Clinical trial NCT02865720
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire
Start date: 2016-09-08; Completion date: 2017-06-23
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if an investigational treatment is safe and well tolerated when administered by intravenous (IV) infusion in Japanese subjects with HAE.

Detailed description:

Arms: arm 1: 500 U of CINRYZE will be administered by IV infusion twice weekly for 12 weeks arm 2: 1000 U of CINRYZE will be administered by IV infusion twice weekly for 12 weeks.
Interventions: intervention 1: CINRYZE 500 U intervention 2: CINRYZE 1000 U
Intervention descriptions: intervention 1: IV infusion administered twice weekly intervention 2: IV infusion administered twice weekly

Protocol documents:
Prot_000.pdf: 






Shire
CONFIDENTIAL
Page 4
Protocol 0624-209 with Amendments 1, 2, 3, 4, and 5
30 Aug 2016
CINRYZE (C1 inhibitor [human])
Clarified collection of PK blood samples for subjects who present to the 
site with a breakthrough angioedema attack and receive treatment with 
CINRYZE.
Schedule 4 and Section 6.8
Clarified that vital sign assessments include the measurement of pulse 
rather than heart rate.  In addition, the window around collection of pre-
and post-dose vital signs has been extended to allow flexibility for site 
personnel. 
Schedule 1, Schedule 3, and 
Section 6.3
Extended the duration for recording of concomitant medications to include 
from the start of dosing (Dosing Visit 1) through the 1-Month Post-
treatment Follow-up Visit.
Schedule 3 and Section 6.5.2
Added 3 post-marketing studies with IV CINRYZE to clinical experience 
section of the introduction, along with a cross-reference to CINRYZE
Investigator’s Brochure.
Section 1.1.2
Deleted text allowing sites to use the PQ interval if the PR interval was not 
reported on the 12-lead ECG. The PR interval is more clinically relevant 
than the PQ interval.
Section 6.4
Revised the total volume of blood collected during the study for subjects 
who weigh 25 kg or more.
Section 6.9
Removed the requirement to record in the CRF the total amount of 
investigational product received for subjects who discontinue study 
medication.
Section 6.15
Added definition for considering a subject is lost to follow-up.
Section 6.15.1
Provided a definition of treatment-emergent adverse events (TEAEs) and 
clarified that the safety endpoint will include TEAEs.
Synopsis and Section 7.4
Added a summary table of all previous protocol amendments.
Appendix 1
Other administrative and clarifying revisions have been made throughout the protocol for 
consistency with these modifications.
See Appendix 1 for protocol history, including all amendments.




S hire
C O N FI D E N TI A L
P a ge 6
Pr ot oc ol 0 6 2 4 -2 0 9 wit h A m e n d me nts 1, 2, 3, 4, a n d 5
3 0 A u g 2 0 1 6
CI N R Y Z E ( C 1 i n hi bit or [ h u m a n])
P R O D U C T Q U A LI T Y  C O M P L AI N T S
I n vesti gat ors are re q uire d t o re p ort i n vesti gati o nal pr o duct q ualit y  c o m plai nts t o S hire wit hi n 
2 4 h o urs.  T his i ncl u des a n y  i nsta nces w herei n t he q ualit y or perf or ma nce of a S hire pr o d uct 
( mar kete d or i n vesti gati o nal) d oes n ot meet e x pectati o ns (e g, i na de q uate or fa ult y cl os ure, 
pr o d uct c o nta mi nati o n) or t hat t he pr o d uct di d n ot meet t he s pecificati o ns defi ne d i n t he 
a p plicati o n f or t he pr o d uct ( e g, wr o n g pr o d uct s uc h t hat t he la bel a n d c o nte nts are differe nt 
pr o d ucts).  F or i nstr ucti o ns o n re p orti n g A Es relate d t o pr o d uc t c o m plai nts, see Secti o n 9 .
Please use t he i nf or mati o n bel o w as a p plica ble t o re p ort t he Pr o d uct Q ualit y C o m plai nt:
Ori gi n of Pr o d uct Q u alit y C o m pl ai nt
E m ail A d dress
N ort h a n d S o ut h A merica
E ur o pea n U ni o n a n d Rest of W orl d
P P D
Tele p h o ne n u m bers ( pr o vi de d f or refere nce if nee de d):
S hire, Wa y ne, P A ( U S A)
 or 
S hire, Basi n gst o ke, Ha m ps hire ( U K)
P P D
P P D
P P D
P P D


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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
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................11
PROTOCOL SYNOPSIS ..............................................................................................................13
1
INTRODUCTION..................................................................................................................28
1.1
CINRYZE (C1 Inhibitor [Human]).............................................................................29
1.1.1
Nonclinical Experience..........................................................................................30
1.1.2
Clinical Experience................................................................................................30
1.2
Study Rationale ........................................................................................................32
2
STUDY OBJECTIVES ..........................................................................................................33
3
INVESTIGATIONAL PLAN.................................................................................................34
4
STUDY POPULATION.........................................................................................................37
4.1
Inclusion Criteria......................................................................................................37
4.2
Exclusion Criteria.....................................................................................................38
5
STUDY DRUG ADMINISTRATION...................................................................................39
5.1
Dose Selection..........................................................................................................39
5.2
Randomization .........................................................................................................40
5.3
Study Drug ...............................................................................................................40
5.3.1
Self-administration.................................................................................................40
5.4
Blinding....................................................................................................................42
5.5
Stopping Rules .........................................................................................................42
5.5.1
Anaphylactic Reaction...........................................................................................42
5.5.2
Thrombotic or Thromboembolic Event .................................................................42
6
STUDY PROCEDURES........................................................................................................43
6.1
Medical History and Physical Examination.............................................................43
6.2
Adverse Event Collection.........................................................................................44
6.3
Vital Signs................................................................................................................44
6.4
12-Lead Electrocardiogram......................................................................................44
6.5
Prior and Concomitant Medications.........................................................................45
6.5.1
Prior Medications...................................................................................................45


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6.5.2
Concomitant Medications......................................................................................45
6.5.3
Prohibited Medications..........................................................................................45
6.6
Nonpharmacologic Treatments and Procedures.......................................................45
6.7
Clinical Laboratory Parameters................................................................................45
6.8
Sample Collection for Pharmacokinetic, Pharmacodynamic, and C1 INH 
Antibody Analyses ...................................................................................................46
6.9
Total Blood Volume Collected ................................................................................47
6.10
Restrictions...............................................................................................................47
6.11
Study Diary ..............................................................................................................47
6.12
Angioedema Attacks ................................................................................................47
6.12.1 Treatment of Breakthrough Angioedema Attacks.................................................48
6.12.2 Assessment of Breakthrough Angioedema Attacks...............................................49
6.13
Quality of Life..........................................................................................................50
6.13.1 Angioedema Quality of Life (AE-QoL) Questionnaire.........................................50
6.14
Self-administration Survey.......................................................................................50
6.15
Discontinuation of Subjects .....................................................................................50
6.15.1 Reasons for Discontinuation..................................................................................51
7
STATISTICAL METHODOLOGY.......................................................................................52
7.1
Sample Size..............................................................................................................52
7.2
Populations...............................................................................................................52
7.3
Statistical Methods ...................................................................................................52
7.4
Safety Analyses........................................................................................................52
7.5
Pharmacokinetic and Pharmacodynamic Analyses..................................................52
7.6
Efficacy Analyses.....................................................................................................53
7.6.1
Prevention of Angioedema Attacks .......................................................................53
7.6.2
Treatment of Breakthrough Angioedema Attacks.................................................54
8
DRUG SUPPLIES..................................................................................................................55
8.1
How Supplied...........................................................................................................55
8.1.1
For at Home Use....................................................................................................55
8.2
Reconstitution of CINRYZE for Intravenous Infusion............................................55
8.3
Drug Accountability.................................................................................................55
8.4
Drug Labels..............................................................................................................56
9
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................57
9.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................57
9.1.1
Severity Categorization..........................................................................................57
9.1.2
Relationship Categorization...................................................................................58
9.1.3
Outcome Categorization ........................................................................................58


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9.1.4
Symptoms of the Disease Under Study .................................................................58
9.1.5
Clinical Laboratory and Other Safety Endpoints...................................................58
9.1.6
Pregnancy...............................................................................................................59
9.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................59
9.2
Serious Adverse Event Procedures ..........................................................................60
9.2.1
Reference Safety Information................................................................................60
9.2.2
Reporting Procedures.............................................................................................60
9.2.3
Serious Adverse Event Definition .........................................................................61
9.2.4
Serious Adverse Event Collection Time Frame.....................................................61
9.2.5
Serious Adverse Event Onset and Resolution Dates .............................................61
9.2.6
Fatal Outcome........................................................................................................62
9.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................62
10 STUDY MONITORING ........................................................................................................63
11 DATA HANDLING ...............................................................................................................64
11.1
Data Collection.........................................................................................................64
11.2
Clinical Data Management.......................................................................................64
12 ETHICAL CONDUCT OF THE STUDY..............................................................................65
13 SUBJECT CONFIDENTIALITY ..........................................................................................66
14 INFORMED CONSENT........................................................................................................67
14.1
Adults .......................................................................................................................67
14.2
Children or Minors...................................................................................................67
15 INDEPENDENT REVIEWING AUTHORITY APPROVAL ..............................................68
16 PUBLICATION POLICY ......................................................................................................69
17 INVESTIGATOR'S STATEMENT (PROTOCOL 0624-209) ..............................................70
18 LIST OF REFERENCES........................................................................................................72


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LIST OF TABLES
Schedule 1:
Clinical Study Assessments – Screening and Treatment Period..................23
Schedule 2:
Investigational Product and Self-administration Training ...........................25
Schedule 3:
Clinical Study Assessments – Early Discontinuation Visit and 1-week 
and 1-month Post-treatment Follow-up Visits ..............................................26
Schedule 4:
Blood Sample Collection Time Points for PK/PD Assessments...................27
LIST OF FIGURES
Figure 1:
Study Design .................................................................................................35
LIST OF APPENDICES
Appendix 1
PROTOCOL HISTORY................................................................................75
Appendix 2
RECOMMENDED PROCEDURES FOR THE MANAGEMENT OF 
SUSPECTED  VENOUS THROMBOEMBOLISM or OTHER 
THROMBOTIC OR  THROMBOEMBOLIC EVENTS..............................79


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACE
Angiotensin-converting enzyme
AE
Adverse event
AE-QoL
Angioedema quality of life
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC0-τ
Area under the plasma concentration-versus-time curve from time 0 to selected time point
BP
Blood pressure
BUN
Blood urea nitrogen
C1 INH
C1 esterase inhibitor or C1 inhibitor
Cavg
Average concentration at steady state
CBC
Complete blood count
CFR
Code of Federal Regulations
CL
Clearance
Cmax
Maximum concentration
Cmin
Minimum concentration
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRA
Clinical research associate
CRF
Case report form
CRO
Contract research organization
EACA
Epsilon-aminocaproic acid
EC
Ethics Committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ER
Emergency room
FDA
Food and Drug Administration
GCP
Good clinical practice
HAE
Hereditary angioedema
HIV
Human immunodeficiency virus
HR
Heart rate
ICH
International Conference on Harmonisation
ICSR
Individual case safety report
INR
International normalized ratio
IRB
Institutional Review Board
ISR
Incurred sample reproducibility
ISS
Incurred sample stability
ITT-S
Intent-to-Treat Safety (population)
IV
Intravenous
Kel
Elimination rate constant
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PT
Prothrombin time
RBC
Red blood cells
SAE
Serious adverse event
SOP
Standard operating procedure
SWFI
Sterile Water for Injection
T/TE
Thrombotic/thromboembolic


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Abbreviation
Definition
t1/2
Terminal elimination half-life
tmax
Time to maximum concentration or maximum pharmacodynamic response
US
United States
USP
United States Pharmacopeia
VAS
Visual analogue scale
VZ
Volume of distribution
WBC
White blood cell
WHO
World Health Organization


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PROTOCOL SYNOPSIS
Study Title:  A Phase 3, open-label, single-period study to evaluate the safety and treatment 
effect of intravenous administration of CINRYZE® (C1 inhibitor [human]) for the prevention of 
angioedema attacks and treatment of breakthrough attacks in Japanese subjects with hereditary 
angioedema (HAE) (Protocol 0624-209).
Study Objectives:
The objectives of the study are to assess:

The safety and tolerability of CINRYZE administered by intravenous (IV) infusion in Japanese 
subjects with HAE;

The pharmacokinetics (PK) and pharmacodynamics (PD) of CINRYZE administered by IV 
infusion in this subject population; and

The treatment effect of CINRYZE administered by IV infusion for the prevention of 
angioedema attacks and treatment of breakthrough attacks in this subject population.
NOTE:  A breakthrough attack is defined as an angioedema attack that occurs during long-term 
prevention therapy with CINRYZE.
Study Population:
Number of Subjects
A sufficient number of subjects will be enrolled to ensure that a minimum of 6 subjects complete 
the study.  When 6 subjects have completed the 12-week treatment period, no further subjects 
will be enrolled; however, all subjects already enrolled in the study will be followed to study 
completion.  If subjects withdraw or discontinue after enrollment, additional subjects may be 
enrolled to ensure at least 6 subjects complete the study.
Inclusion Criteria
To be eligible for this protocol, a subject must:
1. Be of Japanese descent, defined as born in Japan and having Japanese parents and 
Japanese maternal and paternal grandparents.
2. Be ≥2 years of age.
3. Meet the following minimum body weight criteria:

Subjects 2 to 5 years of age must weigh at least 12.5 kg; and

Subjects 6 years of age and above must weigh at least 25 kg.
4. Have a confirmed diagnosis of Type I or Type II HAE.  NOTE:  Diagnosis may be based 
on historical data including family history, clinical symptoms (characteristic attacks), and 
documentation of low level of C1 INH protein and/or C1 INH activity.
5. Have a history of at least one angioedema attack per month (on average) during the 
3 consecutive months immediately before enrollment.


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6. Agree to adhere to the protocol-defined schedule of assessments and procedures.
7. Agree to avoid his/her known angioedema attack triggers during the study to the best of 
his/her ability.
8. If a female of reproductive age, be postmenopausal (≥12 months following cessation of 
menstruation), surgically sterile, or following an acceptable method of birth control (and 
agree to continue its use through 1 month after the last dose of study drug):

Non-hormonal methods (eg, abstinence, barrier control) for at least 1 complete menstrual 
cycle before the Screening Visit.

