacy Score for Subject i, (the normalized score expressed as score 
per Month), which is calculated as (Yi / Xi) * 30.4 
19.3 
Angioedema Quality of Life Questionnaire – American English Version 2012 
Instructions for evaluation of the AE-QoL 
 
The structure of AE-QoL 
AE-QoL consists of four dimensions and a total score 
Functioning 
1. Impairment of work 
2. Impairment of physical activity 
3. Impairment of spare time activities 
4. Impairment of social relations 
 
Fatigue/Mood 
6. Difficulties of falling asleep 
7. Waking up during the night 
8. Feeling tired during the day 
9. Difficulties in concentrating 


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10. Feeling downhearted 
 
Fears/Shame 
12. Feeling burdened at having swellings 
13. Fear of new suddenly appearing swellings 
14. Fear of increased frequency of swellings 
15. Ashamed to visit public places 
16. Embarrassed by the apppearence of swellings 
17. Fear of long term negative drug effects 
 
Nutrition 
5. General limitations in foods and eating 
11. Limitations in the selection of food and beverages 
 
Total Score  
Items 1 to 17 
 
How to calculate AE-QoL scales and the AE-QoL total score 
 
AE-QoL is meant to be evaluated by using its four individual dimensions (profile instrument) but 
is can also be used to determine a total score (index instrument): 
The AE-QoL dimension scores as well as the AE-QoL total score are calculated by using the 
following formula: 
(Ȉ items – min Ȉ items / max Ȉ items – min Ȉ items) x 100 
Example: 
Dimension “Functioning”: 
Item 1: answer 3 
Item 2: answer 2 
Item 3: answer 4 
Item 4: answer 5 
Ȉ items: (3+2+4+5) = 14 
min Ȉ items: (1+1+1+1) = 4 
max Ȉ items: (5+5+5+5) = 20 
Enter values in formula: (14 - 4 / 20 – 4) x 100 = 62.5% 
 
The AE-QoL dimension scores correspond to the mean of the items within each dimension. If 
some items are missing, the total of the items within the dimension is divided by the number of 
the non missing items. 
The same holds for the AE-QoL total score. 
An AE-QoL dimension score should not be calculated if more than one item is missing in that 
dimension. 


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The AE-QoL total score should not be calculated if more than 25% of items (>4 items) are 
missing. 
Please note that only calculating the raw dimension scores (mean of the item scores within each 
scale) and the raw total score score (mean of all item scores) would be easier than the above 
described procedure. However, in case of missing answers, an interindividual as well as an 
intraindividual comparison of AE-QoL results would be limited. The above described linear 
transformation of all raw scores into percentage scores (indicating the location of the raw scores 
in relation (in percent) to its maximum possible score) solves this problem and makes it possible 
to judge and compare AE-QoL results even when single items are missing. The linear 
transformation of raw scores results in minimal and highest possible scale and total scores of 0 
and 100, respectively. 
19.4 
Major Protocol Deviations 
The following protocol deviations are classified as major protocol deviations that may affect the 
primary efficacy endpoint. Subjects who satisfy these protocol deviations will be excluded from 
the Per-protocol Set. 
1. Subject <12 years and subject was randomized into the study (I1) 
2. Subject was NOT diagnosed by a physician to have HAE (Type I or II) and subject was 
randomized into the study (I2)  
3. Subject was NOT diagnosed by a physician to have a functional C1 inhibitor (C1 INH) 
level less than 50% of normal and subject was randomized into the study (I2)  
4. Adult subject currently receiving prophylactic therapy with C1 INH, NOT having a 
history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to starting prevention therapy and subject was randomized into the study (I3) 
5. Subject (>12 years of age) not receiving prophylactic therapy with C1 INH, NOT having 
a history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive 
months prior to the screening visit and subject was randomized into the study (I3) 
6. Adult subject currently receiving a stable dose of attenuated androgens, NOT having a 
history of ≥2.0 angioedema attacks per month (average) during the 3 consecutive months 
prior to the screening visit and subject was randomized into the study (I3). 
7. Adults (>18 years of age) receiving prophylactic IV CINRYZE that exceeds the approved 
dosing regimen of 1000 U every 3 or 4 days (receiving a weekly dose >2000 U). (E1) 
8. Adolescents (>12 and <18 years of age) currently receiving prophylactic therapy with C1 
INH. (E2) 


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9. Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1. (E4) 
10. If female, have started or changed the dose of any hormonal contraceptive regimen or 
hormone replacement therapy (ie, estrogen/progestin containing products) within 2 
months prior to the screening visit. (E5) 
11. Have a history of hypercoagulability (abnormal blood clotting) or other predisposition for 
thromboembolism. (E6) 
12. Have a diagnosis of acquired angioedema or known presence of anti-C1 INH antibodies. 
(E7) 
13. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), or other blood products. (E8) 
14. Be pregnant or breastfeeding. (E9) 
15. Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. (E10) 
16. Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. (E11) 
17. Subject administered “damaged” IP (e.g., IP with unapproved temperature excursion) 
18. Calculated study drug compliance of <85% among subjects whose treatment duration is 
at least 6 weeks in the treatment period.  
19. Subject missed ≥ 3 consecutive doses 
20. Subject was randomized but did not receive study drug 
21. Investigator did not complete a separate angioedema attack CRF for each attack based 
upon their review of the data in the subject eDiary. 
22. Concomitant use of Use of C1 INH therapy (other study drug) for prophylaxis against 
angioedema attacks after randomization upto 1 wk FU period 
23. Initiation of long term therapy (including IV C1-INH, Transexamic acid or androgen 
therapy) after randomization upto the last dose 
24. Change in dose of hormonal contraceptive regimen or hormone replacement therapy (ie, 
estrogen/progestin containing products) after randomization 


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25. Study drug is restarted later than 30 days of the temporary interruption after a 
Thrombotic/Thrombo-embolic event 
26. Accidental Unblinding 
27. Subject receiving 3 or more consecutive doses of incorrect treatment assigned by IXRS 
28. Study drug exposed to temperature excursion (deemed unusable by Shire) dispensed to 
subject with reported AEs being associated with the exposed drug in the opinion of the 
PI. 
 
 
 


HRQoL STATISTICAL ANALYSIS PLAN
Protocol No.:
SHP616-300
Project No.:
0238-0431
Protocol Title:
A Phase 3, Randomized, Double-blind, Placebo-
controlled, Two-period, Three-sequence, Partial 
Crossover Study to Evaluate the Efficacy and 
Safety of Subcutaneous Administration of 2000 IU 
of C1 Esterase Inhibitor [Human] Liquid for 
Injection for the Prevention of Angioedema Attacks 
in Adolescents and Adults with Hereditary 
Angioedema: Assessment of Health-related Quality 
of Life (HRQoL)
Drug:
SHP616, C1 esterase inhibitor [human] liquid for 
injection
Sponsor: 
Shire Development LLC and International 
Affiliates
300 Shire Way, Lexington, MA  02421 USA
Version No. and Date:
Version 0.6, Date 22 August 2017
Version No:
Document History
Description of Update
Author(s)
Effective Date
0.1
Original Draft
, 
 20 Oct 2016
0.2
Review and comments
, 
, 
 
8 May 2017
0.3
Revisions
, 
 19 May 2017
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Version No:
Document History
Description of Update
Author(s)
Effective Date
0.4
Revisions
, 
, 
 
7 July 2017
0.5
Revisions
, 
, 
 
21 Aug 2017
0.6
Revisions
22 Aug 2017
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................3
LIST OF IN-TEXT TABLES ..........................................................................................................5
LIST OF IN-TEXT FIGURES.........................................................................................................5
ABBREVIATIONS .........................................................................................................................6
1.
INTRODUCTION....................................................................................................................7
2.
STUDY DESIGN .....................................................................................................................7
2.1
Study Design Overview .............................................................................................7
2.2
The Cross-over Design...............................................................................................8
2.3
Study Design Considerations .....................................................................................9
3.
ANALYSIS OBJECTIVES....................................................................................................10
3.1
Analysis of PRO data ...............................................................................................10
3.2
Analysis of HRUA-HAE data..................................................................................11
4.
STUDY MEASURES.............................................................................................................11
4.1
Responder Definition (RD) ......................................................................................11
4.2
PRO Measures and Scoring......................................................................................11
4.2.1
Angioedema Quality of Life (AE-QoL) Questionnaire.........................................11
4.2.2
EuroQol 5-dimensional 5-level (EQ-5D-5L) descriptive system and EQ 
Visual Analogue Scale (EQ-VAS).........................................................................12
4.2.3
Work Productivity and Activity Impairment – General Health (WPAI-GH)........12
4.2.4
Sheehan Disability Scale (SDS).............................................................................13
4.2.5
Angioedema Activity Score (AAS) .......................................................................13
4.2.6
Healthcare Resource Utilization Assessment related to HAE (HRUA-HAE).......13
4.3
Study Assessments ...................................................................................................14
5.
DATA MANAGEMENT .......................................................................................................19
5.1
Data Handling Considerations..................................................................................19
5.1.1
Data Analysis Populations.....................................................................................19
5.1.2
Baseline data..........................................................................................................19
5.1.3
Missing Data..........................................................................................................19
5.2
Variables...................................................................................................................19
6.
STATISTICAL ANALYSIS ..................................................................................................21
6.1
Distributional Considerations...................................................................................21
6.2
Descriptive Statistics................................................................................................21
6.3
Statistical Tests.........................................................................................................22
6.4
Data Analysis ...........................................................................................................22
6.4.1
Analysis of PRO data.............................................................................................22
6.4.2
Analysis of HRUA-HAE data................................................................................27


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7.
REFERENCES .......................................................................................................................29
8.
LIST OF TABLES..................................................................................................................30
9.
LIST OF FIGURES ................................................................................................................37
10. PROGRAMMING CONVENTIONS ....................................................................................39
10.1
Study Measure Scoring ............................................................................................39
10.1.1 Angioedema Quality of Life (AE-QoL) Questionnaire.........................................39
10.1.2 EuroQol 5-dimensional 5-level (EQ-5D-5L) Descriptive System and EQ 
Visual Analogue Scale (EQ-VAS).........................................................................39
10.1.3 Work Productivity and Activity Impairment – General Health (WPAI-GH)........39
10.1.4 Sheehan Disability Scale (SDS).............................................................................40
10.1.5 Angioedema Activity Score (AAS) .......................................................................40
10.1.6 Healthcare Resource Utilization Assessment related to HAE (HRUA-HAE).......40
10.2
Calculating Change in Scores ..................................................................................41
10.3
Responder Definition Variables...............................................................................41
10.4
Dummy Variable for Carry-over Effect...................................................................42
10.5
Explanation of the Standard Deviation Rule............................................................42


