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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the 
nature of the study provide written informed consent for the child to participate in the 
study before any study-specific procedures are performed (with assent from the child 
when appropriate). Alternatively, certain sites/Independent Reviewing Authorities 
may permit adolescents who are <18 years of age to be informed of the nature of the 
study and provide written informed consent without consent from a parent(s)/legal 
guardian.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 
1000 U every 3 or 4 days (receiving a weekly dose >2000 U).
2.
Have had signs or symptoms of an angioedema attack within 2 days prior to the first 
dose of the investigational product in Treatment Period 1.
3.
Have received any C1 INH therapy or any blood product for the treatment or prevention 
of angioedema attacks within 3 calendar days prior to the first dose of investigational 
product in Treatment Period 1.
4.
Have a history of hypercoagulability (abnormal blood clotting) or other predisposition 
for thromboembolism. 
5.
Have a diagnosis of acquired angioedema or known presence of anti-C1 INH 
antibodies. 
6.
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any 
components of CINRYZE), or other blood products. 
7.
Be pregnant or breastfeeding. 
8.
Have received an investigational drug within 30 days prior to the first dose of 
investigational product in Treatment Period 1. 
9.
Have, as determined by the investigator and/or the sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of 
investigational product or interpretation of study results. 
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception, as described below. Females of childbearing potential must be advised to use 
acceptable contraceptives throughout the study period and for 30 days following the last dose 
of investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of childbearing potential who are not currently 
sexually active must agree to use acceptable contraception, as defined below, if they become 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until 7 days after the last 
dose of investigational product. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research subject.

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

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satisfying the serious criteria should be recorded as a SAE and reported to Shire 
Pharmacovigilance.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range (either 
while continuing treatment or after the end of treatment with the investigational product), and 
the range of variation of the respective parameter within its reference range must be taken into 
consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department 
using the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Shire ViroPharma Medical Monitor using the 
details specified in the emergency contact information section of the protocol. The pregnant 
female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to Global Pharmacovigilance using the Shire 
Clinical Trial Serious Adverse Event Form. Note: An elective abortion is not considered an 
SAE.

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

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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the CINRYZE Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event. Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, 
or medication errors (Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 
Trial Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to 
the contract research organization/Shire ViroPharma Medical Monitor using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as an SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
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definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be 
reported to the Shire Pharmacovigilance Department and the contract research 
organization/Shire ViroPharma Medical Monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
Note: Investigators will report all SAEs that occur ≤30 days after the last dose of 
investigational product and related SAEs that occur >30 days after the last dose of 
investigational product to Shire Pharmacovigilance Department.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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12.
APPENDICES

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

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

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

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

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

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

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

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