Stable doses of estrogen and/or progestin containing products for at least 2 months before 
the Screening Visit.
9. If a male of reproductive age, 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 study drug.
10. If an adult, be informed of the nature of the study and provide written informed consent 
before any study-specific procedures are performed.
OR
If a child or minor (<20 years of age), have a parent/legal guardian who is informed of 
the nature of the study provide written informed consent (ie, permission) for the child to 
participate in the study before any study-specific procedures are performed.  Assent will 
be obtained from children ≥14 years of age.
Exclusion Criteria
To be eligible for this protocol, a subject must not:
1. Have a history of hypercoagulability (abnormal blood clotting).
2. Have a diagnosis of acquired angioedema or be known to have C1 INH antibodies.
3. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any of the 
components of CINRYZE) or other blood products.
4. Have received C1 INH therapy or any blood products within 3 days before the first dose 
of study drug.
5. Have had signs or symptoms of an angioedema attack within 2 days before the first dose 
of study drug.
6. Have any change (start, stop, or change in dose) in androgen therapy (eg, danazol, 
oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid 
(EACA), or other antifibrinolytics within 14 days before the first dose of study drug.
7. If female, have started taking or changed the dose of any hormonal contraceptive regimen 
or hormone replacement therapy (eg, estrogen/progestin containing products) within 2 
months before the first dose of study drug.
8. Be pregnant or breastfeeding.


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9. Have received an investigational drug other than those required for prevention or 
treatment of angioedema attacks within 30 days before the first dose of study drug.
10. 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 study drug or 
interpretation of study results.
Duration of Study:  Individual participation from Screening through completion of the 1-Month 
Post-treatment Follow-up Visit will last approximately 5 months.
Drug Product: CINRYZE is supplied as a lyophilized powder in single use vials containing 
500 U of C1 INH per vial.  Each vial of CINRYZE will be reconstituted with 5 mL of Sterile 
Water for Injection, USP.  When reconstituted, CINRYZE contains C1 INH at a concentration of 
100 U/mL in a citrate-buffered solution comprising sucrose, sodium chloride, L-valine, L-
alanine, and L-threonine.  Each 500 U dose will require reconstitution of 1 vial, and each 1000 U 
dose will require reconstitution of 2 vials.  The solution must be used within 3 hours after 
reconstitution.
Study Drug Administration:  Doses of CINRYZE for the prevention of angioedema attacks will 
be administered at the investigational site or at the subject’s home (including the option for 
independent self-administration).  Two different doses of CINRYZE will be administered 
depending on subject age, as described below:
Subjects 2 to 5 years of age – 500 U of CINRYZE will be administered by IV infusion twice 
weekly (every 3 or 4 days) for 12 weeks.
Subjects 6 years of age and older – 1000 U of CINRYZE will be administered by IV infusion 
twice weekly (every 3 or 4 days) for 12 weeks.
Study Design: This single-period, open-label study will be conducted at multiple investigational 
sites in Japan.  All study sites will conduct the study in accordance with the protocol, 
International Conference on Harmonisation, and Good Clinical Practice standards.  Data from all 
sites will be pooled for purposes of analysis and will be reported in the final clinical study report.
This is an outpatient study; however, subjects may require an overnight stay at the site for those 
days on which serial PK/PD blood samples are collected.  Subjects would be discharged the 
following day after collection of the 24-hour PK/PD blood sample.
Subjects will be administered CINRYZE by IV infusion twice weekly (every 3 or 4 days) for 12 
weeks.  Study drug will be administered to all subjects at the investigational site for Dosing 
Visits 1 through 8, 16, and 24; during these visits, subjects may also have physical examinations 
and other procedures performed (see Schedule 1).  Other doses of study drug may be 
administered at the investigational site or at the subject’s home.  
Subjects who are at least 12 years of age and/or considered suitable candidates (ie, those with a
physical and mental capability of learning, adequate venous access, and willing to self-
administer) will undergo detailed training at the study site on the skills needed for self-
administration of investigational product (see Schedule 2).  Alternatively, a subject’s caregiver 


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(such as a parent or guardian) can receive this training and will be allowed to administer the 
investigational product to a subject who requires assistance.  The administration of the first 2 
doses of investigational product should be done by the Investigator or qualified delegate at the 
study site, while subjects (or caregivers) who elect to self-administer will receive training 
materials and be instructed on the process of handling and reconstituting CINRYZE, proper 
venous access, and correct administration by IV infusion.  Initiation of subject (or caregiver) 
self-administration with supervision by the Investigator or qualified delegate can begin on 
Dosing Visit 3 and continue as long as needed, but it is expected that subjects (or caregivers) 
may require supervised training through to Dosing Visit 8.  After completing the required 
training, and provided the subject (or caregiver) is deemed independent according to the criteria 
described in Section 5.3.1, a subject (or caregiver) may elect to self-administer one or more 
doses of CINRYZE at home or at the study site.  The Investigator’s acknowledgement that a 
subject (or caregiver) is certified for independent self-administration will be entered in the CRF.
During the study, subjects will be asked to avoid known triggers of angioedema attacks to the 
best of their ability (eg, foods, activities, medical procedures, environments).  To the extent 
possible, subjects should postpone elective procedures (eg, dental work) while participating in 
the study.  If a procedure cannot be postponed, the subject (or caregiver) will notify the 
Investigator and the information will be recorded in the CRF.
It is recommended that treatment of breakthrough attacks (ie, angioedema attacks that occur 
during long-term prevention therapy with CINRYZE) occurs at the investigational site whenever 
possible so that clinical assessments can be completed as specified.  It is preferred that subjects 
receive CINRYZE within 4 hours but not more than 8 hours after the onset of breakthrough attack 
symptoms if treatment can occur at the investigational site.
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 PAREXEL International Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
Post-treatment follow-up visits will be performed 1 week (±1 day) and 1 month (30 ±2 days) 
after the last dose of study drug.  If a subject prematurely discontinues investigational product, 
regardless of the reason, the Early Discontinuation Visit procedures listed in Schedule 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 Follow-up visits.
The schedules of study procedures are provided immediately following the synopsis:

Schedule 1:  Clinical Study Assessments – Screening and Treatment Period;

Schedule 2:  Investigational Product and Self-administration Training;

Schedule 3:  Clinical Study Assessments – Early Discontinuation Visit and 1-Week and 1-
Month Post-treatment Follow-up Visits;

Schedule 4:  Blood Sample Collection Time Points for PK/PD Assessments.


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Study Diary
Throughout the study, subjects (or caregivers) will use a study diary each day to document 
specific information about any angioedema attack symptoms that occur (eg, including the 
location, severity, pain score, and duration of symptoms) and details on self-administration of 
investigational product.  At the first dosing visit (Dosing Visit 1), study personnel will instruct 
each subject (or caregiver) how to complete the study diary.
Study personnel will review the diary for completeness and accuracy at each scheduled dosing 
visit.  The Investigator or designee will use subject-reported diary data as reference information, 
in addition to any other available medical records, to record and evaluate events related to 
breakthrough angioedema attacks in the CRF.
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported (or caregiver-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; and

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar day 
reported after the appearance of resolution will be considered 1 attack.
NOTE:  An angioedema attack does NOT include swelling due to trauma or arthritis, or 
symmetrical non-painful swelling of the lower extremities.
In this study, angioedema attacks will not be reported as adverse events unless the attack meets 
the definition of a serious adverse event.
Treatment of Breakthrough Angioedema Attacks
A breakthrough attack is defined as an angioedema attack that occurs during long-term 
prevention therapy with CINRYZE.  If a subject receives CINRYZE for treatment of a breakthrough 
angioedema attack, they should continue their protocol-defined treatment schedule without 
alteration regardless of when the supplemental dose is administered.
If a breakthrough angioedema attack occurs during the 12-week treatment period through 1-week 
post-treatment, a supplemental dose of CINRYZE may be administered by IV infusion for 
treatment of the attack either by the Investigator (or qualified delegate) or subject (or caregiver) 
if trained and deemed independent to self-administer (1000 U for subjects ≥6 years of age or 500 
U for subjects 2-5 years of age).  If the subject does not adequately respond to the initial dose 
within 1 hour, a second dose of CINRYZE may be administered (1000 U for subjects ≥6 years of 
age or 500 U for subjects 2-5 years of age).  It is recommended that treatment of breakthrough 


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attacks occurs at the investigational site whenever possible so that clinical assessments can be 
completed as specified.  It is preferred that subjects receive CINRYZE within 4 hours, but not 
more than 8 hours after the onset of breakthrough attack symptoms, if treatment can occur at the 
investigational site.  
Subjects at least 12 years of age or their caregivers) who have completed the required self-
administration training and deemed independent (per criteria specified in Section 5.3.1) may 
elect to self-administer CINRYZE for a breakthrough attack.  Note: Subjects (or caregivers) who 
are participating in self-administration training and not yet qualified as independent cannot self-
administer CINRYZE for a breakthrough attack; rather they must seek treatment at the 
investigational site.  If a subject (or caregiver) who self-administers CINRYZE for treatment of a 
breakthrough attack does not respond adequately after instructed treatment (ie, 2 doses separated 
by 1 hour), they should notify the Investigator and seek medical attention or report to study site 
to seek further treatment and relief of symptoms.
In addition to administration of CINRYZE, subjects are allowed to receive symptomatic treatment 
for breakthrough angioedema attacks (eg, IV fluids).  The administration of narcotics and 
antiemetics is discouraged during the 4-hour post-infusion assessment period to allow for 
evaluation of the response to CINRYZE.  Other treatments for angioedema attacks (eg, another C1 
INH product such as Berinert P, tranexamic acid, fresh frozen plasma) are not permitted at the 
investigational site unless a subject does not adequately respond following treatment with 
CINRYZE (ie, 2 doses separated by 1 hour).
Assessment of Breakthrough Angioedema Attacks
If a breakthrough attack occurs, subjects (or caregivers) should assess and record the following 
information in the study diary:

Presence of pain or swelling at each anatomic location (ie, upper airway [laryngeal], 
gastrointestinal/abdominal, facial, genitourinary, and extremity/peripheral) by indicating the 
overall severity (ie, mild, moderate, or severe [as defined below]) 

Overall amount of pain associated with the breakthrough attack using a visual analogue scale 
(VAS; only for subjects at least 5 years of age)

Any triggers associated with the attack

Any health care visit for the attack (investigational site, clinic or hospital/emergency 
department)

Any medications received to manage attack symptoms

Duration of symptoms (ie, time symptoms start to improve and time symptoms completely 
resolve)
In addition to the subject’s self-assessment, the Investigator should assess and record the overall 
severity of the attack if the subject seeks treatment for symptoms at the site.


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Treatment with CINRYZE
The Investigator (or qualified delegate) or subject (trained and deemed independent) may 
administer a supplemental dose of CINRYZE to treat the breakthrough attack.  Subjects self-
administering CINRYZE will record clinical assessments associated with breakthrough attacks in 
the study diary.
Following the administration of CINRYZE, subjects (or caregivers) will record their symptoms
(the presence of pain or swelling at each anatomic location) and assess the overall severity of the 
breakthrough attack every 15 minutes for up to 4 hours post-infusion using the following scale:

No symptoms.

Mild:  The attack symptoms are noticeable but are easily tolerated by the subject and do not 
interfere with the subject’s daily activities.

Moderate:  The attack symptoms interfere with the subject’s ability to attend work/school or 
participate in family life and social/recreational activities.

Severe:  The attack symptoms significantly limit the subject’s ability to attend work/school 
or participate in family life and social/recreational activities.
Subjects (or caregivers) also will rate the overall amount of pain associated with the 
breakthrough attack using a VAS (for subjects at least 5 years of age) on the same schedule as 
overall attack severity.  
In addition to the subject’s self-assessment, the Investigator should assess and record the overall 
severity every 15 minutes for up to 4 hours post-infusion if the subject seeks treatment at the site.
NOTE:  If a subject has adequately responded to treatment with CINRYZE, the subject may omit 
further assessments up to 4 hours post-infusion (and if applicable, be discharged from the 
investigational site) provided that overall attack severity has been assessed for at least 1 hour.
Subject diary data will be used by study personnel to record the onset date and time of the 
breakthrough attack, as well as the date and time of onset of symptom improvement and 
Complete Resolution (defined in Efficacy Endpoints) in the CRF.
Safety Monitoring
Safety will be assessed by monitoring adverse events and changes in physical examinations, vital 
signs, and clinical safety laboratory testing.  In addition, subjects will be monitored for the 
development of antibodies to C1 INH.  If clinically indicated, study personnel may perform 
examinations to actively monitor subjects for possible venous thromboembolism or other 
thrombotic or thromboembolic (T/TE) events.  Investigators will comply with recommended 
procedures for the management of all suspected T/TE events.


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Stopping Rules
If an anaphylactic reaction or a thrombotic or thromboembolic event occurs in any subject, 
stopping rules for the individual subject and for the overall study will be employed (see 
Section 5.5).
Sample Collection for PK, PD, and C1 INH Antibody Analyses
Subjects will have blood samples collected for the determination of plasma concentrations of C1 
INH antigen (protein volume), functional C1 INH activity (potency), complement C4, and C1q. 
In addition, blood samples will be collected at Visits 1 (baseline), 8, 16, and 24 and 1 month (30 
±2 days) after the last dose of study drug for C1 INH antibody analyses.
Quality of Life
The Angioedema Quality of Life (AE-QoL) is a questionnaire on the quality of life of patients 
suffering from recurrent angioedema.  It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and diet.  Subjects will be asked by study 
personnel 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 questionnaire will be completed at the time points specified in Schedule 1 and Schedule 3.  
This instrument will be administered as appropriate for each subject’s age (ie, includes option of 
guidance from parent/guardian).
Self-administration Survey
A self-administration survey containing questions for subjects (or caregivers) and the 
Investigator’s assessment of the overall experience with self-administration of IV CINRYZE will 
be completed on Visit 24 (see Schedule 1). 
Statistical Considerations:
Statistical Methods: Data will be summarized using the same methods that were used in the 
overseas development program for IV CINRYZE. Experimental results will be summarized using 
descriptive statistics (n, mean, standard deviation or standard error, median, and range for 
continuous endpoints; number and percent of subjects in each category for categorical 
endpoints). To establish context, efficacy/pharmacology results from this study may be 
superimposed (eg, graphically) on experimental data from previous overseas studies, as 
appropriate.
Safety Analyses:
The following will be assessed:

Adverse events (including treatment-emergent adverse events).

Summary statistics and changes from baseline to post-baseline for laboratory testing, vital 
signs, and, if applicable, any ECG findings will be presented.