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LIST OF IN-TEXT TABLES
Exhibit A:
Treatment Sequences............................................................................................8
Table 1:
Schedule of Assessments – Study period 1........................................................15
Table 2:
Schedule of Assessments – Study period 2........................................................17
Exhibit C: 
Variables to be used in the analyses...................................................................20
LIST OF IN-TEXT FIGURES
Exhibit B: 
Study Design Flow Chart .....................................................................................9


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ABBREVIATIONS
AAS
Angioedema Activity Score
AE-QoL
Angioedema Quality of Life (questionnaire)
AUC
Area Under the Curve
EQ-5D-5L
EuroQol 5-Dimensional 5-Level Descriptive System
EQ-VAS
EuroQol Visual Analogue Scale
HAE
Hereditary Angioedema
HRU
Healthcare Resource Utilization
HRUA-HAE
Healthcare Resource Utilization Assessment related to HAE
HRQoL
Health Related Quality of Life
MCID
Minimal Clinical Important Difference
MDC95
Minimal Detectable Change with 95% confidence
NNA
Normalized Number of Attacks
PRO
Patient Reported Outcome
RD
Responder Definition
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SDS
Sheehan Disability Scale
SE
Standard Error
SEM
Standard Error of Measurement
VAS
Visual Analogue Scale
WPAI-GH
Work Productivity and Activity Impairment - General Health (questionnaire)


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) outlines the analyses to be conducted on the Patient 
Reported Outcome (PRO) data for Study SHP616-300: A Phase 3, randomized, double-blind, 
placebo-controlled, two-period, three-sequence, partial crossover study to evaluate the efficacy 
and safety of subcutaneous (SC) administration of 2000 IU of C1 esterase inhibitor [human] 
liquid for injection for the prevention of angioedema attacks in adolescents and adults with 
hereditary angioedema (HAE). Specifications for PRO tables and figures will be provided in a 
separate document.
The primary efficacy endpoint in SHP616-300 is the normalized number of angioedema attacks 
(NNA) during a treatment period, measured as observed. The impact of treatment on health 
related quality of life (HRQoL), health status, work, and activity impairment due to health, 
disability, and disease symptoms were assessed as secondary endpoints using several PROs:
Angioedema Quality of Life Questionnaire (AE-QoL), EuroQol 5-dimensional 5-level (EQ-5D-
5L) descriptive system, and the EuroQol Visual Analogue Scale (EQ-VAS), Work Productivity 
and Activity Impairment Questionnaire - General Health (WPAI-GH), Sheehan Disability Scale 
(SDS), and Angioedema Activity Score (AAS). Healthcare resource utilization (HRU) data are 
also collected as part of the study. This document outlines the analyses to be conducted on the 
PRO and HRU data.
2.
STUDY DESIGN
2.1
Study Design Overview
Data will be collected in Study SHP616-300, a phase 3, randomized, double-blind, placebo-
controlled, two-period, three-sequence, partial crossover study to evaluate the efficacy and safety 
of SC administration of 2000 IU of C1 esterase inhibitor [human] liquid for injection for the 
prevention of angioedema attacks in adolescents and adults with HAE. The trial uses a partial 
Balaam’s cross-over study design with two periods (each lasting 14 weeks), two treatments 
(active and placebo), and three treatment sequence groups (Exhibit A). The Study Design Flow 
Chart is shown in Exhibit B.
This multicenter study is being conducted at approximately 40 sites globally (North America and 
EMEA). The study aims to screen 75 subjects, enroll 66, and ensure that 54 subjects complete 
both study periods. Treatment sequence groups 1 (AB) and 2 (BA) will each contain 26 subjects, 
with treatment sequence 3 (AA) containing 14 subjects. 


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Exhibit A: Treatment Sequences
Treatment Sequence
Treatment 
Period 1
Treatment 
Period 2
Approximate Number of 
Subjects Randomized
1 (AB)
A
B
26
2 (BA)
B
A
26
3 (AA)
A
A
14
Treatment A: 2000 IU (4.0 mL) C1 esterase inhibitor [human] liquid for injection administered SC twice weekly (every 3 or 4 
days) for 14 weeks. 
Treatment B: Placebo (4.0 mL) administered SC twice weekly (every 3 or 4 days) for 14 weeks.
2.2
The Cross-over Design
A cross-over design is one in which the effects of different treatments (here C1 esterase inhibitor 
[human] liquid for injection and placebo) are compared on the same subject during different 
study periods. This study design was chosen as the best way to jointly address the protocol 
objectives of establishing efficacy (relative to placebo) and safety (i.e., adequate numbers of 
subjects for precision of estimation in detecting potential safety signals). An advantage of such a 
design is that a comparison of treatments on the same subject is expected to be more precise than 
a comparison between subjects and therefore to require fewer subjects for the same precision. 
The simple analysis of a cross-over trial assumes that the effect of treatment is the same during 
each study period, i.e., that the effect of any treatment given during the second period is not 
influenced by the treatment received in the first. This assumption, no interaction between 
treatment and period, can be tested. Hills and Armitage (1979) provide a comprehensive 
overview of the fundamentals of cross-over trial design and analysis.


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Exhibit B: 
Study Design Flow Chart
2.3
Study Design Considerations
The present trial uses a partial Balaam’s cross-over study design with two periods (each lasting 
14 weeks), two treatments (active and placebo), and three treatment sequence groups: AB, BA, 
AA (Exhibit A). Balaam (1968) proposed a design-based approach to assess the problem of 
carry-over effects, by pointing out that if the AB/BA design were extended to include the 
sequences AA and BB, then within-subject estimates of a direct treatment effect could be 
obtained even in the presence a carryover effect. However, Balaam's design was able to achieve 
this because it assumed a particular model for the carryover effect which no longer enjoys wide 
support (Senn, 2002). The Balaam’s design is typically chosen to when it is hypothesised that 
there is a self-carryover effect, i.e., the response during the second period on the same treatment 
is affected by the response during the first study period, or when there is a treatment by period 
interaction. In this study, a partial Balaam’s design is used, in the absence of a BB sequence 
group; the Balaam’s design is not completely balanced. The Balaam’s design is particularly 
relevant since there will be no washout between the 2 study periods, each of 14 weeks. The 
omission of a washout period is to minimize the duration that subjects will be without active 
treatment.
In this trial, there are six-sequence by period means, two in each treatment sequence group (AB, 
BA, and AA). The five resulting degrees of freedom can be decomposed into 2 for sequence, 1 
for treatment, 1 for period, and 1 for carryover. In the trial, the primary efficacy endpoint will be
analyzed (in the subjects in the Full Analysis Set randomised to the AB/BA groups) by using a 


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mixed effect linear model with period, sequence, stratification factor (use of prophylactic therapy 
with C1 INH, which was derived by long-term prevention with C1 INH at randomization), and 
treatment as fixed effects, and subject nested within sequence as a random effect. The mean 
treatment difference (µ C1 INH - µ placebo) will be estimated with a 95% CI provided. The main 
analytic approach for the analysis of the PRO data will be similar and include only subjects 
randomised to the AB/BA groups, unless specified in the analyses section.
(Note: The Full Analysis Set is all subjects who have taken at least 1 dose of investigational 
product (the Safety Set) who have at least 1 post baseline (e.g., randomization) primary efficacy 
assessment.)
The trial was powered to demonstrate superior efficacy even in the presence of carryover effects. 
To assess any carryover effect, a sensitivity analysis excluded from the evaluation of the NNA 
any attacks occurring within the first 2 weeks of Study period 2 for both sequences when 
carryover is suspected to be maximal. Since carryover should occur only with the A/B treatment 
sequence, its effect (if present) will be to spread C1 esterase inhibitor [human] liquid for 
injection efficacy into the placebo study period, thereby diluting the efficacy of C1 INH and 
favouring the null hypothesis of the primary efficacy analysis; it is not anticipated that any 
placebo effect will similarly benefit C1 esterase inhibitor [human] liquid for injection within the 
B/A treatment sequence.
3.
ANALYSIS OBJECTIVES
3.1
Analysis of PRO data
The main objectives of the analyses of the PRO data collected in SHP616-300 are:
1. To describe AE-QoL, WPAI-GH, SDS, and AAS scores by treatment and period (absolute, 
change and percentage change from baseline at each scheduled visit for AB, BA, and AA 
sequences) and assess differences between treatments (A or B), controlling for study period 
(1 or 2) and sequence (AB, BA) (change and percentage change).
2. To describe and estimate whether the effect of an attack on EQ-5D-5L index and EQ-VAS 
scores differs between treatments (A or B), controlling for study period (1 or 2) and sequence 
(AB, BA).
3. To describe and assess differences in the proportion of subjects achieving the responder 
definition (RD) in AE-QoL and AAS scores from baseline to final assessment between
treatments (A or B), controlling for study period (1 or 2) and sequence (AB, BA).
The exploratory objective is:
1. To explore the relationship between efficacy (as defined in the protocol) and scores on the 
AE-QoL, WPAI-GH, SDS, and AAS (Hypothesis: Subjects with improved efficacy also have 
improved scores).


