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
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

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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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.
CONFIDENTIAL
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Protocol Amendment 4
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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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CONFIDENTIAL
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Protocol Amendment 4
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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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CONFIDENTIAL
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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 .......................................................................................................................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 
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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 
attack

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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 
new attack). Therefore, 

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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 
file at the analytical laboratory.

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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 

Recovering/Resolving

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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 
separately.

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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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(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

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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.

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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
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 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