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
Results of C1 INH antibody testing will be reported for individual subjects and summarized 
as appropriate.
PK/PD Analyses: Concentrations of C1 INH antigen (protein volume), functional C1 INH 
activity (potency), and complement C4 and C1q for individual subjects will be determined using 
fully validated bioanalytical methods. Results will be summarized using descriptive statistics at 
each time point with and without baseline correction. C1q concentrations will be assessed at 
baseline only (ie, pre-infusion, Dosing Visit 1).
Pharmacokinetic/pharmacodynamic parameters will be calculated using observed and/or 
baseline-corrected concentration-versus-time data using non-compartmental techniques.  An 
exploratory PK/PD analyses may be performed based on correlation of plasma concentrations of 
C1 INH antigen (protein volume), functional C1 INH activity (potency), and C4 complement and 
efficacy and safety responses. 
Efficacy Analyses:
Prevention of Angioedema Attacks
The following efficacy endpoints for prevention of angioedema attacks will be assessed:

The number of angioedema attacks recorded during the treatment period, normalized for the 
number of days the subject participated in the period.

The overall frequency of angioedema attacks occurring during the treatment period will be 
calculated and compared with historical baseline values.

Summary of all attacks during the treatment period, including:

Anatomic location.

Severity (intensity).

Duration.

Number of rescue treatments (including antiemetics, narcotics, or C1 INH therapy, 
including administration of rescue CINRYZE).

Effects of therapy on quality of life (results of AE-QoL questionnaire).
Treatment of Breakthrough Angioedema Attacks
The following efficacy endpoints for treatment of breakthrough angioedema attacks will be 
assessed by CINRYZE-treated attack number:

The number of subjects who achieve Clinical Relief.  Clinical Relief is defined as a sustained 
reduction from pre-infusion in the attack severity within 4 hours after initiation of treatment 
with CINRYZE.

Time to onset of Clinical Relief.

The number of subjects who achieve Complete Resolution.  Complete Resolution is defined 
as the cessation of all symptoms of the breakthrough angioedema attack.


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
Time to Complete Resolution.
Other analyses may be performed to establish context of the efficacy results from this study with
previous Phase 3 CINRYZE studies.


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Schedule 1:
Clinical Study Assessments – Screening and Treatment Period
Procedure
Screening 
a
TREATMENT PERIOD (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
DOSING VISITS (1 to 24)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Informed consent (or 
written permission and 
assent)
X
Medical/angioedema 
history and physical 
exam
X b
Physical exam update c
X
X
X
X
Prior/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
Vital signs (BP, pulse) d, 
e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG d
X
Hematology and clinical 
chemistry c
X
X
X
X
X
Urinalysis with 
microscopy c
X
X
X
X
Coagulation (PT, aPTT, 
INR) c
X
X
X
X
Virology screening f
X
Pregnancy testing c, g
X
X
X
Study drug administration 
See Schedule 2
Daily angioedema attack 
monitoring and study 
diary h
X
X
Adverse events
X i
X
X
Immunogenicity (C1 INH 
antibody) c
X
X
X
X
Quality of life 
questionnaire (AE-QoL) c
X
X
X
X
Self-administration survey
X
PK/PD assessments
X
See Schedule 4
X


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Schedule 1:
Clinical Study Assessments – Screening and Treatment Period
Procedure
Screening 
a
TREATMENT PERIOD (BY STUDY WEEK)
1
2
3
4
5
6
7
8
9
10
11
12
DOSING VISITS (1 to 24)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
AE-QoL=angioedema quality of life; aPTT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 inhibitor; ECG=electrocardiogram; INR=international normalized ratio; 
PD=pharmacodynamics; PK=pharmacokinetics; PT=prothrombin time
a:
All subjects will have a screening evaluation within 21 days before the first dose (Dosing Visit 1).  Subjects must not have received any C1 INH or blood products within 3 days before 
the first dose of study drug and must not have had signs or symptoms of an angioedema attack within 2 days before the first dose of study drug.  If at the screening visit, a subject meets 
both of these criteria, the screening and Dosing Visit 1 assessments can occur on the same day (see Section 6).  For subjects who weigh less than 25 kg, screening must occur at least 14 
days before Dosing Visit 1.
b:
If functional C1 INH testing is not performed as standard of care to diagnose HAE, a blood sample will be collected at screening to confirm the deficiency in the levels of C1 INH 
and/or C1 INH activity.
c:
On dosing days, specified procedures and blood and urine sample collections should be performed prior to study drug 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. Vital sign measurements will not be collected at Visits 10, 12, 14, 18, 20, and 22 from subjects who independently self-administer investigational product at home.
e:
On dosing days, vital signs should be obtained ≤30 min before the start of the infusion, ≤15 min after completion of the infusion, and between 30 min and 1 h after completion of the 
infusion.
f:
HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
g:
All females of childbearing potential (in accordance with standards at the site).
h:
Subjects (or caregivers) will also record information on the self-administration of investigational product in the study diary.
i:
Adverse events will be collected from the time informed consent is signed.
See Schedule 3 for clinical study assessments at the Early Discontinuation Visit (if applicable) and the 1-Week and 1-Month Post-treatment Follow-up Visits.




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Schedule 3:
Clinical Study Assessments – Early Discontinuation Visit and 1-week and 1-month 
Post-treatment Follow-up Visits
Procedure
Early Discontinuation Visit a
[If Applicable]
1-Week (±1 day)
Post-treatment Visit
[All Subjects]
1-Month (30 ±2 days)
Post-treatment Visit
[All Subjects]
Physical exam update
X
Concomitant/post-treatment medications
X
X
X
Body weight
X
Vital signs (BP, pulse) b
X
Hematology and clinical chemistry
X
Urinalysis with microscopy
X
Coagulation (PT, aPTT, INR)
X
Pregnancy testing c
X
Daily angioedema attack monitoring and 
study diary
X d
X
Adverse events/SAEs e
X
X
X
Immunogenicity (C1 INH antibody)
X
X
Quality of life questionnaire (AE-QoL)
X
PK/PD assessments
X f
AE-QoL=angioedema quality of life; aPTT=activated partial thromboplastin time; BP=blood pressure; C1 INH=C1 inhibitor; INR=international normalized ratio;
PD=pharmacodynamics; PK=pharmacokinetics; PT=prothrombin time; SAE=serious adverse event
a:
If a subject prematurely discontinues investigational product, regardless of the reason, the Early Discontinuation Visit procedures listed in Schedule 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 Follow-up visits.
b:
Vital signs will be measured using standard methods at each study site.
c:
All females of childbearing potential (in accordance with standards at the site).
d:
Subjects who prematurely discontinue should complete the study diary on the day of discontinuation.
e:
Adverse events will be collected through 7 days after the last dose of investigational product.  Investigators will report all serious adverse events (SAEs) that occur up to 30 
days after the last dose of study drug to PAREXEL International Pharmacovigilance.  In addition, SAEs considered by the Investigator to be related to study drug that occur 
>30 days after the last dose will be reported.
f:
If a subject prematurely discontinues on a blood sample collection day for PK/PD assessments (see Schedule 4), every effort should be made to collect the PK/PD sample(s)
according to schedule. If a subject discontinues on a day when PK/PD assessments are not scheduled, a single PK/PD blood sample should be collected with sampling time 
recorded in the CRF.


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Schedule 4:
Blood Sample Collection Time Points for PK/PD Assessments
C1 INH 
Antigen 
(Protein 
Volume), 
Functional 
C1 INH 
Activity 
(Potency),
and Complement C4
TREATMENT PERIOD (BY STUDY WEEK)
Early 
Discontinuation 
Visit
[If Applicable]
Week 1
Week 2
Week 3
Week 12
Sample Time
Dosing Visit 1
Dosing Visit 3
Dosing Visit 5
Dosing Visit 24
Prior to infusion of study drug
X a
X
X
X
X g
0.5 hour after start of infusion
X b
X b
1 hour after start of infusion
X c
X c
2 hours after start of infusion
X c
X c
6 hours after start of infusion
X c
X c
24 hours after start of infusion
X d
X d
48 hours after start of infusion
X d
X d
72 hours after start of infusion
X d, e
X d
96 hours after start of infusion
X d, f
X d
C1 INH=C1 inhibitor; PD=pharmacodynamics; PK=pharmacokinetics
a:
C1q concentration will also be assessed from the baseline sample (pre-infusion at Dosing Visit 1).
b:
Collect within ± 5 min of the specified time.
c:
Collect within ± 15 min of the specified time.
d:
Collect within ± 2 h of the specified time.
e:
If Dose 2 is scheduled to be administered 3 days after Dose 1, the 72-hour sample should be collected pre-infusion and the 96-hour sample should be omitted.
f:
If Dose 2 is scheduled to be administered 4 days after Dose 1, the 96-hour sample should be collected pre-infusion.
g:
If a subject prematurely discontinues on a day when PK/PD assessments are scheduled every effort should be made to collect the PK/PD sample(s) as indicated. If a subject 
discontinues on a day when PK/PD assessments are not scheduled, a single PK/PD blood sample should be collected with sampling time recorded in the CRF.
NOTE:
If a subject presents to the site with a breakthrough angioedema attack, every effort should be made to obtain a PK blood sample before treatment.  In addition, if the 
subject receives CINRYZE for treatment of the attack, every effort should be made to obtain a 1-hour post-treatment sample; if a second dose of CINRYZE is 
administered, an additional 1-hour post-treatment sample should be obtained if possible.  These samples will be collected as an unscheduled visit and analyzed for C1 
INH antigen (protein volume) and functional C1 INH activity (potency).


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1
INTRODUCTION
Hereditary angioedema (HAE) is a rare, autosomal dominant disease caused by an inherited or 
spontaneous gene mutation on chromosome 11 that results in a quantitative or functional 
deficiency of C1 inhibitor (C1 INH) protein (Bernstein 2011).1  C1 inhibitor is a serine protease 
inhibitor (or “serpin”) that 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.  
Replacement of C1 INH through intravenous (IV) administration of CINRYZE® (C1 inhibitor 
[human]) increases serum concentrations of C1 INH antigen (protein volume) and functional C1 
INH activity (potency), temporarily restoring the natural regulation of the complement, contact 
(bradykinin-forming), and fibrinolytic systems.  C1 inhibitor replacement therapy can prevent 
the occurrence of angioedema attacks associated with HAE or stop and control the mechanism 
that causes swelling if an attack does occur.
Most HAE patients have a positive family history of angioedema, but the disease also occurs 
spontaneously, with de novo mutations accounting for approximately 25% of cases 
(Bowen et al. 2010).  Symptoms typically first appear during childhood or adolescence, worsen 
during puberty, and persist throughout a patient’s lifetime (Lumry 2013).  Angioedema attacks 
can affect the face, tongue, larynx, gastrointestinal tract, genitourinary system, and extremities 
(Zuraw 2008).  Gastrointestinal involvement can mimic an acute surgical emergency, and 
misdiagnosis often results in unnecessary procedures to remove normal appendices and 
gallbladders (Weis 2009).  Laryngeal swelling can occlude the airway and cause death by 
asphyxiation.
The frequency and severity of angioedema attacks vary widely, even among members of the 
same family, and are unrelated to the degree of C1 INH deficiency or dysfunction.  Although it is 
often unclear what precipitates attacks, commonly cited triggers include trauma, physical and 
psychological stress, medical, surgical, or dental procedures, menstruation, infections, use of 
estrogen-containing oral contraceptives, and angiotensin-converting enzyme (ACE) inhibitors 
(Longhurst and Nzeako 2012).
The estimated prevalence of HAE is 1:50,000 people worldwide (range:  1:10,000 to 1:150,000) 
(Horiuchi et al. 2012; Bowen et al. 2008).  However, the current medical literature reflects far 
fewer identified cases in Japan.  In 2009, a nationwide prevalence survey of 1389 larger hospitals 
in Japan identified 52 patients with HAE (Iwamoto et al. 2011).  Yamamoto et al. (2012) 
reviewed the medical literature from 1969 to 2010 and identified 132 unique Japanese patients 
                                                
1 The World Health Organization disease classification for C1 INH deficiency is D84.1, “Defects in the 
Complement System,” under “Other Immunodeficiencies” in “Diseases of the Blood and Blood-forming Organs 
and Certain Disorders Involving the Immune Mechanism” (ICD-10, Version 2010).  The Japan Nanbyo Research 
Foundation classifies C1 INH deficiency as a subcategory of Specified Rare and Intractable Disease (Tokutei 
Shikkan) No. 35, Primary Immunodeficiency Syndrome.


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with HAE.  Although the prevalence of patients with HAE appears to be lower in Japan, the 
distribution and pattern of C1 INH mutations and clinical features of the patients identified 
appear to be similar to Western populations (Yamamoto et al. 2012).
The burden of HAE on patients and family members is considerable with respect to its 
detrimental effects on physical health, career and work productivity (missed days), education 
(missed days), and mental health (feelings of panic and anxiety) (Aygören-Pürsün et al. 2012; 
Caballero et al. 2014; Lumry et al. 2010).  Individual patients may be debilitated by their 
symptoms for up to 100 days per year, making employment or education difficult (Nzeako et al. 
2001).  Because of its unpredictability, HAE can be life-altering regardless of angioedema attack 
frequency.  Patients live in constant fear of the next attack, and often arrange their lives around 
these events.  Some patients who have had laryngeal attacks, or who have had family members 
die due to laryngeal attacks, never leave their local environment for fear of being distant from the 
safety of their home and the physicians who know and understand their illness (Levi et al. 2006).
The only product approved in Japan for the management of patients with HAE is Berinert P, a 
human C1 inactivator indicated to treat acute attacks of HAE.  There is no approved therapy in 
Japan for long-term C1 INH protein replacement or prevention of angioedema attacks in patients 
with HAE.  Given the questionable safety and efficacy of unapproved therapies currently being 
used to prevent angioedema attacks in Japan (ie, danazol, tranexamic acid), an unmet medical 
need exists for a subset of Japanese patients who experience frequent or life-threatening attacks 
and are not adequately managed with repeated acute treatments.  CINRYZE is the only C1 INH 
protein replacement therapy in the world that is approved for both long-term (routine) prevention 
of angioedema attacks and treatment of acute attacks in patients with HAE.  Routine replacement 
of C1 INH in patients who experience frequent attacks, severe attacks, and/or laryngeal attacks 
has been associated with improved patient outcomes, including a reduction in potential mortality, 
number of hospitalizations, and increased quality of life (eg, relief from anxiety, flexibility to 
travel, freedom to pursue educational and professional goals) (Craig et al. 2009; Kalfus et al.
2012; Gower et al. 2012).  Consequently, international consensus guidelines have endorsed long-
term replacement of C1 INH in the appropriate patient populations (Cicardi et al. 2012; Bowen
2011; Bowen et al. 2010).
1.1
CINRYZE (C1 Inhibitor [Human])
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 drug-drug interactions exhibited by many low molecular weight compounds.
In October 2008, IV administration of CINRYZE was approved by the US FDA for routine 
prophylaxis against angioedema attacks in adolescent and adult patients with HAE. In June 
2011, CINRYZE was approved by the EMA via the Centralized Procedure for treatment and pre-
procedure prevention of angioedema attacks in adults and adolescents with HAE, and for routine 
prevention of angioedema attacks in adults and adolescents with severe and recurrent attacks of 
HAE who are intolerant to or insufficiently protected by oral prevention treatments, or patients 