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3.2
Analysis of HRUA-HAE data
The main objective of the analysis of the HRUA-HAE data collected in SHP616-300 is:
1. To describe HRUA-HAE (absolute values) according to treatment, study period (1 or 2) and 
sequence (AB, BA).
4.
STUDY MEASURES
4.1
Responder Definition (RD)
A RD is the absolute change value, at an individual patient level, which indicates that a 
meaningful change in a PRO instrument score has occurred. 
When no RD has been estimated, it has been proposed that a one-standard error measurement 
(one-SEM) criterion, or equivalently 0.5 standard deviations (SDs) when the reliability of the 
instrument is ≥0.75, can be used as a proxy for minimal change (Norman et al., 2003). This 
distribution-based method provides the smallest change which, for an individual, is likely to be 
beyond the measurement error of the instrument, thus understood to represent true change. 
However, it is not known whether this change is clinically relevant. While not acceptable as a 
RD in itself, this distribution-based approach provides boundary information as any value 
proposed as a RD will need to be at least as large to rule out the possibility of responder 
classification occurring by chance.
In the absence of any known RDs in the HAE, or any other population, RDs for minimal change 
will be estimated using one-half a SD in the study baseline (Visit 1a) AE-QoL, EQ-5D-5L and 
AAS scores. It is reasonable to assume that these instruments have reliabilities of ≥0.75. This 
estimate is based on the distributional characteristics of the sample under study. In addition, a 
number of pre-defined values (based on existing estimates for the minimal clinically important 
difference (MCID) or RD) will be applied in a sensitivity type analysis.
4.2
PRO Measures and Scoring
4.2.1
Angioedema Quality of Life (AE-QoL) Questionnaire
The AE-QoL questionnaire is a self-administered validated angioedema disease-specific quality 
of life instrument (Weller et al., 2012). Each of the 17 items has a five-point response scale 
ranging from 1 (Never) to 5 (Very Often). The questionnaire will be scored according to the 
developers’ guidelines (Weller et al., 2012) to produce a total score and four domain scores
(functioning, fatigue/mood, fear/shame, nutrition). Raw domain scores (mean of the item scores 
within each scale) and the raw total score (mean of all item scores) will be rescaled using linear 
transformations into final percentage scores ranging 0 to 100, based on the maximum possible 
score, where the higher the score the greater the QoL impairment. The minimal clinically 
important difference (MCID) for the total score is 6 (Weller et al., 2016). However, there is no 
evidence on the MCID/RD for the AE-QoL domain scores. Therefore, in addition to applying the 


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value of 6 for the total score, the method of using 0.5 SD in baseline domain scores will be used 
to determine the RD:

Rescaled AE-QoL total score =  6, Baseline SD*0.5

Rescaled AE-QoL functioning domain score = 6, Baseline SD*0.5

Rescaled AE-QoL fatigue/mood domain score = 6, Baseline SD*0.5

Rescaled AE-QoL fear/shame domain score = 6, Baseline SD*0.5

Rescaled AE-QoL nutrition domain score = 6, Baseline SD*0.5
4.2.2
EuroQol 5-dimensional 5-level (EQ-5D-5L) descriptive system and EQ 
Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L is a standardized measure of health status comprised of a descriptive system 
including five health-related quality of life states (i.e., mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a VAS of overall health. Each dimension is rated 
on a 5-point response scale indicating severity of problems, where 1 is “no problems” and 5 is 
“extreme problems”. The five questions are scored and together contribute to the EQ-5D-5L
index (utility) score between 0 and 1 (1 being perfect health), which will be calculated using the 
developers’ algorithm based on country-specific reference score sets (Van Hout et al., 2012). 
Score sets are available for Denmark, France, Germany, Japan, Netherlands, Spain, UK, US and 
Zimbabwe. For countries in which no score set exists (Canada, Hungary, Israel, Romania, and 
Sweden) the closest neighboring country will be used as a proxy (EuroQol Group, 2015).
The EQ-VAS is a measure of overall self-rated health status, used and analyzed separately from 
the index score. The EQ-VAS records the subject’s self-rated health on a 20-cm vertical VAS 
with endpoints labelled “the best health you can imagine” and “the worst health you can 
imagine”. The EQ-VAS score ranges from 0 to 100, with higher scores indicative of better 
overall health. 
4.2.3
Work Productivity and Activity Impairment – General Health (WPAI-GH)
The WPAI-GH is a 6-item questionnaire assessing work and activity impairment due to health 
problems during the past 7 days.  It will be scored for each assessment according to the scoring 
guidelines listed below (Reilly et al., 1993). The instrument elicits four main scores in relation to 
general health specifically: absenteeism (the percentage of work time missed because of one's 
health in the past seven days), presenteeism (the percentage of impairment experienced while at
work in the past seven days because of one's health), overall work productivity loss (an overall 
impairment estimate that is a combination of absenteeism and presenteeism), and activity 
impairment (the percentage of impairment in daily activities because of one's health in the past 
seven days) (Reilly et al., 1993).  The domains are calculated as follows:
1. Absenteeism (work time missed = (Q2/(Q2+Q4))*100)
2. Presenteeism (impairment at work or reduced on-the-job effectiveness = (Q5/10)*100)
3. Work productivity loss (overall work impairment/absenteeism plus presenteeism = 
(Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)])*100)
4. Activity Impairment = ((Q6/10)*100)


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The scores are percentages with higher values indicating greater percentage impairment.
4.2.4
Sheehan Disability Scale (SDS)
The SDS is a 5-item, self-rated questionnaire designed to measure the extent to which a person’s 
disability due to an illness or health problem interferes with each of the following three 
dimensions: work/school, social life/leisure activities, and family life/home responsibilities 
(Sheehan, 1983). Three items ask subjects to rate the extent to which three aspects of daily life
are impaired by his or her symptoms using a 10-point scale. Two items ask subjects how many 
days have been lost or unproductive in the last week. A total global functioning impairment score 
is calculated as the sum of the three individual dimensions, ranging from 0 (unimpaired) to 30
(highly impaired), with higher scores indicative of greater impairment. The raw numerical scores 
will also be rescaled to a percentage of the maximum score (Sheehan, 1983). Higher scores show 
greater impairment.
4.2.5
Angioedema Activity Score (AAS)
The AAS collects information of disease activity in the last 24 hours. The following items are 
assessed: experience of swelling, severity of the swelling, timing of the swelling, extent of 
discomfort due to the swelling, extent that the swelling caused limitations in daily life, and 
feelings of being disfigured by the swelling. The instrument uses a binary response option for the 
first item and a three-point response scale for the 5 items thereafter. Total scores range between 0 
and 15 points (Weller et al., 2013). The total disease activity score for the duration of an entire 
study period is the sum of each daily score post-treatment in each 14-week study period – the 98-
day AAS. The weekly average daily disease activity scores will also be calculated for each study 
week, and compared with the baseline day score, for each study period. An overall daily average 
AAS score will also be calculated for each study period.
The MID for a 7-day total score is 8 (Weller et al., 2013). This is equivalent to a MID of 64 for a 
14-week study period and around 1 for an average daily score. In the absence of known MCIDs 
or RDs for the AAS in HAE, the MID will be used as well as one-half of the SD of baseline 
scores as an MCID/RD estimate:

AAS Index Score = 1, Baseline SD*0.5

AAS VAS Score = 1, Baseline SD*0.5
4.2.6
Healthcare Resource Utilization Assessment related to HAE (HRUA-HAE)
The usage of healthcare resources related to HAE in the last month (HRUA-HAE) is assessed 
(every four weeks) with a 5-item questionnaire collecting:
i.
Number of hospital admissions
ii.
Number of healthcare provider visits
iii.
Number of tests required
iv.
Number of emergency medicine unit or out-of-hours care clinic visits
v.
Number of days of home care


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The total number of hospital admissions, healthcare provider visits, tests required, 
emergency/out-of-hours clinic visits, and days of home care will be calculated, using the 
information collected in the HRUA-HAE, for the duration of each study period by summing all 
of the responses to each individual item during each period.
4.3
Study Assessments
The administration of study measures for each study period will follow the schedule of 
assessments provided in the study protocol (see Table 1 and Table 2). The PRO measures will be 
completed using the electronic subject diary and will be assessed as follows:
AE-QoL: Administered every 4 weeks on weeks 1 (prior to treatment administration), 5, 9, and 
13, of each study period. It will also be administered at the early discontinuation visit, if 
applicable, and at the 1-week post-treatment visit.
EQ-5D-5L: Administered on weeks 1 (prior to treatment administration), and 12, of each study 
period, and on each day subjects experience signs or symptoms of AE attack. It will also be 
administered at the early discontinuation visit, if applicable, and at the 1-week post-treatment 
visit.
WPAI-GH: Administered on week 1 (prior to treatment administration) and once a week, for the 
duration of each study period. It will also be administered at the early discontinuation visit, if 
applicable, and at the 1-week post-treatment visit.
SDS: Administered on week 1 (prior to treatment administration) and once a week, for the 
duration of each study period. It will also be administered at the early discontinuation visit, if 
applicable, and at the 1-week post-treatment visit.
AAS: Administered daily. It will also be administered at the early discontinuation visit, if 
applicable, and at the 1-week post-treatment visit.
HRUA-HAE: Administered on weeks 1 (prior to treatment administration), 4, 8, and 12, of each 
study period. It will also be administered at the 1-month post-treatment visit.


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Table 1:
Schedule of Assessments – Study period 1
Procedures
Screena
STUDY PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
Informed consent

Medical history

Inclusion/Exclusion criteria

c
Adverse eventsb

---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Randomization (predose)
c
Physical examination

c




Prior/concomitant meds

c



























Height and body weight

Vital signs (BP, pulse)d, e









12-lead ECGd

Safety labsf

c




UA with microscopy
c

Virology screeningg

Pregnancy testingh

c
IP injection
i






i







i







i



i
ISR assessmentj







j







j







j



j
Acceptability surveyk

Self-administration surveyk

Angioedema attack 
monitoringk, l
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASk
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnairek
c



EQ-5D-5Lk, m,
c

WPAI-GH and SDSk
c













HRUA-HAE
c



Anti-C1 INH antibodies
c
c
c
c
c,n
c,n
PK/PD sampling
See protocol


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Table 1:
Schedule of Assessments – Study period 1
Procedures
Screena
STUDY PERIOD 1 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1a to 28a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; 
ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HIV=human immunodeficiency virus; HRUA=health resource 
utilization assessment; INR=international normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; 
SDS=Sheehan Disability Scale; UA=urinalysis; WPAI-GH=Work Productivity and Activity Impairment General Health Questionnaire
a All subjects will have a screening evaluation within 21 days prior to the first dose of investigational product (Visit 1a=Dosing Day 1).
b Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
c Specified procedures should be performed prior to investigational product administration.
d Vital signs and ECGs will be measured using standard methods at each study site. Additional vital signs measurements and ECGs may be performed during the study if clinically indicated.
e On dosing days, vital signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.
f Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
g HIV (single assay antibody/INNO-LIA) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h Female subjects of childbearing potential; serum pregnancy test at screening and urine pregnancy test at all other time points.
i Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1a, 8a, 16a, 24a, and 28a.
j Injection site reaction assessments will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visits 8a, 16a, 24a, and 28a an overall assessment of injection site severity (mild, 
moderate, and severe as defined in Section 11.1 in main study SAP) and the overall duration of the injection site reactions  will be captured in the CRF.k In the electronic subject diary.
l The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
m In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack. 
n Collection of blood sample for the immunogenicity assessment should coincide with the subject’s PK/PD sampling schedule and will occur at either Visit 27a or Visit 28a (see Table 5 in main study 
SAP).