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who are inadequately managed with repeated acute treatment. Shire ViroPharma Incorporated 
also received marketing authorizations for CINRYZE in Canada (2012), Australia (2012), India 
(2013), Switzerland (2013), and Israel (2013). The marketing authorisations in India and Israel 
were later withdrawn for commercial reasons.
1.1.1
Nonclinical Experience
The acute toxicity of C1 INH following IV administration of CINRYZE was studied in a combined 
dose-ranging acute toxicity (single dose) and 7-day repeat-dose toxicity study in Sprague-
Dawley rats at dose levels of 20, 100, and 400 U/kg/day.  In addition, a 14-day repeat-dose study 
was conducted in rats at the same dose levels.  No signs of toxicity were observed in the single 
dose study.  In the 14-day repeat-dose study, no signs of toxicity were observed at the two lower 
doses (20 and 100 U/kg/day).  Repeat dosing in the rat resulted in an antibody response between 
Days 1 and 14, but an immunologic response is expected because CINRYZE is derived from 
human plasma.
In a poorly designed study in the Wessler stasis model using an earlier generation C1 INH 
product, a potential thrombogenic threshold was suggested at doses greater than 200 U/kg (14-
fold greater than recommended clinical dose for a 70 kg adult).  However, results of an ex vivo
thrombogenicity study utilizing healthy human whole blood and platelet poor plasma showed no 
evidence of a hypercoagulable effect of CINRYZE at concentrations of 0.14-7.0 U/mL 
(approximately 7 times the physiologic concentration).  These findings are consistent with a 
toxicology study of CINRYZE in rats, where no signs of thrombogenicity were observed at doses 
up to 400 U/kg/day for 14 days.
Reproductive studies in Sprague-Dawley rats at doses up to 400 U/kg showed no evidence of 
harm to the fetus due to CINRYZE treatment during the period of organogenesis; however, it is 
unknown if there was an antibody-mediated effect due to administration of a heterologous 
protein.  No specific studies on fertility, early embryonic, and postnatal development or 
carcinogenicity studies were conducted because they cannot be reasonably performed using 
conventional animal models due to development of antibodies following administration of 
heterologous human proteins.  No genotoxicity studies were performed because C1 INH is 
unlikely to interact directly with DNA or other chromosomal material. 
1.1.2
Clinical Experience
The overseas development program for IV CINRYZE included 2 multicenter studies of CINRYZE
for prevention of angioedema attacks (1 double-blind, placebo-controlled study and 1 open-label 
study) and 2 multicenter studies of CINRYZE for treatment of angioedema attacks (1 double-
blind, placebo-controlled study and 1 open-label study).  All 4 studies were conducted in the US 
(LEVP 2005-1/A, LEVP 2005-1/B, LEVP 2006-1, and LEVP 2006-4).  In the double-blind, 
placebo-controlled prevention study (LEVP 2005-1/B), CINRYZE was shown to reduce the 
incidence of angioedema attacks in 22 subjects analyzed (mean normalized 12-week angioedema 
attack rate:  6.3 for CINRYZE vs. 12.8 for placebo; p<0.0001).  In the double-blind, placebo-
controlled treatment study (LEVP 2005-1/A), subjects receiving CINRYZE achieved beginning of 
unequivocal relief of the defining attack symptom at a rate 2 times greater than subjects 
receiving placebo (p=0.017 for the Efficacy Dataset of 68 subjects [35 CINRYZE, 33 placebo]).


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receiving placebo (p=0.017 for the Efficacy Dataset of 68 subjects [35 C CINRYZE INRYZE, 33 
placebo]).
More than 14,500 IV infusions of CINRYZE were administered to 262 unique subjects in 
8 completed clinical studies in the overseas development program for IV CINRYZE.  The vast 
majority of infusions were doses of 1000 U.  In the placebo-controlled study with the longest 
administration period (LEVP 2005-1/B, prevention of angioedema attacks), 1000 U of IV 
CINRYZE was administered every 3 or 4 days for 12 weeks.  In this study, the only CINRYZE -
related treatment-emergent adverse events that occurred in more than 1 subject were viral upper 
respiratory tract infection and rash, each occurring in 3 subjects (12%).  Across studies, there 
were only occasional reports of infusion site pain, bruising, rash, or related localized conditions.  
No subjects were discontinued from CINRYZE due to an adverse event in any of the studies.
Thrombotic events have been observed following IV administration of the approved dose of 
CINRYZE.  In the open-label prevention study (LEVP 2006-4), in which subjects received 1000 U 
of CINRYZE every 3 to 7 days (median duration of exposure:  8 months), 5 serious thrombotic 
events occurred (myocardial infarction, deep vein thrombosis, pulmonary embolism, and 2 
events of cerebrovascular accident).  The majority of these events occurred in subjects with 
thrombogenic risk factors.  Patients with known risk factors for thrombotic events (including 
indwelling catheters) should be monitored closely.  In the overseas development program for IV 
CINRYZE, no serious adverse events were considered by the Investigator to be possibly, probably, 
or definitely related to treatment with CINRYZE.
The pharmacokinetics (PK) and pharmacodynamics (PD) of CINRYZE following IV 
administration in subjects with HAE are primarily based on the results of Study LEVP 2006-5.  
After IV administration of 1000 U, functional C1 INH activity (potency) increased from a mean 
baseline value of 0.31 U/mL to a maximum concentration (Cmax) of 0.68 U/mL.  Two 
consecutive 1000 U doses administered 60 minutes apart produced a mean Cmax of 0.85 U/mL.  
Median time to maximum concentration (tmax) was approximately 1 to 2 hours.  The mean 
terminal elimination half-life (t1/2) of functional C1 INH activity (potency) was approximately 60 
hours using non-compartmental methods.  Mean clearance (CL) values were 0.85 and
1.17 mL/min for the single and double doses, respectively.  Mean Cmax values for C1 INH 
antigen (protein volume) following IV administration of CINRYZE were 1.48 and 1.70 U/mL for 
the single and double doses, respectively.  Median tmax was approximately 1.5 hours.  The mean 
t1/2 of C1 INH antigen (protein volume) was approximately 45 to 47 hours and mean CL was 
0.70 mL/min.
Three post-marketing studies of IV CINRYZE in subjects with HAE were initiated after US 
marketing approval.  The 3 studies evaluated doses of CINRYZE higher or lower than the 
approved 1000 U dose and the doses were considered to be appropriate for the target population. 
Study 0624-400, now complete, was a post-marketing requirement mandated by the US FDA.  
This open-label study assessed the safety and efficacy of escalating doses of IV CINRYZE (1500 
U, 2000 U, and 2500 U twice per week) as prophylactic therapy in subjects ≥6 years of age who 
were not adequately controlled (>1 angioedema attack/month, regardless of severity) while 
receiving 1000 U of CINRYZE every 3 or 4 days. Study 0624-203, now complete, was an open-


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label, single-dose study evaluating 3 different doses (500, 1000, or 1500 U) of IV CINRYZE
(based on subject body weight category) for treatment of acute angioedema attacks in children 
≥2 to <12 years of age. Study 0624-301 is currently an ongoing, randomized, single-blind, 
crossover study evaluating 2 dosing regimens (500 U and 1000 U twice per week) of IV 
CINRYZE for the prevention of angioedema attacks in pediatric subjects 6 to 11 years of age. 
For additional details regarding CINRYZE clinical studies please refer to the latest edition of the 
CINRYZE Investigator’s Brochure. 
1.2
Study Rationale
Currently, there is no product approved in Japan for both prevention of angioedema attacks and 
treatment of angioedema attacks associated with HAE.  In clinical trials conducted outside of 
Japan, CINRYZE was proven to be safe, well tolerated, and effective for the prevention and 
treatment of angioedema attacks in a broad age range of patients with HAE (pediatrics through 
patients ≥65 years old).  Overseas studies have shown that self-administration allows patients to 
manage their disease symptoms with minimal disruption to their daily activities resulting in 
reduced absences from work or school and overall improvement in quality of life 
(Cicardi et al. 2013; Caballero et al. 2013).  It is expected that CINRYZE will fulfill an unmet 
medical need for Japanese patients with HAE, and the present study is being performed to 
confirm its safety and efficacy in this patient population.


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2
STUDY OBJECTIVES
The objectives of the study are to assess:

The safety and tolerability of CINRYZE administered by IV infusion in Japanese subjects with 
HAE;

The PK and PD of CINRYZE administered by IV infusion in this subject population; and

The treatment effect of CINRYZE administered by IV infusion for the prevention of 
angioedema attacks and treatment of breakthrough attacks in this subject population.
NOTE:  A breakthrough attack is defined as an angioedema attack that occurs during long-term 
prevention therapy with CINRYZE.


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3
INVESTIGATIONAL PLAN
This single-period, open-label study will be conducted at multiple investigational sites in Japan. 
All study sites will conduct the study in accordance with the protocol, International Conference 
on Harmonisation (ICH), and Good Clinical Practice (GCP) standards.  All sites will be trained 
by Sponsor/designee for self-administration (see Section 5.3.1).  Data from all sites will be 
pooled for purposes of analysis and will be reported in the final clinical study report. Each 
subject will participate for approximately 5 months (Figure 1).
Potential subjects will be screened within 21 days before receiving their first dose of study drug.  
Subjects who are deemed eligible will be enrolled (see Section 4).  If subjects withdraw or 
discontinue after enrollment, additional subjects may be enrolled to ensure at least 6 subjects 
complete the study (see Section 6.15).  
Subjects will be administered CINRYZE by IV infusion twice weekly (every 3 or 4 days) for 12 
weeks.  Subjects may not receive C1 INH therapy or any blood products within 3 days before the 
first dose of study drug or have signs or symptoms of an angioedema attack within 2 days before 
the first dose of study drug.
This is an outpatient study; however, subjects may require an overnight stay at the site for those 
days on which serial PK/PD blood samples are collected.  Subjects would be discharged the 
following day after collection of the 24-hour PK/PD blood sample.
Study drug will be administered to all subjects at the investigational site for Dosing Visits 1 
through 8, 16, and 24; during these visits, subjects may also have physical examinations and 
other procedures performed (see Schedule 1).  Other doses of study drug may be administered at 
the investigational site or at the subject’s home.  
Subjects who are at least 12 years of age and considered suitable candidates (ie, those with a 
physical and mental capability of learning, adequate venous access, and willing to self-
administer) will undergo detailed training at the study site on the skills needed for self-
administration of investigational product (see Schedule 2).  Alternatively, a subject’s caregiver 
(such as a parent or guardian) can receive this training and will be allowed to administer the 
investigational product to a subject who requires assistance.  The administration of the first 2 
doses of investigational product should be done by the Investigator or qualified delegate at the 
study site, while subjects (or caregivers) who elect to self-administer will receive training 
materials and be instructed on the process of handling and reconstituting CINRYZE, proper 
venous access, and correct administration by IV infusion.  Initiation of subject (or caregiver) 
self-administration with supervision by the Investigator or qualified delegate can begin on 
Dosing Visit 3 and continue as long as needed, but it is expected that subjects (or caregivers)
may require supervised training through to Dosing Visit 8.  After completing the required 
training, and provided the subject (or caregiver) is deemed independent according to the criteria 
described in Section 5.3.1, a subject (or caregiver) may elect to self-administer one or more 
doses of CINRYZE at home or at the study site.  The Investigator’s acknowledgement that a 
subject (or caregiver) is certified for independent self-administration will be entered in the CRF.


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Figure 1:
Study Design
It is recommended that treatment of breakthrough attacks (ie, angioedema attacks that occur 
during long-term prevention therapy with CINRYZE) occurs at the investigational site whenever 
possible so that clinical assessments can be completed as specified.  It is preferred that subjects 
receive CINRYZE within 4 hours but not more than 8 hours after the onset of breakthrough attack 
symptoms if treatment can occur at the investigational site (see Section 6.12.1).  Details on the 
assessment of breakthrough angioedema attacks treated with CINRYZE are provided in Section 
6.12.2.
Throughout the trial, a study diary will be used by subjects (or caregivers) to record specific 
information about any angioedema attack symptoms and details on the self-administration of 
investigational product (see Section 6.11).  Because of the potential to precipitate an angioedema 
attack, subjects will be requested to postpone elective medical procedures (eg, dental work) and 
avoid other known attack triggers while participating in the study (see Section 6.10).
Safety will be assessed by monitoring adverse events and changes in physical examinations, vital 
signs, and clinical safety laboratory testing.  In addition, subjects will be monitored for the 
development of antibodies to C1 INH.  If clinically indicated, study personnel may perform 
examinations to actively monitor subjects for possible venous thromboembolism or other 
thrombotic or thromboembolic (T/TE) events.  Stopping rules are provided in Section 5.5.


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In this study, angioedema attacks will not be reported as adverse events unless the attack meets 
the definition of a serious adverse event (see Section 9.1.4).
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 PAREXEL International Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
Post-treatment follow-up visits will be performed 1 week (±1 day) and 1 month (30 ±2 days) 
after the last dose of study drug.  If a subject prematurely discontinues investigational product, 
regardless of the reason, the Early Discontinuation Visit procedures listed in Schedule 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 Follow-up visits.
The schedules of study procedures are provided as follows:

Schedule 1:  Clinical Study Assessments – Screening and Treatment Period;

Schedule 2:  Investigational Product and Self-administration Training;

Schedule 3:  Clinical Study Assessments – Early Discontinuation Visit and 1-Week and 1-
Month Post-treatment Follow-up Visits;

Schedule 4:  Blood Sample Collection Time Points for PK/PD Assessments.


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4
STUDY POPULATION
Inclusion and exclusion criteria for enrolling subjects in this study are presented in Sections 4.1
and 4.2 below.  If there is any question about subject eligibility, the Investigator should consult 
with the Sponsor before enrolling the subject.
4.1
Inclusion Criteria
To be eligible for this protocol, a subject must:
1. Be of Japanese descent, defined as born in Japan and having Japanese parents and 
Japanese maternal and paternal grandparents.
2. Be ≥2 years of age.
3. Meet the following minimum body weight criteria:

Subjects 2 to 5 years of age must weigh at least 12.5 kg; and

Subjects 6 years of age and above must weigh at least 25 kg.
4. Have a confirmed diagnosis of Type I or Type II HAE.  NOTE:  Diagnosis may be based 
on historical data including family history, clinical symptoms (characteristic attacks), and 
documentation of low level of C1 INH protein and/or C1 INH activity.
5. Have a history of at least one angioedema attack per month (on average) during the 
3 consecutive months immediately before enrollment.
6. Agree to adhere to the protocol-defined schedule of assessments and procedures.
7. Agree to avoid his/her known angioedema attack triggers during the study to the best of 
his/her ability.
8. If a female of reproductive age, be postmenopausal (≥12 months following cessation of 
menstruation), surgically sterile, or following an acceptable method of birth control (and 
agree to continue its use through 1 month after the last dose of study drug):

Non-hormonal methods (eg, abstinence, barrier control) for at least 1 complete 
menstrual cycle before the Screening Visit.