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Table 2:
Schedule of Assessments – Study period 2
Procedures
STUDY PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
Adverse eventsa
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Physical examination
b




Concomitant medications




























Body weight

Vital signs (BP, pulse)c








Safety labsd
b




UA with microscopy
b

Pregnancy testinge
b
IP injection
f






f







f







f



f
ISR assessmentg







g







g







g



g
Acceptability survey

Self-administration surveyh

Angioedema attack 
monitoringh, i
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AASh
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
AE-QoL questionnaireh
b



EQ-5D-5Lh, j
b

WPAI-GH and SDSh
b













HRUA-HAE
b



Anti-C1 INH antibodies
b
b
b
b
b
PK/PD sampling
See protocol
AAS=angioedema activity score; AE-QoL=angioedema quality of life; aPPT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 esterase inhibitor; CRF=case report form; 
ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; HAE=hereditary angioedema; HRUA=health resource utilization assessment; INR=international 
normalized ratio; IP=investigational product; ISR=injection site reaction; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; SDS=Sheehan Disability Scale; UA=urinalysis; 
WPAI-GH=Work Productivity and Activity Impairment-General Health Questionnaire
Note: ECGs may be performed during Study period 2 if clinically indicated, using standard methods at each study site.
a Adverse events will be collected from the time of informed consent through 7 days after the last dose of investigational product.
b Specified procedures should be performed prior to investigational product administration.
c Vital signs will be measured using standard methods at each study site. Additional vital signs measurements may be performed during the study if clinically indicated. On dosing days, vital 
signs should be measured ≤30 min before the start of the injection, ≤10 min after the end of the injection, and then between 30 min and 1 h after the end of the injection.
d Biochemistry, hematology, and coagulation (aPPT, PT, INR, D-dimer). In addition, D-dimer should be evaluated in any subject who presents at a study visit with signs and symptoms 
consistent with suspected venous thromboembolism.
e Urine pregnancy test for female subjects of childbearing potential.
f Investigational product will be administered by qualified personnel at the investigational site at Dosing Visits 1b, 8b, 16b, 24b, and 28b.


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Table 2:
Schedule of Assessments – Study period 2
Procedures
STUDY PERIOD 2 (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DOSING VISITS (1b to 28b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
g Injection site reaction assessment will be performed 15 min, 30 min, and 1 h after the end of the injection. At Visits 8b, 16b, 24b, and 28b an overall assessment of injection site severity (mild, 
moderate, and severe as defined in Section 11.1 in the main study SAP) and the overall duration of the injection site reactions will be captured in the CRF. h In the electronic subject diary.
i The investigator will complete a separate angioedema attack CRF for each attack based upon their review of the data in the subject diary.
j In addition to the scheduled time points, subjects should complete the EQ-5D-5L on each day that they experience signs or symptoms of an angioedema attack.


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5.
DATA MANAGEMENT
5.1
Data Handling Considerations
5.1.1
Data Analysis Populations
The analyses will use data from the full analysis data set: all enrolled subjects randomized to 
treatment sequence AB or BA who completed at least the baseline data collection. Subjects 
enrolled in the AA sequence will be included in the analyses where stated.
5.1.2
Baseline data
For analyses using mixed models, a common baseline will be taken as visit 1a. For other 
analyses, as appropriate, the baseline visit will be the baseline for each specific study period: 
visit 1a will be the baseline visit for period 1, and visit 1b will be the baseline visit for period 2.
5.1.3
Missing Data
Frequencies will be used to evaluate missing data and measures will be scored in accordance 
with the instrument developers’ recommendations listed below:

AE-QoL: Domains can be calculated if no more than 1 item is missing and the total score 
if no more than 25% of items (> 4 items) are missing (Weller et al., 2012).

EQ-5D-5L: Index scores cannot be calculated if any of the five dimensions is missing
(Simons et al., 2015).

EQ-VAS: EQ-VAS score cannot be calculated if the EQ-VAS is not completed at an 
assessment. 

WPAI GH: Scores cannot be calculated if there is a missing response to a corresponding 
item (Reilly Associates, 2002). 

SDS: No established conventions exist but since the Global functioning impairment score 
is comprised of only three items, the score will not be calculated if at least one of the three 
dimensions is missing.

AAS: Total scores can be calculated so long as no more than a week (7 days) of data are 
missing (Weller et al., 2013). 
Imputation of missing data will be limited to end of treatment data used in the calculation of 
change scores. In the event that a subject is missing end of treatment data, the closest available 
score to the period end or discontinuation will be used so long as the value was obtained a 
minimum of 9 weeks past the period start date. If not available, no change score will be 
calculated. No other missing data will be imputed.
5.2
Variables
The relevant variables from Study SHP616-300 to be used in the analyses are shown in 
Exhibit C.


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Exhibit C: Variables to be used in the analyses
Variable
Type
Subject ID
Categorical variable
Age
Continuous variable
Gender
Dichotomous variable
Prophylaxis use 
Dichotomous variable
Treatment
Dichotomous variable
Sequence
Categorical variable
Period
Dichotomous variable
Carry-over effect
Dummy variable
Time point
Ordinal variable
AE-QoL total score
Continuous variable
AE-QoL functioning score
Continuous variable
AE-QoL fatigue/mood score
Continuous variable
AE-QoL fear/shame score
Continuous variable
AE-QoL nutrition score
Continuous variable
EQ-5D-5L index score
Continuous variable
EQ-VAS score
Continuous variable
WPAI-GH absenteeism
Continuous variable
WPAI-GH presenteeism
Continuous variable
WPAI-GH work productivity loss
Continuous variable
WPAI-GH activity impairment
Continuous variable
Rescaled SDS work/school score
Continuous variable
Rescaled SDS social life/leisure activities score
Continuous variable


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Exhibit C: Variables to be used in the analyses
Variable
Type
Rescaled SDS family life/home responsibilities score
Continuous variable
Rescaled SDS total global functioning score
Continuous variable
AAS activity score – daily
Continuous variable
AAS activity score – weekly daily average
Continuous variable
AAS activity score – overall total
Continuous variable
AAS activity score – overall average
Continuous variable
Number of hospital admissions
Continuous variable
Number of healthcare provider visits
Continuous variable
Number of tests required
Continuous variable
Number of emergency medicine unit/out-of-hours care clinic visits
Continuous variable
Number of days home care
Continuous variable
6.
STATISTICAL ANALYSIS
6.1
Distributional Considerations
Normality will be assessed visually by examination of frequency distributions and histograms, 
with superimposed normal curves, and statistically using values of skewness and kurtosis and 
their standard errors (SEs, with the population assumed to be normal if the SE is > ½ the value) 
and Shapiro-Wilk’s tests. Based on the results of these analyses appropriate descriptive and 
inferential analyses (statistical tests) will be conducted (detailed below).
6.2
Descriptive Statistics
Data will be summarised using descriptive statistics. Continuous variables will be presented as 
mean and standard deviation (SD) for normally distributed variables, and as median and 
interquartile range for non-normally distributed variables. Categorical variables will be presented 
as frequencies (n) and percentages (%).


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6.3
Statistical Tests
Statistical tests used throughout will correspond to the data distribution. If the data are not 
normally distributed, the majority of tests conducted will be non-parametric: either chi-squared 
(Ȥ2) or McNemar’s tests for testing associations between unpaired and paired categorical data, 
respectively, Spearman’s correlation coefficients for testing associations between variables of at 
least ordinal scale, Mann-Whitney U tests for comparing median scores between two groups, 
Kruskal-Wallis tests for comparing median scores between three or more groups, Wilcoxon 
matched pairs tests for comparing paired data, and Friedman tests for comparing groups of 
paired data. If parametric tests are undertaken (e.g., Pearson’s r instead of Spearman correlation 
coefficients; independent sample t-tests instead of Mann-Whitney tests; ANOVAs instead of 
Kruskal-Wallis tests; paired t-tests instead of Wilcoxon tests; repeated measures ANOVAs 
instead of Friedman tests), consideration will be given to transformations to achieve a normal 
distribution first. Significance will be taken at the 5% level (p<0.05, two-tailed) throughout, with 
95% confidence intervals (CIs) used to express the uncertainty in the data.
6.4
Data Analysis
The analyses will be undertaken using SAS v9.4. The analysis will be performed on the Full 
Analysis Set according to the steps outlined below.
6.4.1
Analysis of PRO data
Objective 1: To describe AE-QoL, WPAI-GH, SDS, and AAS scores by treatment and 
period (absolute, change and percentage change from baseline at each scheduled visit for 
AB, BA, and AA sequences) and assess differences between treatments (A or B), controlling 
for study period (1 or 2) and sequence (AB, BA) (change and percentage change).
Descriptive statistics (i.e. mean and SD, range, plus median and interquartile range if required 
based on the distribution of the data) will be used to summarize AE-QoL, WPAI-GH, SDS, and 
AAS scores at each assessment. The data will be presented for each subject group (AB, BA, 
AA), treatment and period, in terms of absolute score, absolute change (end of treatment minus 
baseline), and percentage change (end of treatment minus baseline as a percentage of baseline)
scores for each treatment (A or B) within each study period (1 or 2). For the AE-QoL, the 
absolute scores for each visit by treatment will be taken from the main SAP analyses. For the 
other measures, only item-level information is presented in the main SAP analyses and thus 
score level data are required. Summary results for each PRO measure will be tabled in a form 
similar to that shown below:
Study Period
Sequence A/B
Sequence B/A
Sequence A/A
Total
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Period 1: 
Placebo 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
2000 IU 
Cinryze 
(N=xx)
Placebo 
(N=xx)
Study Period #
Absolute 
Scores