Stable doses of estrogen and/or progestin containing products for at least 2 months 
before the Screening Visit.
9. If a male of reproductive age, 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 study drug.
10. If an adult, be informed of the nature of the study and provide written informed consent 
before any study-specific procedures are performed.
OR
If a child or minor (<20 years of age), have a parent/legal guardian who is informed of 
the nature of the study provide written informed consent (ie, permission) for the child to 


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participate in the study before any study-specific procedures are performed.  Assent will 
be obtained from children ≥14 years of age.
4.2
Exclusion Criteria
To be eligible for this protocol, a subject must not:
1. Have a history of hypercoagulability (abnormal blood clotting).
2. Have a diagnosis of acquired angioedema or be known to have C1 INH antibodies.
3. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any of the 
components of CINRYZE) or other blood products.
4. Have received C1 INH therapy or any blood products within 3 days before the first dose 
of study drug.
5. Have had signs or symptoms of an angioedema attack within 2 days before the first dose 
of study drug.
6. Have any change (start, stop, or change in dose) in androgen therapy (eg, danazol, 
oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid 
(EACA), or other antifibrinolytics within 14 days before the first dose of study drug.
7. If female, have started taking or changed the dose of any hormonal contraceptive regimen 
or hormone replacement therapy (eg, estrogen/progestin containing products) within 2 
months before the first dose of study drug.
8. Be pregnant or breastfeeding.
9. Have received an investigational drug other than those required for prevention or 
treatment of angioedema attacks within 30 days before the first dose of study drug.
10. 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 study drug or 
interpretation of study results.


S hire
C O N FI D E N TI A L
P a ge 3 9
Pr ot oc ol 0 6 2 4 -2 0 9 wi t h A me n d me nts 1, 2, 3, 4, a n d 5
3 0 A u g 2 0 1 6
CI N R Y Z E ( C 1 i n hi bit or [ h u m a n])
5
S T U D Y D R U G A D MI NI S T R A TI O N
5. 1
D ose Selecti o n
I n c o u ntries w here C I N R Y Z E is a p pr o ve d f or r o uti ne pre ve nti o n of a n gi oe de ma attac ks i n patie nts 
wit h H A E, t he rec o m me n de d d ose f or a d olesce nts a n d a d ults is 1 0 0 0 U a d mi nistere d 
i ntra ve n o usl y e ver y 3 or 4 da ys.  Si nce t he prese nt st u d y will e nr oll Ja pa nese s u bjects as yo u n g 
as 2 years of a ge, t w o differe nt d oses of C I N R Y Z E will be a d mi nistere d de pe n di n g o n s u bject a ge, 
as descri be d bel o w.
S u bjects 2 t o 5 ye ars of a ge – 5 0 0 U of C I N R Y Z E will be a d mi nistere d b y I V i nf usi o n t wice 
wee kl y (e ver y 3 or 4 da ys) f or 1 2 wee ks.
F or c hil dre n y o u n ger t ha n 6 years of a ge, t he use of a 1 0 0 0 U d ose ma y be e xcessi ve a n d attai n 
u n necessaril y  hi g h C 1 I N H plas ma c o nce ntrati o ns.  T he scie ntific rati o nale s u p p orti n g a l o wer 
d ose of 5 0 0 U is t he re d uce d plas ma v ol u me prese nt i n patie nts < 6 y ears of a ge.  S pecificall y , 
c hil dre n bet wee n 2 a n d 5 years of a ge ha ve a n a vera ge plas ma v ol u me bet wee n 5 0 0 -9 0 0 m L.  
T he rec o m me n de d d ose of 5 0 0 U e ver y  3 t o 4 da ys is e x pecte d t o i ncrease plas ma C 1 I N H 
c o nce ntrati o ns bet wee n 5 5 -1 0 0 % fr o m baseli ne.  T his d ose was well t olerate d w he n 
a d mi nistere d t o 2 s u bjects bet wee n t he a ges of 2 a n d 5 i n t he o verseas de vel o p me nt pr o gra m f or 
I V CI N R Y Z E, a n d is bei n g e val uate d i n an o n g oi n g pe diatric st u d y ( 0 6 2 4-3 0 1) of C I N R Y Z E i n n o n-
Asia n c hil dre n wit h C 1 I N H deficie nc y .
I n a l o n g-ter m, o pe n-la bel cli nical trial of CI N R Y Z E f or pre ve nti o n of a n gi oe de ma attac ks ( L E V P 
2 0 0 6- 4), a 
 b o y recei ve d 5 0 0 U of I V C I N R Y Z E e ver y 3 t o 7 da ys f or a t otal of 4 2 d oses 
o ver a 2 8 8 -d a y  st u d y peri o d (
 t o 
).  T his d ose was well t olerate d a n d 
efficaci o us.  O ver t he c o urse of his partici pati o n i n t he st u d y, o nly t w o a d verse e ve nts were 
re p orte d (a b d o mi nal a n gi oe de ma attac k o n Da y 1 0 1 a n d u p per res pirat or y tract i nfecti o n o n Da y 
1 0 3).  [ N O T E:  T here was a 9- d a y  la g bet wee n his last d ose of C I N R Y Z E a n d t he a n gi oe de ma 
attac k.]  Neit her e ve nt was c o ns i dere d b y t he I n vesti gat or t o be relate d t o C I N R Y Z E, a n d b ot h 
res ol ve d.  T he s u bject c o m plete d t he st u d y.
Als o s u p p orti n g t his d osi n g rati o nale are data fr o m pe diatric patie nts ( w h o o n a vera ge ha ve a 
s maller plas ma v ol u me) de m o nstrati n g t he safety a n d effi cac y of a d osi n g re gi me n of 1 0 0 0 U 
e ver y 3 t o 4 d a y s i n c hil dre n as yo u n g as 6 ye ars of a ge ( L u mr y  et al. 2 0 1 3 ).
S u bjects 6 ye ars of a ge a n d ol der – 1 0 0 0 U of C I N R Y Z E will be a d mi nistere d b y  IV i nf usi o n 
t wice wee kl y (e ver y 3 or 4 da ys) f or 1 2 wee ks.
T he C 1 I N H acti vit y  of a 1 0 0 0 U d ose of C I N R Y Z E
P P D
re prese nts t he acti vity prese nt i n 1 litre of 
n or mal plas ma ( 1 U/ m L); c o nse q ue ntl y, i n a n a vera ge Wester n pers o n wit h a 3 litre plas ma 
v ol u me t his re prese nts a 3 3 % i ncrease i n t he a bs ol ute c o nce ntrati o n of f u ncti o nal C 1 I NH 
acti vit y ( p ote nc y).  I n a s maller s u bject wit h a plas ma v ol u me of 2 litres, t his d ose w o ul d 
i ncrease t he C 1 I N H c o nce ntrati o n by 5 0 % w hic h is cl oser t o t he n or mal ra n ge b ut d oes n ot 
res ult i n s u pra-p h y si ol o gic c o nce ntrati o ns.  He nce, t he d ose rati o nale of a 1 0 0 0 U d ose e ver y  3 t o 
4 da y s is a p pr o priate f or t he Ja pa nese p o p ulati o n w hic h ma y ha ve a l o wer plas ma v ol u me.  
P P D
P P D


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Summary – Dosage recommendations of 500 U of CINRYZE for subjects 2 to 5 years of age and 
1000 U of CINRYZE for subjects 6 years of age and older are justified by the safety, efficacy, and 
PK results from the overseas development program.  The similar safety and efficacy profiles 
observed in adults, adolescents, and children indicate that CINRYZE offers safe and effective 
therapy for long-term replacement therapy (prevention of angioedema attacks) and treatment of 
both acute and breakthrough angioedema attacks.  In addition, the similarity in functional 
C1 INH activity (potency) concentrations attained at 1 hour post-dose across age groups allays 
the potential concern that supra-physiologic levels of C1 INH might be attained in children as 
young as 2 years of age.
5.2
Randomization
Subjects will not be randomized in this study.
5.3
Study Drug
See Section 8 for a complete description of study drug.  Instructions for the reconstitution of 
CINRYZE will be provided in a separate study manual.  CINRYZE treatments will be prepared and 
administered at the investigational site or at the subject’s home.
For a 500 U dose, 1 vial of CINRYZE is reconstituted with 5 mL of Sterile Water for Injection, 
USP for a total volume of 5 mL.  For a 1000 U dose, 2 vials of CINRYZE are reconstituted for a 
total volume of 10 mL.  CINRYZE will be administered intravenously at a rate of approximately 
1 mL (100 U) per minute, as tolerated.
CINRYZE will be administered to all subjects at the investigational site for Dosing Visits 1 
through 8, 16, and 24.  Other doses of study drug may be administered at the investigational site 
or at the subject’s home (including the option for independent self-administration).  For each 
dose administered, the date and time of the start and end of the infusion and if self-administered 
(Y/N) will be recorded in the CRF.
5.3.1
Self-administration
The Sponsor has developed a set of training materials (eg, illustrated patient pamphlet, 
instructional video, dummy kit for injection) to assist the Investigators to teach and subjects to
learn the skills needed for self-administering CINRYZE.  The training materials were developed 
after careful review of Japanese and international guidelines for self-administration (MHLW 
2005; Caballero et al. 2013; Cicardi et al. 2013).  
The Investigator or qualified delegate responsible for teaching self-administration skills to the 
subjects will be required to undergo training (by Shire’s designated physician) specifically on 
CINRYZE product labelling, including instruction on handling, reconstitution, administration, and 
disposal of used equipment (eg, sharps and infectious material). This will ensure that all subjects 
receive uniform training consistent with CINRYZE product information.
Subjects who are at least 12 years of age and considered suitable candidates (ie, those with a 
physical and mental capability of learning, adequate venous access, and willing to be trained)


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will be allowed to self-administer after receiving detailed training as described below and 
demonstrating the necessary skills for independent self-treatment.  Alternatively, a caregiver 
(such as a parent or guardian) can receive this training and will be allow to administer the 
investigational product to a subject who requires assistance. Multiple training sessions will be 
needed however the actual number will differ for each subject (or caregiver) based on attainment 
of the required skill set and the personal comfort level with the technical and medical aspects of 
self-administration.  Hereditary angioedema patients in the US typically completed CINRYZE
self-administration training within an average of 5 visits (Gregory et al. 2014).  A subject (or 
caregiver) will be considered independent if they are able to correctly reconstitute study drug, 
access a vein for infusion, and successfully administer the drug on at least 2 consecutive training 
visits.
The administration of the first 2 doses of investigational product should be done by the 
Investigator or qualified delegate at the study site, while subjects (or caregivers) who elect to 
self-administer will receive training materials and be instructed as outlined below.  Initiation of 
subject (or caregiver) self-administration with supervision by the Investigator or qualified 
delegate can begin on Dosing Visit 3 and continue as long as needed, but it is expected that 
subjects may require supervised training through Dosing Visit 8.  After completing the required 
training, and provided the subject (or caregiver) is deemed independent, a subject (or caregiver) 
may elect to self-administer one or more doses of CINRYZE at home or at the study site.  The 
Investigator’s acknowledgement that a subject (or caregiver) is certified for independent self-
administration will be entered in the CRF.
Training sessions will include the following:

General information on CINRYZE, including storage and reconstitution of the lyophilized 
product according to manufacturer’s instructions

Techniques for safe and successful IV infusion (ie, proper venous access with infusion set 
and administration of study drug using aseptic techniques, safe disposal of used equipment 
[eg, needles and syringes])

Manage and report any occurrence of adverse effects

Trouble-shooting solutions (eg, if unable to perform an IV infusion)

Appropriate action for treating laryngeal attacks or if there is inadequate relief of a 
breakthrough attack after treatment with CINRYZE (2 doses separated by 1 hour).
For compliance with study procedures, subjects (or caregivers) will also be instructed on 
recording in the study diary the date and time (both start and end) of each CINRYZE infusion, 
location of infusion site, and study drug lot number.  In the case of self-administration of 
CINRYZE for a breakthrough attack (only if the subject or caregiver has completed training and is 
deemed independent), subjects (or caregivers) will also need to record the onset date and time of 
the attack, the overall amount of pain associated with the attack, assess symptom severity pre-
infusion and every 15 minutes up to 4 hours after completing the CINRYZE infusion, onset time of 
symptom improvement and the time symptoms completely resolve (see Section 6.12.2 for 
details).  Doses of CINRYZE that are self-administered will be entered as such in the CRF.


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5.4
Blinding
This is an open-label study; therefore, blinding is not applicable.
5.5
Stopping Rules
5.5.1
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, study drug will be discontinued for that subject.  
The subject will follow the schedule of assessments for the Early Discontinuation Visit and the 
1-Week and 1-Month Post-treatment Follow-up Visits (see Schedule 3).  Other enrolled subjects 
will continue with study drug administration and procedures.
5.5.2
Thrombotic or Thromboembolic Event
If a thrombotic or thromboembolic (T/TE) event occurs in any subject, no further enrollment will 
occur pending a complete review of all available data.  Other enrolled subjects will continue with 
study drug administration and procedures.  Following a safety review of the T/TE event, study 
enrollment may be restarted if it is determined that the event is not related to study drug or other 
C1 inhibitors, which may have been administered for an angioedema attack.
If a T/TE event occurs in any subject, study drug administration for that subject will be 
interrupted; however, other study procedures will continue, as deemed appropriate by the 
Investigator in conjunction with the Sponsor.  Investigators will comply with protocol-defined 
algorithms to assist in the diagnosis and management of all suspected T/TE events (see Appendix 
2).  Following a complete medical review by the Sponsor in conjunction with the Investigator, 
dosing with study drug may be resumed to complete a total of 24 doses if it is determined that 
the T/TE event is not related to study drug.  Study procedures, including PK/PD testing, will 
resume relative to dosing.  If study drug cannot be restarted within 30 days of temporary 
interruption, the subject will be discontinued from treatment and will follow the schedule of 
assessments for the Early Discontinuation Visit and the 1-Week and 1-Month Post-treatment 
Follow-up Visits (see Schedule 3).