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HRQoL Statistical Analysis Plan 
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Study Period
Sequence A/B
Sequence B/A
Sequence A/A
Total
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Period 1: 
Placebo 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
2000 IU 
Cinryze 
(N=xx)
Placebo 
(N=xx)
n
xx
xx
xx
xx
xx
xx
xx
xx
Mean (SD)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
Change in 
Scores
n
xx
xx
xx
xx
xx
xx
xx
xx
Mean (SD)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
Percentage 
Change
n
xx
xx
xx
xx
xx
xx
xx
xx
Mean (SD)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx


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For each PRO measure the data presented will be as follows:
Measure
Absolute
Change
Percentage change
AE-QoL
1a/1b (baseline) 9a/9b 
(week 5) 17a/17b (week 
9) 25a/25b (week13)
Mean post baseline
-                         Week 
5 – baseline week 9 –
baseline week 13 –
baseline
-                         Week 
5 – baseline week 9 –
baseline week 13 –
baseline
EQ-5D-5L 
-5L 
utility and VAS
1a/1b (baseline)   24a/b 
(week 12)     
-                          
Week 12 – baseline
-                          
Week 12 – baseline
WPAI-GH
and 
SDS
1a/1b (baseline) 3a/3b 
(week 2)   5a/5b (week 3)   
7a/7b (week 4)      9a/9b 
(week 5)    11a/11b 
(week 6)    13a/13b 
(week 7)    15a/15b 
(week 8)    17a/17b 
(week 9)    19a/19b 
(week 10)  21a/21b 
(week 11)   23a/23b 
(week 12) 25a/25b 
(week13)  27a/27b (week 
14)
Mean post baseline
-                          week 
2 – baseline  week 3 –
baseline   week 4 –
baseline    week 5 –
baseline    week 6 –
baseline    week 7 –
baseline  week 8 –
baseline    week 9 –
baseline    week 10 –
baseline  week 11 –
baseline  week 12 –
baseline   week 13 –
baseline week 14 –
baseline     
-                          week 
2 – baseline  week 3 –
baseline   week 4 –
baseline    week 5 –
baseline    week 6 –
baseline    week 7 –
baseline  week 8 –
baseline    week 9 –
baseline    week 10 –
baseline  week 11 –
baseline  week 12 –
baseline   week 13 –
baseline week 14 –
baseline     
AAS – 7-day daily 
average 
1a/1b (baseline) 3a/3b 
(week 2)   5a/5b (week 3)  
7a/7b (week 4)      9a/9b 
(week 5)    11a/11b 
(week 6)    13a/13b 
(week 7)    15a/15b 
(week 8)     17a/17b 
(week 9)    19a/19b 
(week 10)   21a/21b 
(week 11)   23a/23b 
(week 12) 25a/25b 
(week13)  27a/27b (week 
14)
Total score    
Average daily score
-                          week 
2 – baseline  week 3 –
baseline   week 4 –
baseline    week 5 –
baseline    week 6 –
baseline    week 7 –
baseline  week 8 –
baseline    week 9 –
baseline    week 10 –
baseline  week 11 –
baseline  week 12 –
baseline   week 13 –
baseline week 14 –
baseline     
-                          week 
2 – baseline  week 3 –
baseline   week 4 –
baseline    week 5 –
baseline    week 6 –
baseline    week 7 –
baseline  week 8 –
baseline    week 9 -
baseline    week 10 –
baseline  week 11 –
baseline  week 12 –
baseline   week 13 –
baseline week 14 –
baseline     


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The AE-Qol, WPAI-GH, SDS, and AAS data will be presented in Table 1.1.1, Table 1.1.2, Table 
1.1.3, Table 1.1.4, Table 1.1.5, Table 1.1.6, and Table 1.1.7; Table 1.2.1, Table 1.2.2, Table 
1.2.3, Table 1.2.4, Table 1.2.5, and Table 1.2.6; Table 1.3.1, Table 1.3.2, Table 1.3.3, Table 
1.3.4, Table 1.3.5, and Table 1.3.6; and Table 1.4.1, Table 1.4.2, Table 1.4.3, and Table 1.4.4, 
respectively. The data will also be depicted graphically. These graphs will be simple line plots of 
mean scores with standard errors in each subject group at each visit (Figure 1.1.1, Figure 1.1.2, 
Figure 1.1.3, Figure 1.1.4, and Figure 1.1.5; Figure 1.2.1, Figure 1.2.2, Figure 1.2.3, and Figure 
1.2.4; Figure 1.3.1, Figure 1.3.2, Figure 1.3.3, and Figure 1.3.4; and Figure 1.4.1).
These tables and figures will allow informal assessment of whether there is a) a treatment effect, 
b) a sequence effect, c) a period effect, and d) and treatment by period interaction. A treatment 
by period interaction occurs when the effect of the treatment/placebo depends on the period in 
which it was administered. For example, if there is a carry-over effect of active treatment (the 
effect of the treatment persisting beyond the period in which it was administered), then the 
placebo effect would be expected to be larger in period 2, when it follows the active treatment, 
than in period 1 when it precedes it.
Separate mixed effects regression models will be used to assess the effect of treatment on change
in each of the PRO measure scores (for AAS scores, the change from baseline to the weekly 
average daily score in the final week of the study period will be considered). The dependent 
variable will be the change in score across the study period from baseline to the last visit at 
which the measure was administered. Treatment group will be a fixed effect (AB, BA). 
Additional fixed effects will be included to control for baseline score (visit 1a or 1b), age, 
gender, country, prophylaxis use, period, sequence, and carry-over effects. Random effects will 
be included comprising random intercepts of subject crossed with treatment. The results of the 
models will be shown in Table 1.1.8, Table 1.1.9, Table 1.1.10, Table 1.1.11, and Table 1.1.12; 
Table 1.2.7, Table 1.2.8, Table 1.2.9, and Table 1.2.10; Table 1.3.7, Table 1.3.8, Table 1.3.9, and 
Table 1.3.10; and Table 1.4.5.
Objective 2: To describe and estimate whether the effect of an attack on EQ-5D-5L index
and EQ-VAS scores differs between treatments (A or B), controlling for study period (1 or 
2) and sequence (AB, BA).
The change in EQ-5D index and EQ-VAS scores from the previous assessment to the first attack
during a study period will be summarised using appropriate descriptive statistics (e.g. mean and 
SD, range, median, and interquartile range). The EQ-5D-5L index and EQ-VAS scores at 
subsequent attacks will also be described. All data will be presented for each subject group (AB, 
BA, AA), for each treatment (A or B) within each study period (1 or 2). The data will be 
presented in Table 2.1.1 and Table 2.1.2.
These tables for the AB and BA subject groups will allow informal assessment of whether there 
is a) a treatment effect, b) a sequence effect, c) a period effect, and d) and treatment by period 
interaction. A treatment by period interaction occurs when the effect of the treatment/placebo 
depends on the period in which it was administered. For example, if there is a carry-over effect 
of active treatment (the effect of the treatment persisting beyond the period in which it was 


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administered), then the placebo effect would be expected to be larger in period 2, when it follows 
the active treatment, than in period 1 when it precedes it.
Objective 3: To describe and assess differences in the proportion of subjects achieving the 
responder definition (RD) in AE-QoL and AAS scores from baseline to final assessment
between treatments (A or B), controlling for study period (1 or 2) and sequence (AB, BA).
Frequencies and percentages will be used to summarize the proportion of subjects achieving the 
RD on the AE-QoL and AAS from baseline to end of each study period. For the AAS this will be 
the change from baseline to the average daily score during the last 7 days of the study period.
The data will be presented for each subject group (AB, BA, AA), presenting the frequencies for 
each treatment (A or B) within each study period (1 or 2). Results will be tabled in a form similar 
to that shown below:
PRO 
Measure
Sequence A/B
Sequence B/A
Sequence A/A
Total
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Period 1: 
Placebo 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Placebo 
(N=xx)
Placebo 
(N=xx)
AE-QoL
n
xx
xx
xx
xx
xx
xx
xx
xx
Percent
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
AAS
n
xx
xx
xx
xx
xx
xx
xx
xx
Percent
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
xx.x%
The AE-Qol and AAS data will be presented in Table 3.1.1, Table 3.1.2, Table 3.2.1, and Table 
3.2.2, respectively. The data will also be presented graphically. These graphs will be bar charts 
showing the frequency in each treatment group in each period (Figure 3.1.1, Figure 3.1.2, and 
Figure 3.2).
These tables and figures will allow informal assessment of whether there is a) a treatment effect, 
b) a period effect, and c) and treatment by period interaction. A treatment by period interaction 
occurs when the effect of the treatment/placebo depends on the period in which it was 
administered. For example, if there is a carry-over effect of active treatment (the effect of the 
treatment persisting beyond the period in which it was administered), then the placebo effect 
would be expected to be larger in period 2, when it follows the active treatment, than in period 1 
when it precedes it.
Mixed effects logistic regression models will be constructed for each of the PRO measure scores. 
The dependent variable will be a binary variable created for whether a subject achieved the RD 
in each study period (for AAS scores, the change from baseline to the weekly average daily score 
in the final week of the study period will be considered). Treatment group will be a fixed effect