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6
STUDY PROCEDURES
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study after the 
nature and purpose of the protocol have been explained and written informed consent to 
participate has been voluntarily granted by the subject or permission for minors has been granted 
by a parent/legal guardian and assent has been provided by appropriate subjects (Section 14).  
For subjects who are screened (ie, those with signed written informed consent) but not enrolled, 
demographic information and reason for screen failure will be recorded in the CRF.  Schedule 1,
Schedule 2, and Schedule 3 provide details of study procedures and clinical assessments, and 
Schedule 4 provides timing of PK/PD blood sampling.
NOTE:  It is possible for the Screening Visit and Dosing Visit 1 to occur on the same day.  If 
this occurs—to prevent repetition of protocol procedures and avoid duplicate blood draws on the 
same day—following Screening procedures, only the following Dosing Visit 1 procedures will 
be performed:

Concomitant medications

Vital signs relative to study drug administration

Study drug administration

Daily angioedema attack monitoring and study diary

Adverse event monitoring

PK/PD and immunogenicity (C1 INH antibody) blood sampling

Quality of life questionnaire
6.1
Medical History and Physical Examination
A medical history will be taken at the screening visit.  All medical history findings that have 
been present/active within the 5 years before enrollment will be recorded in the CRF regardless 
of clinical relevance or presence at study start.  Medical history findings that have not been 
present within the 5 years before enrollment will be recorded if deemed clinically relevant to the 
conduct of the study by the Investigator.  The medical history should include any history of 
allergic reactions to drugs.  In addition, the following information associated with the history of 
angioedema will be recorded in the CRF:

HAE Type (I or II).  If a subject does not have a confirmed diagnosis of HAE based on 
historical data, including C1 INH functional deficiency, the subject’s diagnosis must be 
confirmed prior to treatment by C1 INH test results which demonstrate a quantitative and/or 
functional C1 INH deficiency; a blood sample may be collected at screening to determine a 
deficiency in the levels of C1 INH and/or C1 INH activity.

Family history of HAE within first degree relatives (offspring, siblings, parents).

If a central line has ever been used for administration of any medication, and if yes, is there 
currently a central line in place?

Estimated onset date of last angioedema attack before enrollment (ie, prior to Day 1).


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
Total number, typical locations, average overall duration (in days), and average overall 
severity of angioedema attacks experienced during the 3 consecutive months before the first 
dose.

Visual Analogue Scale (VAS) - typical score for the subject’s angioedema attack pain during
the 3 consecutive months before the first dose.  Note: Subjects younger than 5 years of age 
do not need to complete the VAS.
The Investigator or designee will perform physical examinations at the time points specified in 
Schedule 1 and Schedule 3.  Physical examinations will be performed in accordance with 
standard practices at the study site.  Physical examination abnormalities observed at the 
screening visit will be recorded as medical history.  New abnormalities or worsened pre-existing 
abnormalities observed post-screening should be recorded as AEs, as determined by the 
Investigator (see Section 9).
Body weight and height will be measured at the time points specified in Schedule 1 and Schedule 
3.
6.2
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 will be collected from the time 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 PAREXEL International Pharmacovigilance and the respective 
Independent Reviewing Authority according to local reporting requirements.
Please refer to Section 9, Adverse and Serious Adverse Events Assessment.
6.3
Vital Signs
Blood pressure (BP) and pulse will be measured at the time points specified in Schedule 1 and 
Schedule 3.  Additional vital signs measurements may be performed during the study if clinically 
indicated.  On dosing days, vital signs should be obtained ≤30 minutes before the start of the 
infusion, ≤15 minutes after completion of the infusion, and between 30 minutes and 1 hour after 
completion of the infusion.  Vital sign measurements will not be collected at Visits 10, 12, 14, 
18, 20, and 22 from subjects who independently self-administer investigational product at home.  
At applicable visits, every effort should be made to measure vital signs before the collection of 
blood samples.  
6.4
12-Lead Electrocardiogram
Subjects will have a 12-lead ECG recorded as specified in Schedule 1.  Additional ECGs may be 
performed during the study if clinically indicated.  The following ECG data will be recorded in 
the CRF:  HR, PR interval, QRS duration, QT interval, and QTc interval.  The Investigator will 


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be responsible for providing the interpretation of all ECGs (clinically significant/not clinically 
significant).
6.5
Prior and Concomitant Medications
Prior and concomitant medications to be recorded at each visit 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 will be recorded only if used to treat an AE.
6.5.1
Prior Medications
A medication history will be taken at the screening visit and updated before the first dose on Day 
1 to ensure that the subject remains eligible for study participation.  Any therapy received for the 
management of HAE within 12 months before Day 1 should be recorded, including overall start 
and stop dates (if known) and the HAE indication (ie, long-term prevention, acute treatment, 
short-term prevention).  All other medications taken within 1 week before Day 1 will be recorded 
in the CRF.  In addition, any medications taken for an AE prior to Day 1 will be recorded.
6.5.2
Concomitant Medications
Concomitant medications taken from the start of dosing (Dosing Visit 1) through the 1-Month 
Post-treatment Follow-up Visit will be recorded in the CRF.  For medications associated with the 
management of angioedema attacks, study personnel will record the start and stop dates, dose, 
unit, frequency, route of administration, and indication in the subject’s CRF.  For medications 
not associated with the management of HAE, study personnel will record the start and stop dates 
(if known), route of administration, and indication for which the medication was administered in 
the subject’s CRF.
6.5.3
Prohibited Medications
Use of C1 INH therapy (other than study drug) for the prevention of angioedema attacks is 
prohibited during the study.  Details on the management of breakthrough angioedema attacks are 
discussed in Section 6.12.
6.6
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments received from the Screening Visit through the 1-Week 
Post-treatment Follow-up Visit will be recorded in the CRF.  To the extent possible, procedures 
(eg, surgical, diagnostic, or dental) should be avoided during study participation (see Section 
6.10); however, those occurring through the 1-Week Post-treatment Follow-up Visit will be 
recorded in the CRF.
6.7
Clinical Laboratory Parameters
Subjects will have blood samples collected for routine clinical laboratory testing at the time 
points specified in Schedule 1 and Schedule 3.  Testing will be performed at a central laboratory.  
The following clinical laboratory parameters will be analyzed:


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
Hematology: CBC consisting of WBC and differential counts and percentages, RBC count, 
hemoglobin, hematocrit, and platelet count.

Coagulation:  PT, aPTT, INR.

Clinical Chemistry:  BUN, creatinine, glucose, sodium, potassium, chloride, CO2, AST, 
ALT, alkaline phosphatase (ALP), CPK, total bilirubin, calcium, phosphorus, total protein, 
and albumin.

Virology:  HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface 
Antigen, Hepatitis C Antibody).

Urinalysis with microscopy:  pH, specific gravity, dipstick (protein, glucose, ketones, 
hemoglobin), and microscopic evaluation (RBCs, WBCs, crystals, casts, bacteria).
For all females of childbearing potential, pregnancy testing (in accordance with standards at the 
site) will be performed at the time points specified in Schedule 1 and Schedule 3.
Additional clinical laboratory testing may be performed during the study if clinically indicated, 
and may be completed locally or sent to the central laboratory.  Site staff will manually enter 
local laboratory results into the CRF.
6.8
Sample Collection for Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody 
Analyses
Subjects will have blood samples collected for the determination of plasma concentrations of C1 
INH antigen (protein volume), functional C1 INH activity (potency), complement C4, and C1q at 
the time points specified in Schedule 4. In addition, blood samples will be collected at Visits 1 
(baseline), 8, 16, and 24 and 1 month (30 ±2 days) after the last dose of study drug for C1 INH 
antibody analyses (see Schedule 1 and Schedule 3). 
The actual date and time of each sample collection will be recorded. Plasma samples for the 
determination of C1 INH antigen (protein volume), functional C1 INH activity (potency), 
complement C4, and C1q concentrations and C1 INH antibodies will be analyzed using fully 
validated methodology. Details on the processing of blood samples for PK/PD and 
immunogenicity assessments will be provided in a separate study manual.
NOTE: If a subject presents to the site with a breakthrough angioedema attack, every effort 
should be made to obtain a PK blood sample before treatment. In addition, if the subject 
receives CINRYZE for treatment of the attack, every effort should be made to obtain a 1-hour 
post-treatment sample; if a second dose of CINRYZE is administered, an additional 1-hour post-
treatment sample should be obtained if possible. These samples will be collected as an 
unscheduled visit and analyzed for C1 INH antigen (protein volume) and functional C1 INH 
activity (potency). Additional blood samples for PK/PD and C1 INH antibody assessments may 
be collected during the study if clinically indicated.
Selected samples may be analyzed to investigate incurred sample reproducibility (ISR) of the 
bioanalytical methods and/or incurred sample stability (ISS).  These analyses are only to 
investigate the reproducibility of the bioanalytical methods used to determine concentrations of 


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C1 INH antigen (protein volume) and functional C1 INH activity (potency) in study samples 
and/or to investigate the stability of the incurred samples.  All ISR and ISS results collected will 
be reported in a separate table in the bioanalytical report.  All samples will be disposed of at the 
conclusion of the study.  Details of disposal will be documented and maintained with the study 
file at the analytical laboratory.
Selected samples may be retained to investigate immunogenicity to C1 INH.
6.9
Total Blood Volume Collected
During the study, subjects who weigh 25 kg or more will have approximately 220 mL of blood 
collected for clinical safety laboratory testing (hematology, chemistry, coagulation, and 
virology), PK/PD assessments, and immunogenicity (C1 INH antibody) testing (exclusive of 
unscheduled visits).  Subjects who weigh less than 25 kg will have approximately 140 mL of 
blood collected (exclusive of unscheduled visits).  In addition, for subjects who weigh less than 
25 kg, the Screening Visit must occur at least 14 days before Dosing Visit 1.
6.10
Restrictions
Subjects should maintain their normal diets, medications, and activities of daily living. During 
the study, subjects will be asked to avoid known triggers of angioedema attacks to the best of 
their ability (eg, foods, activities, medical procedures, environments).  To the extent possible, 
subjects should postpone elective procedures (eg, dental work) while participating in the study.  
If a procedure cannot be postponed, the subject or parent/guardian will notify the Investigator 
and the information will be recorded in the CRF.
6.11
Study Diary
Beginning at Dosing Visit 1, subjects (or their caregivers such as a parent or guardian, based on 
the ability of a child) will use a study diary each day to document specific information about any 
angioedema attack symptoms that occur (eg, including the location, severity, pain score, and 
duration of symptoms) and details on the self-administration of investigational product.  At the 
first dosing visit (Dosing Visit 1), study personnel will instruct each subject (or caregiver) how to 
complete the study diary.
Study personnel will review the diary for completeness and accuracy at each scheduled dosing 
visit.  The Investigator or designee will use subject-reported diary data as reference information, 
in addition to any other available medical records, to record and evaluate events related to 
breakthrough angioedema attacks in the CRF.
6.12
Angioedema Attacks
An angioedema attack will be defined as any subject-reported (or caregiver-reported) indication 
of swelling or pain at any location following a report of no swelling or pain on the previous day 
(ie, there must be a full symptom-free calendar day preceding the onset of symptoms for an 
attack to be considered a new attack).  Therefore, 


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
Attacks that progress from 1 site to another will be considered a single attack;

Attacks that begin to regress and then worsen before complete resolution will be considered 1 
attack; and

Attacks that begin, appear to resolve, and then reappear without a symptom-free calendar day 
reported after the appearance of resolution will be considered 1 attack.
NOTE:  An angioedema attack does NOT include swelling due to trauma or arthritis, or 
symmetrical non-painful swelling of the lower extremities.
In this study, angioedema attacks will not be reported as adverse events unless the attack meets 
the definition of a serious adverse event (see Section 9.1.4).
6.12.1
Treatment of Breakthrough Angioedema Attacks
A breakthrough attack is defined as an angioedema attack that occurs during long-term 
prevention therapy with CINRYZE. If a subject receives CINRYZE for treatment of a breakthrough
angioedema attack, they should continue their protocol-defined treatment schedule without 
alteration regardless of when the supplemental dose is administered.
If a breakthrough angioedema attack occurs during the 12-week treatment period through 1-week 
post-treatment, a supplemental dose of CINRYZE may be administered by IV infusion for 
treatment of the attack either by the Investigator (or qualified delegate) or subject (or caregiver) 
if trained and deemed independent to self-administer (1000 U for subjects ≥6 years of age or
500 U for subjects 2-5 years of age).  If the subject does not adequately respond to the initial 
dose within 1 hour, a second dose of CINRYZE may be administered (1000 U for subjects ≥6 
years of age or 500 U for subjects 2-5 years of age).  
It is recommended that treatment of breakthrough attacks occurs at the investigational site 
whenever possible so that clinical assessments can be completed as specified. It is preferred that 
subjects receive CINRYZE within 4 hours but not more than 8 hours after the onset of 
breakthrough attack symptoms if treatment can occur at the investigational site.  
Subjects (at least 12 years of age or their caregivers) who have completed the required self-
administration training and deemed independent (per criteria specified in Section 5.3.1) may 
elect to self-administer CINRYZE for a breakthrough attack.  Note: Subjects (or caregivers) who 
are participating in self-administration training and not yet qualified as independent cannot self-
administer CINRYZE for a breakthrough attack; rather they must seek treatment at the 
investigational site.  If a subject (or caregiver) who self-administers CINRYZE for treatment of a 
breakthrough attack does not respond adequately after instructed treatment (ie, 2 doses separated 
by 1 hour), they should notify the Investigator and seek medical attention or report to study site 
to seek further treatment and relief of symptoms.  
In addition to the administration of CINRYZE, subjects are allowed to receive symptomatic 
treatment for breakthrough angioedema attacks (eg, IV fluids).  The administration of narcotics 
and antiemetics is discouraged during the 4-hour post-infusion assessment period to allow for 
evaluation of the response to CINRYZE.  Other treatments for angioedema attacks (eg, another C1 


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INH product such as Berinert P, tranexamic acid, fresh frozen plasma) are not permitted at the 
investigational site unless a subject does not adequately respond following treatment with 
CINRYZE (ie, 2 doses separated by 1 hour).
6.12.2
Assessment of Breakthrough Angioedema Attacks
If a breakthrough attack occurs, subjects (or caregivers) should assess and record the following 
information in the study diary:

Presence of pain or swelling at each anatomic location (ie, upper airway [laryngeal], 
gastrointestinal/abdominal, facial, genitourinary, and extremity/peripheral) by indicating the 
overall severity (ie, mild, moderate, or severe [as defined below]) 

Overall amount of pain associated with the breakthrough attack using a VAS (only for 
subjects at least 5 years of age)

Any triggers associated with the attack

Any health care visit for the attack (investigational site, clinic or hospital/emergency 
department)

Any medications received to manage attack symptoms

Duration of symptoms (ie, time symptoms start to improve and time symptoms completely 
resolve)
In addition to the subject’s self-assessment, the Investigator should assess and record the overall 
severity of the attack if the subject seeks treatment for symptoms at the site.
Treatment with CINRYZE
The Investigator (or qualified delegate) or subject (trained and deemed independent) may 
administer a supplemental dose of CINRYZE to treat the breakthrough attack.  Subjects self-
administering CINRYZE will record clinical assessments associated with breakthrough attacks in 
the study diary.
Following the administration of CINRYZE, subjects (or caregivers) will record their symptoms 
(the presence of pain or swelling at each anatomic location) and assess the overall severity of the 
breakthrough attack every 15 minutes for up to 4 hours post-infusion using the following scale:

No symptoms.