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(AB, BA). Fixed effects will be included to control for baseline score (visit 1a or 1b), age, 
gender, country, prophylaxis use, period, sequence, and carry-over effects. Random effects will 
be included comprising subject crossed with treatment. Results of models will be shown in Table 
3.1.3a, Table 3.1.3b, Table 3.1.4a, Table 3.1.4b, Table 3.1.5a, Table 3.1.5b, Table 3.1.6a, Table 
3.1.6b, Table 3.1.7a, Table 3.1.7b, Table 3.2.3, and Table 3.2.4.
Exploratory Objective 1: To assess the relationship between efficacy (as defined in the 
protocol) and scores on the AE-QoL, WPAI-GH, SDS, and AAS scores (Hypothesis: 
Subjects with improved efficacy also have improved scores).
Efficacy will be defined as normalized number of attacks (NNA), per the study protocol. NNA is 
expressed as the number of attacks per month (i.e., 30.4 days) of exposure: 
NNA = 30.4 x (number of attacks during study period)/ (days of study period).
If a subject discontinues during the study period, the denominator of the NNA will be the days 
on treatment for that subject; this is equivalent to the last observation carried forward imputation 
method to impute the missing information following the subject’s discontinuation. 
Separate mixed effects regression models will be used to assess the effect of NNA on change in 
each of the PRO measure scores (for AAS scores, the change from baseline to the weekly 
average daily score in the final week of the study period will be considered). The dependent 
variable will be the change in score across the study period from baseline to the last visit at 
which the measure was administered. NNA will be a fixed effect. Additional fixed effects will be 
included to control for treatment group, baseline score (visit 1a or 1b), age, gender, country, 
prophylaxis use, period, sequence (AB, BA), and carry-over effects. An interaction between 
treatment and NNA will also be tested. Random effects will be included comprising random 
intercepts of subject crossed with treatment. Results of the models will be shown in Table 5.1.1, 
Table 5.1.2, Table 5.1.3, Table 5.1.4, Table 5.1.5, Table 5.2.1, Table 5.2.2, Table 5.2.3, 
Table 5.2.4, Table 5.3.1, Table 5.3.2, Table 5.3.3, Table 5.3.4, and Table 5.2.
6.4.2
Analysis of HRUA-HAE data
Objective 1: To describe HRUA-HAE (absolute values) according to treatment, study 
period (1 or 2) and sequence (AB, BA).
Descriptive statistics (i.e. mean and SD, or median and interquartile range) will be used to 
summarize HRUA-HAE values at each assessment. The data will be presented for each subject 
group (AB, BA, AA) in terms of absolute values for each treatment (A or B) within each study 
period (1 or 2). Results will be shown in a similar way to that shown below:


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HRQoL Statistical Analysis Plan 
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Study Visit
Sequence A/B
Sequence B/A
Sequence A/A
Total
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Period 1: 
Placebo 
(N=xx)
Period 2: 
2000 IU 
Cinryze 
(N=xx)
Period 1: 
2000 IU 
Cinryze 
(N=xx)
Period 2: 
Placebo 
(N=xx)
Placebo 
(N=xx)
2000 IU 
Cinryze 
(N=xx)
Study Visit #
n
xx
xx
xx
xx
xx
xx
xx
xx
Mean (SD)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
xx.x 
(xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
The data will be presented in Table H1, Table H2, Table H3, Table H4, and Table H5. These 
tables will allow informal assessment of whether there is a) a treatment effect, b) a sequence 
effect, c) a period effect, and d) and treatment by period interaction. A treatment by period 
interaction occurs when the effect of the treatment/placebo depends on the period in which it was 
administered. For example, if there is a carry-over effect of active treatment (the effect of the 
treatment persisting beyond the period in which it was administered), then the placebo effect 
would be expected to be larger in period 2, when it follows the active treatment, than in period 1 
when it precedes it.


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7.
REFERENCES
Balaam L.N. 1968. A two-period design with 2 experimental units. Biometrics; 24:61-73.
EuroQol Group. 2015. EQ-5D-5L user guide: Basic information on how to use the EQ-5D-5L 
(V2.1). Retrieved from https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf
Hills M. & Armitage P. 1979. The two-period cross-over clinical trial. Br J Pharmac; 8:7-20.
Norman G.R., Sloan J.A., Wyrwich K.W. 2003. Interpretation of changes in health-related 
quality of life: the remarkable universality of half a standard deviation. Med Care 41:582-592.
Reilly Associates. 2002. WPAI coding. Retrieved from 
http://www.reillyassociates.net/WPAI_Coding.html
Reilly M.C., Zbrozek A.S., & Dukes E.M. 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. PharmacoEconomics, 4, 353-365.
Senn S.J. 2002. Cross-over Trials in Clinical Research. Chapter 10. 2nd edition. Chichester: 
Wiley.
Sheehan D.V. 1983. The Anxiety Disease. New York, Scribner’s.
Simons C., Rivero-Arias O., Yu L.M., Simon J. 2015. Multiple imputation to deal with missing 
EQ-5D-3L data: Should we impute individual domains or the actual index? Qual Life Res
Apr;24(4):805-815.
Van Hout B., Janssen MF., Feng Y.S., Kohlmann T., Busschbach J., Golicki D., Lloyd A., et al. 
2012. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value 
in Health, 15, 708-715.
Weller K., Groffik A., Magerl M., Tohme N., Martus P., Krause K., Metz M., et al. 2012. 
Development and construct validation of the angioedema quality of life questionnaire. Allergy, 
67, 1289-1298.
Weller K., Groffik A., Magerl M., Tohme N., Martus P., Krause K., Metz M., et al. 2013. 
Development, validation, and initial results of the Angiodema Activity Score. Allergy, 68, 1185-
1192.
Weller, K., Magerl, M., PevelingǦOberhag, A., Martus, P., Staubach, P.and Maurer, M. 2016. 
The Angioedema Quality of Life Questionnaire (AEǦQoL) – assessment of sensitivity to change 
and minimal clinically important difference. Allergy, 71, 1203-9. 


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HRQoL Statistical Analysis Plan 
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8.
LIST OF TABLES
PRO Analyses
8.1
Objective 1
Table 1.1.1:
Summary of Angioedema Quality of Life Questionnaire Total Scores, by 
Treatment Sequence, Period, and Study Visit
Table 1.1.2:
Summary of Angioedema Quality of Life Questionnaire Functioning Scores, by 
Treatment Sequence, Period, and Study Visit
Table 1.1.3:
Summary of Angioedema Quality of Life Questionnaire Fatigue-Mood Scores, by 
Treatment Sequence, Period, and Study Visit
Table 1.1.4:
Summary of Angioedema Quality of Life Questionnaire Fear-Shame Scores, by 
Treatment Sequence, Period, and Study Visit
Table 1.1.5:
Summary of Angioedema Quality of Life Questionnaire Nutrition Scores, by 
Treatment Sequence, Period, and Study Visit
Table 1.1.6:
Mean Change in Angioedema Quality of Life Questionnaire Scores from 
Baseline, by Treatment Sequence, Period, and Study Visit 
Table 1.1.7:
Mean Percentage Change in Angioedema Quality of Life Questionnaire Scores 
from Baseline, by Treatment Sequence, Period, and Study Visit
Table 1.1.8:
Mixed Effects Regression Model Results for Change in Angioedema Quality of 
Life Questionnaire Total Score from Baseline (Visit 1a) to Week 13 of Each 
Study Period by Treatment
Table 1.1.9:
Mixed Effects Regression Model Results for Change in Angioedema Quality of 
Life Questionnaire Functioning Score from Baseline (Visit 1a) to Week 13 of 
Each Study Period by Treatment
Table 1.1.10: Mixed Effects Regression Model Results for Change in Angioedema Quality of 
Life Questionnaire Fatigue-Mood Score from Baseline (Visit 1a) to Week 13 of 
Each Study Period by Treatment
Table 1.1.11: Mixed Effects Regression Model Results for Change in Angioedema Quality of 
Life Questionnaire Fear-Shame Score from Baseline (Visit 1a) to Week 13 of 
Each Study Period by Treatment
Table 1.1.12: Mixed Effects Regression Model Results for Change in Angioedema Quality of 
Life Questionnaire Nutrition Score from Baseline (Visit 1a) to Week 13 of Each 
Study Period by Treatment


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Table 1.2.1:
Summary of Work Productivity and Activity Impairment - General Health 
Questionnaire Absenteeism Domain Scores, by Treatment Sequence, Period, and 
Study Visit
Table 1.2.2:
Summary of Work Productivity and Activity Impairment - General Health 
Questionnaire Presenteeism Domain Scores, by Treatment Sequence, Period, and 
Study Visit
Table 1.2.3:
Summary of Work Productivity and Activity Impairment - General Health 
Questionnaire Work Productivity Loss Domain Scores, by Treatment Sequence, 
Period, and Study Visit
Table 1.2.4:
Summary of Work Productivity and Activity Impairment - General Health 
Questionnaire Activity Impairment Domain Scores, by Treatment Sequence, 
Period, and Study Visit
Table 1.2.5: 
Mean Change in Work Productivity and Activity Impairment - General Health 
Questionnaire Scores from Baseline, by Treatment Sequence, Period and Study 
Visit
Table 1.2.6: 
Mean Percentage Change in Work Productivity and Activity Impairment -
General Health Questionnaire Scores from Baseline, by Treatment Sequence, 
Period and Study Visit
Table 1.2.7: 
Mixed Effects Regression Model Results for Change in Work Productivity and 
Activity Impairment - General Health Questionnaire Absenteeism Score from 
Baseline (Visit 1a) to Week 14 of Each Study Period by Treatment
Table 1.2.8: 
Mixed Effects Regression Model Results for Change in Work Productivity and 
Activity Impairment - General Health Questionnaire Presenteeism Score from 
Baseline (Visit 1a) to Week 14 of Each Study Period by Treatment
Table 1.2.9: 
Mixed Effects Regression Model Results for Change in Work Productivity and 
Activity Impairment - General Health Questionnaire Work Productivity Loss 
Score from Baseline (Visit 1a) to Week 14 of Each Study Period by Treatment
Table 1.2.10: Mixed Effects Regression Model Results for Change in Work Productivity and 
Activity Impairment - General Health Questionnaire Activity Impairment Score 
from Baseline (Visit 1a) to Week 14 of Each Study Period by Treatment
Table 1.3.1
Summary of Sheehan Disability Scale Total Scores, by Treatment Sequence, 
Period, and Study Visit
Table 1.3.2: 
Summary of Sheehan Disability Scale Work/School Domain Scores, by 
Treatment Sequence, Period, and Study Visit


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Table 1.3.3: 
Summary of Sheehan Disability Scale Social Life/Leisure Activities Domain 
Scores, by Treatment Sequence, Period, and Study Visit
Table 1.3.4: 
Summary of Sheehan Disability Scale Family Life/Home Responsibilities 
Domain Scores, by Treatment Sequence, Period, and Study Visit
Table 1.3.5: 
Mean Change in Sheehan Disability Scale Scores from Baseline, by Treatment 
Sequence, Period and Study visit
Table 1.3.6: 
Mean Percentage Change in Sheehan Disability Scale Scores from Baseline, by 
Treatment Sequence, Period and Study Visit
Table 1.3.7: 
Mixed Effects Regression Model Results for Change in Sheehan Disability Scale 
Total Score from Baseline (Visit 1a) to Week 14 of Each Study Period by 
Treatment 
Table 1.3.8: 
Mixed Effects Regression Model Results for Change in Sheehan Disability Scale 
Work/School Domain Score from Baseline (Visit 1a) to Week 14 of Each Study 
Period by Treatment 
Table 1.3.9: 
Mixed Effects Regression Model Results for Change in Sheehan Disability Scale 
Social Life/Leisure Activities Domain Score from Baseline (Visit 1a) to Week 14 
of Each Study Period by Treatment
Table 1.3.10: Mixed Effects Regression Model Results for Change in Sheehan Disability Scale 
Family Life/Home Responsibilities Domain Score from Baseline (Visit 1a) to 
Week 14 of Each Study Period by Treatment 
Table 1.4.1:
Summary of Total and Daily Average Angioedema Activity Scores, by Treatment 
Sequence and Period
Table 1.4.2: 
Summary of Weekly Average Angioedema Activity Daily Scores, by Treatment 
Sequence, Period, and Study Visit
Table 1.4.3: 
Mean Change in Weekly Average Angioedema Activity Daily Scores from 
Baseline, by Treatment Sequence, Period, and Study Visit
Table 1.4.4: 
Mean Percentage Change in Weekly Average Angioedema Activity Daily Scores 
from Baseline, by Treatment Sequence, Period, and Study Visit 
Table 1.4.5: 
Mixed Effects Regression Model Results for Change in Weekly Average 
Angioedema Activity Daily Score from Baseline (Day 1) to Week 14 of Each 
Study Period by Treatment 


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8.2
Objective 2
Table 2.1.1: 
Summary of Change in EuroQoL 5-Dimensional 5-Level Index and Visual 
Analogue Scale Scores from Previous Assessment to First Day of First 
Angioedema Attack, by Treatment Sequence and Period
Table 2.1.2: 
Summary of EuroQoL 5-Dimensional 5-Level Index and Visual Analogue Scale 
Scores on First Day of Each Subsequent Angioedema Attack, by Treatment 
Sequence and Period
8.3
Objective 3
Table 3.1.1: 
Frequencies and Percentages of Subjects Reaching the Responder Definition of 
One-half a Standard Deviation of the Common Baseline for Change in 
Angioedema Quality of Life Questionnaire Scores from Baseline to Week 13 by 
Treatment Sequence and Period
Table 3.1.2: 
Frequencies and Percentages of Subjects Reaching the Responder Definition of 6 
for Change in Angioedema Quality of Life Questionnaire Scores from Baseline to 
Week 13 by Treatment Sequence and Period
Table 3.1.3a: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (8.84) in Angioedema Quality of Life Questionnaire Total 
Score from Baseline (Visit 1a) to Week 13 of Each Study Period by Treatment
Table 3.1.3b: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 6 in Angioedema Quality of Life 
Questionnaire Total Score from Baseline (Visit 1a) to Week 13 of Each Study 
Period by Treatment
Table 3.1.4a: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (10.82) in Angioedema Quality of Life Questionnaire 
Functioning Score from Baseline (Visit 1a) to Week 13 of Each Study Period by 
Treatment
Table 3.1.4b: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 6 in Angioedema Quality of Life 
Questionnaire Functioning Score from Baseline (Visit 1a) to Week 13 of Each 
Study Period by Treatment
Table 3.1.5a: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (9.45) in Angioedema Quality of Life Questionnaire 
Fatigue/Mood Score from Baseline (Visit 1a) to Week 13 of Each Study Period 
by Treatment


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Table 3.1.5b: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 6 in Angioedema Quality of Life 
Questionnaire Fatigue/Mood Score from Baseline (Visit 1a) to Week 13 of Each 
Study Period by Treatment
Table 3.1.6a: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (10.97) in Angioedema Quality of Life Questionnaire 
Fear/Shame Score from Baseline (Visit 1a) to Week 13 of Each Study Period by 
Treatment
Table 3.1.6b: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 6 in Angioedema Quality of Life 
Questionnaire Fear/Shame Score from Baseline (Visit 1a) to Week 13 of Each 
Study Period by Treatment
Table 3.1.7a: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (12.19) in Angioedema Quality of Life Questionnaire Nutrition 
Score from Baseline (Visit 1a) to Week 13 of Each Study Period by Treatment
Table 3.1.7b: Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 6 in Angioedema Quality of Life 
Questionnaire Nutrition Score from Baseline (Visit 1a) to Week 13 of Each Study 
Period by Treatment
Table 3.2.1: 
Frequencies and Percentages of Subjects Reaching the Responder Definition of 
One-half a Standard Deviation of the Common Baseline of 1.33 for Change in 
Weekly Average Angioedema Activity Daily Score from Baseline (Day 1) to 
Week 14 by Treatment Sequence and Period 
Table 3.2.2: 
Frequencies and Percentages of Subjects Reaching the Responder Definition of 1 
for Change in Weekly Average Angioedema Activity Daily Score from Baseline 
(Day 1) to Week 14 by Treatment Sequence and Period
Table 3.2.3: 
Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of One-half a Standard Deviation of the 
Common Baseline (1.33) in Weekly Average Angioedema Daily Score from 
Baseline (Day 1) to Week 14 of Each Study Period by Treatment
Table 3.2.4: 
Mixed Effects Logistic Regression Model Results for Proportion of Subjects 
Achieving the Responder Definition of 1 in Weekly Average Angioedema 
Activity Daily Score daily from Baseline (Day 1) to Week 14 of Each Study 
Period by Treatment


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HRQoL Statistical Analysis Plan 
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8.4
Exploratory Objective 1
Table 5.1.1: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Angioedema Quality of Life Questionnaire 
Total Score from Baseline (Visit 1a) to Week 13 of Each Study Period
Table 5.1.2: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Angioedema Quality of Life Questionnaire 
Functioning Score from Baseline (Visit 1a) to Week 13 of Each Study Period
Table 5.1.3: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Angioedema Quality of Life Questionnaire 
Fatigue/Mood Score from Baseline (Visit 1a) to Week 13 of Each Study Period
Table 5.1.4: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Angioedema Quality of Life Questionnaire 
Fear/Shame Score from Baseline (Visit 1a) to Week 13 of Each Study Period
Table 5.1.5: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Angioedema Quality of Life Questionnaire 
Nutrition Score from Baseline (Visit 1a) to Week 13 of Each Study Period
Table 5.2.1: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Work Productivity and Activity Impairment –
General Health Questionnaire Absenteeism Score from Baseline (Visit 1a) to 
Week 14 of Each Study Period
Table 5.2.2: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Work Productivity and Activity Impairment –
General Health Questionnaire Presenteeism Score from Baseline (Visit 1a) to 
Week 14 of Each Study Period
Table 5.2.3: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Work Productivity and Activity Impairment –
General Health Questionnaire Work Productivity Loss Score from Baseline (Visit 
1a) to Week 14 of Each Study Period
Table 5.2.4: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Work Productivity and Activity Impairment –
General Health Questionnaire Activity Impairment Score from Baseline (Visit 1a) 
to Week 14 of Each Study Period
Table 5.3.1: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Sheehan Disability Scale Total Score from 
Baseline (Visit 1a) to Week 14 of Each Study Period


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HRQoL Statistical Analysis Plan 
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Table 5.3.2: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Sheehan Disability Scale Work/School Domain 
Score from Baseline (Visit 1a) to Week 14 of Each Study Period
Table 5.3.3: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Sheehan Disability Scale Life/Leisure Domain 
Score from Baseline (Visit 1a) to Week 14 of Each Study Period
Table 5.3.4: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Sheehan Disability Scale Family Life/Home 
Responsibilities Domain Score from Baseline (Visit 1a) to Week 14 of Each 
Study Period
Table 5.4: 
Mixed Effects Regression Model Results of the Relationship between Normalized 
Number of Attacks and Change in Weekly Average Angioedema Activity Daily 
Score from Baseline (Day 1) to Week 14 of Each Study Period
8.5
HRUA-HAE Analyses
Objective 1
Table H.1: 
Number of Hospitalizations by Treatment Sequence, Period and Study Visit
Table H.2: 
Number of Provider Visits by Treatment Sequence, Period, and Visit
Table H.3: 
Number of Tests Required by Treatment Sequence, Period, and Study Visit
Table H.4:
Number of ER/Urgent Care Visits by Treatment Sequence, Period and Study Visit
Table H.5: 
Number of Days of Home Care by Treatment Sequence, Period, and Study Visit


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HRQoL Statistical Analysis Plan 
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9.
LIST OF FIGURES
9.1
Objective 1
Figure 1.1.1:
Line Plot of Mean Angioedema Quality of Life Questionnaire Total Scores With 
Standard Error, by Treatment Sequence, Period, and Study Visit
Figure 1.1.2: Line Plot of Mean Angioedema Quality of Life Questionnaire Functioning Scores 
With Standard Error, by Treatment Sequence, Period, and Study Visit
Figure 1.1.3: Line Plot of Mean Angioedema Quality of Life Questionnaire Fatigue-Mood 
Scores With Standard Error, by Treatment Sequence, Period, and Study Visit
Figure 1.1.4: Line Plot of Mean Angioedema Quality of Life Questionnaire Fear-Shame Scores 
With Standard Error, by Treatment Sequence, Period, and Study Visit
Figure 1.1.5: Line Plot of Mean Angioedema Quality of Life Questionnaire Nutrition Scores 
With Standard Error, by Treatment Sequence, Period, and Study Visit
Figure 1.2.1: Line Plot of Mean Work Productivity and Activity Impairment - General Health 
Questionnaire Absenteeism Domain Scores With Standard Error, by Treatment 
Sequence, Period, and Study Visit
Figure 1.2.2: Line Plot of Mean Work Productivity and Activity Impairment - General Health 
Questionnaire Presenteeism Domain Scores With Standard Error, by Treatment 
Sequence, Period, and Study Visit
Figure 1.2.3: Line Plot of Mean Work Productivity and Activity Impairment - General Health 
Questionnaire Work Productivity Loss Domain Scores With Standard Error, by 
Treatment Sequence, Period, and Study Visit
Figure 1.2.4: Line Plot of Mean Work Productivity and Activity Impairment - General Health 
Questionnaire Activity Impairment Domain Scores With Standard Error, by 
Treatment Sequence, Period, and Study Visit
Figure 1.3.1: Line Plot of Mean Sheehan Disability Scale Total Scores with Standard Error, by 
Treatment Sequence, Period and Study Visit
Figure 1.3.2: Line Plot of Mean Sheehan Disability Scale Work/School Domain Scores with 
Standard Error, by Treatment Sequence, Period and Study Visit Line
Figure 1.3.3: Line Plot of Mean Sheehan Disability Scale Social Life/Leisure Activities 
Domain Scores with Standard Error, by Treatment Sequence, Period and Study 
Visit 
Figure 1.3.4: Line Plot of Mean Sheehan Disability Scale Family Life/Home Responsibilities 
Domain Scores with Standard Error, by Treatment Sequence, Period and Study 
Visit 