Mild:  The attack symptoms are noticeable but are easily tolerated by the subject and do not 
interfere with the subject’s daily activities.

Moderate:  The attack symptoms interfere with the subject’s ability to attend work/school or 
participate in family life and social/recreational activities).

Severe:  The attack symptoms significantly limit the subject’s ability to attend work/school 
or participate in family life and social/recreational activities.
Subjects (or caregivers) also will rate the overall amount of pain associated with the 


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breakthrough attack using a VAS (for subjects at least 5 years of age) on the same schedule as 
overall attack severity. 
In addition to the subject’s self-assessment, the Investigator should assess and record the overall 
severity every 15 minutes for up to 4 hours post-infusion if the subject seeks treatment at the site.
NOTE:  If a subject has adequately responded to treatment with CINRYZE, the subject may omit 
further assessments up to 4 hours post-infusion (and if applicable, be discharged from the 
investigational site) provided that overall attack severity has been assessed for at least 1 hour.
Subject diary data will be used by study personnel to record the onset date and time of the 
breakthrough attack, as well as the date and time of onset of symptom improvement and 
Complete Resolution (defined in Section 7.6.2) in the CRF.
6.13
Quality of Life
6.13.1
Angioedema Quality of Life (AE-QoL) Questionnaire
The Angioedema Quality of Life (AE-QoL) is a questionnaire on the quality of life of patients 
suffering from recurrent angioedema.  It consists of 17 specific questions that are associated with 
work, physical activity, free time, social relations, and diet.  Subjects will be asked by study 
personnel 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 questionnaire will be completed at the time points specified in Schedule 1 and Schedule 3.  
This instrument will be administered as appropriate for each subject’s age (ie, includes option of 
guidance from parent/guardian).
6.14
Self-administration Survey
A self-administration survey containing questions for subjects (or caregivers) and the
Investigator’s assessment of the overall experience with self-administration of IV CINRYZE will 
be completed on Visit 24. 
Subjects (or caregivers) who have self-administered treatment during the study, will be asked 
specific questions regarding training materials and oversight by the Investigator or qualified 
delegate, ease of reconstituting and self-administering CINRYZE, any challenges or obstacles 
encountered, and to rate their overall satisfaction with self-administered treatment.  The 
Investigator or qualified delegate will provide their overall assessment of the training process 
and the success/challenges of teaching subject (or caregiver) self-administration skills.  Study 
personnel will enter the survey responses in the CRF.
6.15
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 the withdrawal of a subject from investigational product with the Medical 
Monitor when possible.


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If investigational product is discontinued, regardless of the reason, the Early Discontinuation 
Visit procedures listed in Schedule 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 
Follow-up Visits.  Comments (spontaneous or elicited) or complaints made by the subject must 
be recorded in the source documents.  The reason for termination and the date of stopping 
investigational product must be recorded in the CRF and source documents.
If subjects withdraw or discontinue after enrollment, additional subjects may be enrolled to 
ensure at least 6 subjects complete the study.  
For those subjects who discontinue before receiving study drug, demographic information, 
inclusion/exclusion information, and the reason for not receiving study drug will be recorded in 
the CRF.  No additional study procedures or follow-up will be performed on subjects who 
discontinue before receiving study drug.
6.15.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the Investigator and recorded in the subject’s 
medical record and on the CRF.  If a subject is withdrawn 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 reason on the CRF].
Subjects who discontinue study drug due to an AE will be followed until the event is either 
resolved or assessed as stable by the Investigator.
A subject will be considered lost to follow-up after 3 documented attempts are made, including 
at least one attempt via written communication.


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7
STATISTICAL METHODOLOGY
7.1
Sample Size
A sufficient number of subjects will be enrolled to ensure that a minimum of 6 subjects complete 
the study.  When 6 subjects have completed the 12-week treatment period, no further subjects 
will be enrolled; however, all subjects already enrolled in the study will be followed to study 
completion.
7.2
Populations
All treated subjects (ie, Intent-to-Treat Safety [ITT-S] Population:  subjects who receive any 
amount of study drug) will be included in the safety analyses.  All subjects with evaluable 
PK/PD profiles (ie, PK/PD Population) will be included in PK/PD analyses as appropriate.
7.3
Statistical Methods
Data will be summarized using the same methods that were used in the overseas development 
program for IV CINRYZE.  Experimental results will be summarized using descriptive statistics
according to data type (n, mean, standard deviation or standard error, median, and range for 
continuous endpoints; number and percent of subjects in each category for categorical 
endpoints). To establish context, efficacy/pharmacology results from this study may be 
superimposed (eg, graphically) on experimental data from previous overseas studies, as 
appropriate.
7.4
Safety Analyses
The following will be assessed:

Adverse events (including treatment-emergent adverse events).

Summary statistics and changes from baseline to post-baseline for laboratory testing, vital 
signs, and, if applicable, any ECG findings will be presented.

Results of C1 INH antibody testing will be reported for individual subjects and summarized 
as appropriate.
NOTE: Treatment-emergent events include all adverse events that start during the treatment 
period (and up to 7 days after the last dose of investigational product) and were not seen at
baseline, or were seen at baseline but worsened in frequency and/or severity during the treatment 
period (and up to 7 days after the last dose of investigational product).
7.5
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen (protein volume), functional C1 INH activity (potency), and 
complement C4 and C1q for individual subjects will be determined. Results will be summarized 
using descriptive statistics at each time point with and without baseline correction.  C1q 
concentrations will be assessed at baseline only (ie, pre-infusion, Dosing Visit 1).


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Pharmacokinetic/pharmacodynamic parameters will be calculated using observed and baseline-
corrected concentration-versus-time data using non-compartmental techniques. 
Pharmacokinetic/pharmacodynamic parameters to be determined include Cmax and its time of 
occurrence (tmax), minimum observed concentration (Cmin), average concentration at steady state 
(Cavg), area under the plasma concentration versus time curve from time 0 to selected time point 
(AUC0-), elimination rate constant (Kel), terminal elimination half-life (t1/2), volume of 
distribution (VZ), and plasma clearance (CL), as appropriate. Terminal elimination half-life will 
be estimated by log-linear regression and will use at least three time points. Other non-
compartmental PK/PD parameter values also may be calculated. Non-compartmental PK/PD 
analyses will be performed using commercially available software (Phoenix® WinNonlin®, 
version 6.3 or higher; Pharsight, a Certara company).
If warranted, an exploratory PK/PD analyses will be performed based on correlation of plasma 
concentrations of C1 INH antigen (protein volume), functional C1 INH activity (potency), and 
C4 complement in conjunction with various safety parameters (eg, selected AEs, clinical 
laboratory results, antibodies generation; frequency, severity, or anatomic location of the HAE 
attack). Correlations that will be analyzed will be determined based on observed data.
Pharmacokinetic/pharmacodynamic parameters and PK/PD assessments will be summarized 
using descriptive statistics (number, mean, standard deviation, median, minimum, and 
maximum) and categorical parameters will be summarized using frequency statistics (number 
and percentage of subjects).
7.6
Efficacy Analyses
7.6.1
Prevention of Angioedema Attacks
The following efficacy endpoints for prevention of angioedema attacks will be assessed:

The number of angioedema attacks recorded during the treatment period, normalized for the 
number of days the subject participated in the period.

The overall frequency of angioedema attacks occurring during the treatment period will be 
calculated and compared with historical baseline values.

Summary of all attacks during the treatment period, including:

Anatomic location.

Severity (intensity).

Duration.

Number of rescue treatments (including antiemetics, narcotics, or C1 INH therapy, 
including administration of rescue CINRYZE).

Effects of therapy on quality of life (results of AE-QoL questionnaire).


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7.6.2
Treatment of Breakthrough Angioedema Attacks
The following efficacy endpoints for treatment of breakthrough angioedema attacks will be 
assessed by CINRYZE-treated attack number:

The number of subjects who achieve Clinical Relief.  Clinical Relief is defined as a sustained 
reduction from pre-infusion in the attack severity within 4 hours after initiation of treatment 
with CINRYZE.

Time to onset of Clinical Relief.

The number of subjects who achieve Complete Resolution.  Complete Resolution is defined 
as the cessation of all symptoms of the breakthrough angioedema attack.

Time to Complete Resolution.
Other analyses may be performed to establish context of the efficacy results from this study with 
previous Phase 3 CINRYZE studies.


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8
DRUG SUPPLIES
8.1
How Supplied
CINRYZE is supplied as a lyophilized powder in single use vials containing 500 U of C1 INH per 
vial.  When reconstituted, CINRYZE contains C1 INH at a concentration of 100 U/mL in a citrate-
buffered solution comprising sucrose, sodium chloride, L-valine, L-alanine, and L-threonine.
Vials must be stored at 2oC – 25oC (36oF – 77oF) and protected from light.  Do not freeze.
8.1.1
For at Home Use
Subjects (or their caregivers) who elect to self-administer investigational product at home will be 
provided the following supplies at investigational site for transport to the home location:

4-week supply of investigational product, including sterile water for injection, and 
Mix2vial® transfer devices 

Ancillary supplies, including silicone-free syringes, needles, infusion sets, disinfecting strips, 
and disposal containers (eg, sharps and infectious materials)

Transport container for investigational product

Subject accountability log to record investigational product storage conditions, 
administration, and other details.
All used and unused vials of investigational product should be returned to the study site for 
inspection and drug accountability purposes.
8.2
Reconstitution of CINRYZE for Intravenous Infusion
Each vial of CINRYZE will be reconstituted with 5 mL of Sterile Water for Injection (SWFI).  The 
following supplies will be required for reconstitution using aseptic technique:  United States 
Pharmacopeia (USP) SWFI, disinfecting strips, Mix2Vial transfer device, and silicone-free 
disposable syringes.
For subjects 6 years of age and older, each 1000 U infusion will require reconstitution of two 500 
U vials of CINRYZE; for subjects 2 to 5 years of age, each 500 U infusion will require 
reconstitution of one 500 U vial of CINRYZE.  The solution must be used within 3 hours after 
reconstitution.
Instructions for the reconstitution of CINRYZE will be provided in separate study manual.
8.3
Drug Accountability
The Principal Investigator must maintain records of study drug product received, including dates 
of receipt, expiry and dispensing, in addition to lot numbers.  Study personnel will enter each lot 
number of CINRYZE administered to a subject in the subject’s CRF.  In addition, records must be 
kept on when and how many study drug vials were dispensed and returned for each individual 
subject in the trial.  Reasons for departure from the expected dosing regimen must also be 


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recorded in both source documents and the CRF.  Sponsor representatives will review drug 
accountability on an ongoing basis throughout the study.  An overall summary of all drug 
supplies received and used must be recorded on the appropriate forms and signed by the 
Principal Investigator and clinical monitor at the conclusion of the study.  Written records will be 
maintained documenting a final accounting of study drug received at the investigational site and 
study drug vials dispensed to subjects.  All unopened/unused/used study drug vials will be 
returned by the clinical research associate (CRA) to the central distributor or destroyed by the 
Investigator per local regulations or standard operating procedures (SOPs).
8.4
Drug Labels
Clinical trial labels that are in accordance with applicable regulatory requirements will be 
applied.  The label will comply with Japanese GCP.


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9
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
9.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 3.  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.
9.1.1
Severity Categorization
The severity (intensity) of AEs will be assessed according to the definitions below.  If the 
intensity of an AE changes over time, the maximum intensity experienced should be recorded.
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Worsening of pre-treatment 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).


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9.1.2
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.
9.1.3
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.
9.1.4
Symptoms of the Disease Under Study
In this study, angioedema attacks will not be reported as adverse events unless the attack meets 
the definition of a serious adverse event (see Section 9.2.3).
9.1.5
Clinical Laboratory and Other Safety Endpoints
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 


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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 pre-treatment 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.
9.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 3.
Any report of pregnancy for any female study participant or the female partner of a male study 
participant must be reported within 24 hours to PAREXEL International Pharmacovigilance 
using the Shire Investigational and Marketed Products Pregnancy Report Form.  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 using the Shire Clinical Trial Serious Adverse Event 
Form.  NOTE:  An elective abortion is not considered an SAE.
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.
9.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to PAREXEL 
International Pharmacovigilance according to the SAE reporting procedure whether or not they 
result in an AE/SAE as described in Section 9.2.  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.


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
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 – No case of overdose has been reported.  In the overseas development program 
(see Section 1.1.2), the largest dose of CINRYZE administered to an individual subject for 
treatment of a single angioedema attack was 4000 U (1000 U x 4 IV infusions) over a 4-hour 
time period.  The largest amount of CINRYZE administered to an individual subject for 
prevention and treatment of angioedema attacks was 10,000 U (1000 U x 10 IV infusions) 
over a 7-day time period.  These subjects experienced no adverse reactions.

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/reported for all products under investigation.
Reportable medication errors include the administration and/or use of an expired investigational
product and departures from prescribed procedures for the storage, reconstitution, and 
administration of study drug.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
9.2
Serious Adverse Event Procedures
9.2.1
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.
9.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the Investigator to PAREXEL 
International Pharmacovigilance 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 (see Section 9.1.7) 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 
email the form to PAREXEL International Pharmacovigilance.  


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9.2.3
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, which have not worsened after initiation of treatment, should not be 
classified as SAEs.  For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.  NOTE:  Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this 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.
9.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent up to 30 days after the last dose of study drug, and must be reported to 
PAREXEL International Pharmacovigilance 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 PAREXEL 
International Pharmacovigilance within 24 hours of the first awareness of the event.
9.2.5
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.


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9.2.6
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).
9.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The Sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities/Japanese central IRB/EC of related, unexpected SAEs.
In addition, the Sponsor and/or the clinical CRO is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the VP 20624 
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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10
STUDY MONITORING
The study will be monitored by Sponsor authorized individuals, acting as Sponsor agents with 
respect to current ICH guidelines, GCP, and SOPs for compliance with applicable government 
regulations.  These individuals will have access to all records necessary to ensure integrity of the 
data and will periodically review the progress of the study with the Principal Investigator.
Frequent communication between the study site and the Sponsor is essential to ensure that the 
study is adequately monitored for safety.  The Investigator will make all appropriate safety 
assessments (eg, AEs, clinical laboratory tests, vital signs, ECGs, results from physical 
examinations) on an ongoing basis.  The Sponsor’s Medical Monitor will review safety 
information from all study sites as it becomes available throughout the study.