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HRQoL Statistical Analysis Plan 
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Figure 1.4.1: Line Plots of Mean Weekly Average Angioedema Activity Daily Scores with 
Standard Error, by Treatment Sequence, Period, and Study Visit
9.2
Objective 3
Figure 3.1.1: Proportion of Subjects Reaching an Improvement Greater Than or Equal to the 
Responder Definition of One-half a Standard Deviation of the Common Baseline 
for Change in Angioedema Quality of Life Questionnaire Scores from Baseline to 
Week 13 by Treatment Sequence and Period
Figure 3.1.2: Proportion of Subjects Reaching an Improvement Greater Than or Equal to the 
Responder Definition of 6 for Change in Angioedema Quality of Life 
Questionnaire Scores from Baseline to Week 13 by Treatment Sequence and 
Period
Figure 3.2: 
Proportion of Subjects Reaching an Improvement Greater Than or Equal to the 
Responder Definition for Change in Weekly Average Angioedema Activity Score 
from Baseline (Day 1) to Week 14 by Treatment Sequence and Period


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HRQoL Statistical Analysis Plan 
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10.
PROGRAMMING CONVENTIONS
10.1
Study Measure Scoring
10.1.1
Angioedema Quality of Life (AE-QoL) Questionnaire
The questionnaire will be scored according to the developers’ guidelines (Weller et al., 2012) to 
produce a total score and four domain scores (functioning, fatigue/mood, fear/shame, nutrition). 
Raw domain scores (mean of the item scores within each scale) and the raw total score (mean of 
all item scores) will be rescaled using linear transformations into final percentage scores ranging 
0 to 100, based on the maximum possible score, where the higher the score the greater the QoL 
impairment.
Final variables for analysis (per time-point and per study period): 
1. Rescaled AE-QoL total score
2. Rescaled AE-QoL functioning domain score
3. Rescaled AE-QoL fatigue/mood domain score
4. Rescaled AE-QoL fear/shame domain score
5. Rescaled AE-QoL nutrition domain score
10.1.2
EuroQol 5-dimensional 5-level (EQ-5D-5L) Descriptive System and EQ 
Visual Analogue Scale (EQ-VAS)
The EQ-5D-5L index score will be calculated using the developers’ algorithm based on country-
specific reference score sets developed (Van Hout et al., 2012). Score sets are available for 
Denmark, France, Germany, Japan, Netherlands, Spain, UK, US and Zimbabwe. For countries in 
which no score set exists (Canada, Hungary, Israel, Romania, and Sweden) the closest 
neighboring country will be used as a proxy (EuroQol Group, 2015). 
The EQ-VAS is a measure of overall self-rated health status, used and analyzed separately from 
the index score. The EQ-VAS ranges from 0 to 100, with higher scores indicative of better 
overall health.
Final variables for analysis (per time-point and per study period): 
1. EQ-5D-5L index score
2. EQ-VAS score
10.1.3
Work Productivity and Activity Impairment – General Health (WPAI-GH)
The WPAI-GH will be scored for each assessment according to the scoring guidelines listed 
below (Reilly et al., 1993):
1. Absenteeism (work time missed = (Q2/(Q2+Q4))*100)
2. Presenteeism (impairment at work or reduced on-the-job effectiveness = (Q5/10)*100)
3. Work productivity loss (overall work impairment/absenteeism plus presenteeism = 
(Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)])*100)
4. Activity Impairment = ((Q6/10)*100)


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Final variables for analysis (per time-point and per study period): 
1. Absenteeism score
2. Presenteeism score
3. Work productivity loss score
4. Activity impairment score
10.1.4
Sheehan Disability Scale (SDS)
The raw scores for impairment in work/school, social life/leisure activities, and family life/home 
responsibilities will be rescaled to a percentage of the maximum possible score (maximum score 
is 10). A total global functioning impairme7nt score is calculated as the sum of the three raw 
work/school, social life/leisure activities, and family life/home responsibilities scores. This is 
also rescaled to a percentage of the maximum possible score (maximum score is 30) (Sheehan, 
1983).
Final variables for analysis (per time-point and per study period): 
1. Rescaled SDS total global functioning score
2. Rescaled SDS work/school score
3. Rescaled SDS social life/leisure activities score
4. Rescaled SDS family life/home responsibilities score
10.1.5
Angioedema Activity Score (AAS)
The final AAS daily score is the sum of the five items (Weller et al., 2013). This is calculated for 
each day the instrument is administered.  
The following summary scores will be calculated:
1. The total disease activity score for the full duration of a study period = the sum of each 
final daily score post-baseline in each 14-week study period.
2. The overall average for the full duration of a study period = the mean of all the final daily 
scores post-baseline in each 14-week study period.
3. The weekly average daily disease activity scores = the mean of all the final daily scores 
post-baseline in each week individually.
Final variables for analysis:
1. Daily final AAS score (per day and per study period)
2. Weekly daily average final AAS score (per week and per study period)
3. Overall total AAS score (per study period)
4. Overall average AAS score (per study period)
10.1.6
Healthcare Resource Utilization Assessment related to HAE (HRUA-HAE)
The raw values are used. The total values for the entire treatment period are calculated by 
summing the responses to all assessments during that period for each item separately. 


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Final variables for analysis (per time-point and total, and per study period):
1. Number of hospital admissions
2. Number of healthcare provider visits
3. Number of tests required
4. Number of emergency medicine unit or out-of-hours care clinic visits
5. Number of days of home care
10.2
Calculating Change in Scores
Change in scores will be calculated as follows for each visit and each study period separately:
-
Study period 1:
o
Follow up visit x score - baseline (visit 1a) score 
-
Study period 2:
o
Follow up visit x score - baseline (visit 1b) score 
Change in AAS scores will be calculated as follows:
-
Study period 1:
o
Weekly average daily scores for the each week of follow up - baseline (visit 1a) 
daily score 
-
Study period 2:
o
Weekly average daily scores for the each week of follow up - baseline (visit 1b) 
daily score 
The overall change score is always the final follow up visit minus the baseline visit, for each 
study period separately. For AAS scores, it is change from baseline to the weekly average daily 
score in the final week, for each study period separately.
Imputation of missing data will be limited to end of treatment data used in the calculation of 
change scores. In the event that a subject is missing end of treatment data, the closest available 
score to the period end or discontinuation will be used so long as the value was obtained a 
minimum of 9 weeks past the period start date. If not available, no change score will be 
calculated. No other missing data will be imputed.
10.3
Responder Definition Variables
A RD binary variable will be created for each relevant PRO measure (AE-QoL, and EQ-5D-5L)
and score. Each person will receive a 0 if they did NOT reach the MCID or estimated 
distribution-based RD for the PRO measure and score in the relevant study period, and they will 
receive a 1 if they did.
-
AE-QoL 
o
Rescaled AE-QoL total score = 6, Baseline SD*0.5
o
Rescaled AE-QoL Functioning domain score = 6, Baseline SD*0.5
o
Rescaled AE-QoL Fatigue/mood domain score = 6, Baseline SD*0.5


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o
Rescaled AE-QoL Fear/shame domain score = 6, Baseline SD*0.5
o
Rescaled AE-QoL Nutrition domain score = 6, Baseline SD*0.5
-
EQ-5D-5L 
o
EQ-5D-5L Index Score = 0.05, 0.075, 0.10, 0.125, Baseline SD*0.5
o
EQ-VAS Score = 5, 7.5, 10, Baseline SD*0.5
-
AAS
o
Average daily scores = 1, Baseline SD*0.5.
10.4
Dummy Variable for Carry-over Effect
A dummy variable will be created in order to control for carry-over effect. The study protocol 
states that carry-over effect is possible when the active treatment was given in the first period, 
and may extend over the first two weeks of the second period. 
If the data are in wide format, a 1 for carry-over will be given in period 2 if the active treatment 
was administered in period 1. In all other cases, a 0 will be given.  If the data are in long format, 
a 1 for carry-over will be given for the time-points over the first two weeks of period 2 if the 
active treatment was administered in period 1. In all other cases, a 0 will be given.
10.5
Explanation of the Standard Deviation Rule
-
The standard deviation rule is half of the standard deviation.


PK and PD Analysis Plan 
 
SHP616 (CINRYZE®) 
Protocol SHP616-300 
Shire 
 
CSC Confidential 
1 of 29 
15-Aug-2017 
 
 
1 
TITLE PAGE 
PK AND PD ANALYSIS PLAN 
 
A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-
sequence, Partial Crossover Study to Evaluate the Efficacy and Safety of 
Subcutaneous Administration of 2000 IU of C1 Esterase Inhibitor [Human] Liquid 
for Injection for the Prevention of Angioedema Attacks in Adolescents and Adults 
with Hereditary Angioedema 
 
 
Sponsor Protocol No.: SHP616-300 (Amendment 3) 
Investigational Product: SHP616 (CINRYZE®) 
 
Final 
Date: 15-Aug-2017  
 
CSC Reference No.: SHIR-CSC-142 
 
 
 
Shire  
300 Shire Way,  
Lexington, MA 02421 
 
 
 
 
 
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