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11
DATA HANDLING
11.1
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 enrolled, it is expected that site personnel 
will complete the CRF entry within approximately 3 business days of the subject’s visit.
11.2
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.


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12
ETHICAL CONDUCT OF THE STUDY
Sponsor will require Investigators to conduct the study in accordance with the ethical principles 
stated in the Declaration of Helsinki and in compliance with the ICH Tripartite Guideline for 
GCP, the Ministerial Ordinance on Good Clinical Practice for Drugs, and applicable regulatory 
requirements.


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13
SUBJECT CONFIDENTIALITY
Investigator and his/her staff will be required to manage subject data collected for the study in 
accordance with applicable laws and regulations on personal data protection.
Monitors, auditors and other authorized representatives of Shire ViroPharma Incorporated, the 
IRBs/ECs approving the study, as well as any applicable regulatory authorities, will be granted 
access to the study subjects' original medical records for permitted study purposes, in accordance 
with applicable laws and regulations.  In any presentation of study results at meetings or in 
publications, the subjects' identity will remain confidential.


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14
INFORMED CONSENT
The ICH has issued guidelines to provide protection for human subjects in clinical investigations.  
The ICH Tripartite Guideline for GCP establishes the general requirements for informed consent.  
Legal age for consent to treatments or procedures involved in clinical investigations is defined 
under the applicable law of the jurisdiction in which the clinical investigation will be conducted.
14.1
Adults
A properly executed, written informed consent in compliance with the terms of these guidelines 
shall be obtained from each subject before entering the trial, or before performing any unusual or 
non-routine procedure that involves a risk to the subject.  A copy of the informed consent 
documents to be used will be reviewed and approved by the Sponsor.  The document(s) will then 
be submitted to the IRB/EC for review and approval before the start of the study.  The 
Investigator shall provide a copy of the signed and dated informed consent to the subject and a 
copy shall be maintained in the subject’s medical record.  The Investigator, or his/her designee, 
must document in the case history that informed consent was obtained prior to study 
participation.  All procedures and documentation required for obtaining informed consent should 
be in compliance with ICH guidelines, the Japanese Ministry of Health and Welfare regulations, 
and local IRB/EC requirements, as well as state and local law.
14.2
Children or Minors
A properly executed, written permission statement (ie, informed consent) shall be obtained from 
each parent/legal guardian and assent shall be obtained from each subject aged ≥14 years prior 
to the subject entering the trial, or prior to performing any unusual or non-routine procedure that 
involves a risk to the subject.  The permission statement must meet all of the required elements 
of informed consent.  A separate assent form should be prepared which explains in very general 
terms the purpose of the study, what will be expected of or done to the child, and what risks or 
discomforts may be experienced.  A copy of the written permission statement document and 
assent form to be used will be reviewed and approved by the Sponsor.  The document(s) will 
then be submitted to the IRB/EC for review and approval before the start of the study.  The 
Investigator shall provide a copy of the signed and dated permission statement and assent form to 
the parent/legal guardian and a copy shall be maintained in the subject’s medical record.  The 
Investigator, or his/her designee, must document in the case history that informed consent/assent 
was obtained prior to study participation.  If assent was not obtained, this should be recorded in 
the consent form signed by the parents/legal representative and the Investigator, with the 
reason(s).  All procedures and documentation required for obtaining parental/legal guardian 
permission and assent should be in compliance with ICH guidelines, the Japanese Ministry of 
Health and Welfare regulations, and local IRB/EC requirements, as well as state and local law.


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15
INDEPENDENT REVIEWING AUTHORITY APPROVAL
The IRB/EC is the review panel that is responsible for ensuring the protection of the rights, 
safety, and well-being of human subjects involved in a clinical investigation.  An IRB/EC that is 
adequately constituted to provide assurance of that protection will be utilized by each 
investigative site participating in the study.
The IRB/EC will be provided with all appropriate material, including a copy of the informed 
consent (permission)/assent for review.  The trial will not be initiated at an investigational site 
until written approval of the research plan and the informed consent (permission)/assent 
document is obtained from the appropriate IRB/EC and copies of these documents are received 
by Shire ViroPharma Incorporated.  Appropriate reports on the progress of this study will be 
made to the IRB/EC in accordance with applicable government regulations and in agreement 
with policy established by the Sponsor.


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16
PUBLICATION POLICY
Investigator’s right to publish study results is addressed in the clinical trial agreement between 
Investigator and Sponsor.


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17
INVESTIGATOR'S STATEMENT (PROTOCOL 0624-209)
A Phase 3, Open-Label, Single-Period Study to Evaluate the Safety and Treatment Effect of 
Intravenous Administration of CINRYZE® (C1 Inhibitor [Human]) for the Prevention of 
Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects with 
Hereditary Angioedema (HAE).
In conducting this clinical trial, I agree to be responsible for:
1. Protecting the rights, safety, and welfare of subjects under my care.
2. Controlling the drugs and biological products under investigation.
I also agree to conduct the trial as outlined in the protocol and in accordance with Shire 
ViroPharma Incorporated guidelines and all applicable government regulations.  These 
guidelines and regulations include, but are not limited to:
3. Permission to allow Shire ViroPharma Incorporated (or its designee) and PMDA, or other 
regulatory agencies, to inspect study facilities and pertinent records at reasonable times 
and in a reasonable manner, which ensures subject confidentiality.  If I am notified that 
this study is to be inspected by a regulatory agency, I will notify Shire ViroPharma 
Incorporated as soon as possible thereafter (no later than 1 week).
4. Submission of the proposed clinical investigation, including the protocol and informed 
consent/assent form, to a duly constituted IRB/EC for approval, and acquisition of written 
approval for each, prior to the use of the study drug.
5. Obtaining written informed consent/assent only after ensuring that the subject, or his/her 
legal representative, is competent to make the decision, understands what is contained in 
the informed consent/assent document, and is consenting voluntarily.  Written informed 
consent/assent will be obtained prior to administration of study drug or any non-routine 
procedures that involve risk; the document contains all the essential elements of consent 
and has been previously approved by the Sponsor and IRB/EC.  Reference of such will be 
provided in source documentation.
6. Submission of any proposed protocol amendment to the IRB/EC.  If the protocol 
amendment change(s) increase risk to the study population, or adversely affect the 
validity of the clinical investigation or the subject's rights, full IRB/EC written approval 
must be obtained prior to implementation.  For changes that do not involve increased risk 
or affect the validity of the investigation or the subject's rights, prior IRB/EC approval 
may be obtained by expedited review.
7. Adherence to the study protocol.  For potential inclusion/exclusion criteria protocol 
deviations, submission for approval to Shire ViroPharma Incorporated prior to enrollment 
of study subjects.  Documentation and explanation of individual post-enrollment protocol 
deviations will be recorded on the appropriate CRF page or provided in letters to Shire 
ViroPharma Incorporated.


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8. Notification to Shire ViroPharma Incorporated of all serious adverse events, regardless of 
relationship to study drug, as specified in the protocol.  Notification to the IRB/EC of 
serious adverse events as specified in the protocol and per additional guidelines as 
provided by the IRB/EC.
9. Notification to IRB/EC of all unanticipated problems within timeframes provided by the 
IRB/EC.  Unanticipated problems may include any incident, experience, or outcome that 
meets all of the following criteria: (1) unexpected (in terms of nature, severity); 
(2) related or possibly related to participation in the study; (3) and suggests that the 
research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.
10. Provision of adequate trial oversight by personally conducting or supervising the 
investigation, including, but not limited to: allotting sufficient time to properly conduct 
and complete the trial within the agreed upon time period; having available an adequate 
number of qualified staff and adequate facilities for the expected duration of the trial and 
to conduct the trial properly and safely; and ensuring that all persons assisting with the 
trial are adequately informed about the protocol, the investigational product(s), and are 
capable of performing their trial related duties and functions.  Qualifications of 
individuals assigned responsibility for the administration of the investigational product 
will be compliant with state and local law or national regulations, as applicable.
11. Submission of timely progress reports to the IRB/EC and Shire ViroPharma Incorporated 
at appropriate intervals not to exceed 1 year and submission of a final report to the 
IRB/EC within 3 months after the completion, termination, or discontinuation of the 
clinical investigation. 
12. Maintenance of accurate source records from which case reports are based as well as drug 
accountability records that show the receipt and disposition (on an overall and per subject 
basis) of all study drug(s) shipped to the Investigator by Shire ViroPharma Incorporated.
In addition, I agree to provide all the information requested in the CRF presented to me by Shire 
ViroPharma Incorporated by carefully following the completion guidelines provided as part of 
the CRF.
If I opt to terminate, the foregoing shall equally apply.
Investigator’s Name (Please Print)
Investigator’s Signature
Date


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CINRYZE (C1 inhibitor [human])
18
LIST OF REFERENCES
Aygören-Pürsün E, Bygum A, Caballero T, et al. The economic burden of HAE: Findings from 
the HAE burden of illness study in Europe (HAE-BIOS-Europe). 2012. EAACI Congress 
Geneva. [Abstract].
Bernstein JA.  Update on angioedema: evaluation, diagnosis, and treatment.  Allergy Asthma 
Proc.  2011; 32(6):408-412.
Bowen T. Hereditary angioedema: beyond international consensus - circa December 2010 - The 
Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture. Allergy 
Asthma Clin Immunol. 2011; 7(1):1.
Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, 
therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010; 
6(1):24.
Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, 
VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, 
and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008; 100(1 
Suppl 2):S30-S40.
Caballero T, Aygören-Pürsün E, Bygum A, et al. The humanistic burden of hereditary 
angioedema: results from the HAE burden of illness study in Europe (HAE-BIOS-Europe). 
Allergy Asthma Proc. 2014; 35(1):47-53.
Caballero T, Sala-Cunill A, Cancian M, et al. Current status of implementation of self-
administration training in various regions of Europe, Canada and the USA in the management of 
hereditary angioedema. Int Arch Allergy Immunol. 2013; 161(Suppl 1):10-16.
Cicardi M, Craig TJ, Martinez-Saguer I, et al. Review of recent guidelines and consensus 
statements on hereditary angioedema therapy with focus on self-administration. Int Arch Allergy 
Immunol. 2013; 161(Suppl 1):3-9.
Cicardi M, Bork K, Caballero T, et al. Evidence-based recommendations for the therapeutic 
management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an 
International Working Group. Allergy. 2012; 67(2):147-157.
Craig T, Riedl M, Dykewicz MS, et al. When is prophylaxis for hereditary angioedema 
necessary? Ann Allergy Asthma Immunol. 2009; 102(5):366-372. 
Gower RG, Lumry WR, Davis-Lorton MA, et al. Current options for prophylactic treatment of 
hereditary angioedema in the United States: patient-based considerations. Allergy Asthma Proc.
2012; 33(3):235-240.
Gregory C, Landmesser LM, Corrigan L, et al. Feasibility of home infusion and self-
administration of nanofiltered C1 esterase inhibitor for routine prophylaxis in patients with 


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CONFIDENTIAL
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Protocol 0624-209 with Amendments 1, 2, 3, 4, and 5
30 Aug 2016
CINRYZE (C1 inhibitor [human])
hereditary angioedema and characterization of a training and support program. J Infus Nurs. 
2014; 37(1):29-34. 
Horiuchi T, Ohi H, Ohsawa I, et al.  Guideline for hereditary angioedema (HAE) 2010 by the 
Japanese Association for Complement Research - secondary publication.  Allergol Int.  2012; 
61(4):559-562.
Iwamoto K, Mihara S, Ikezawa Z, et al. National prevalence survey of hereditary angioedema in 
Japan. Arerugi. 2011; 60(1):26-32.
Kalfus IN, Gower RG, Riedl M, et al. Hereditary angioedema: implications for treating a rare 
disease. Ann Allergy Asthma Immunol. 2012; 109(2):150-151.
Kaplan AP.  Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 
inhibitor therapy.  J Allergy Clin Immunol.  2010; 126(5):918-925.
Kaplan AP, Joseph K.  The bradykinin-forming cascade and its role in hereditary angioedema.  
Ann Allergy Asthma Immunol.  2010; 104:193-204.
Levi M, Choi G, Picavet C, et al.  Self-administration of C1-inhibitor concentrate in patients with 
hereditary or acquired angioedema caused by C1-inhibitor deficiency.  J Allergy Clin Immunol.  
2006; 117:904-908.
Longhurst HJ, Nzeako UC.  Diagnosis and treatment of hereditary angio-oedema attacks.  Br J 
Hosp Med.  2012; 73(3):148-154.
Lumry WR.  Overview of epidemiology, pathophysiology, and disease progression in hereditary 
angioedema.  Am J Manag Care.  2013; 19(7):S103-S110.
Lumry W, Manning ME, Hurewitz DS, et al. Nanofiltered C1-esterase inhibitor for the acute 
management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in 
children. J Pediatr. 2013; 162(5):1017-1022.
Lumry WR, Castaldo AJ, Vernon MK, et al. The humanistic burden of hereditary angioedema: 
Impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010; 
31(5):407-414.
MHLW. Considerations to perform self-injection at home. Notification No. 0427002. Head of 
Medical Economics Division, Health Insurance Bureau, MHLW. 2005.
Nzeako UC, Frigas E, Tremaine WJ. Hereditary Angioedema: a broad review for clinicians. 
Arch Intern Med. 2001; 161(20):2417-2429.
Weis M.  Clinical review of hereditary angioedema: diagnosis and management.  Postgrad Med.
2009; 121(6):113-120.
Yamamoto T, Horiuchi T, Miyahara H, et al. Hereditary angioedema in Japan: genetic analysis 
of 13 unrelated cases. Am J Med Sci. 2012; 343(3):210-214.


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CINRYZE (C1 inhibitor [human])
Zuraw BL. 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. 2008; 100(1 Suppl 2):S13-S18.




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CINRYZE (C1 inhibitor [human])
Subjects (≥12 years of age) may also elect to self-administer CINRYZE at 
home for a breakthrough attack provided they have completed the required 
training and deemed independent by the Investigator.  Subjects who are 
participating in self-administration training and not yet qualified as 
independent cannot self-administer CINRYZE for a breakthrough attack; 
rather they should seek treatment at the investigational site.
Synopsis, Section 6.12.1
Clarified procedures for the assessment of breakthrough attacks now that 
subjects are allowed to self-administer CINRYZE and will be responsible 
for capturing all assessments in the study diary.
Synopsis, Section 6.12.2
Added the benefits of self-administration to the study rationale.
Section 1.2
Provided details on investigational product and ancillary supplies needed 
by subjects who elect to independently self-administer CINRYZE at home.
Section 8.1.1
Updated the list of references to reflect changes made throughout the 
document.
Section 18
Other administrative and clarifying revisions have been made throughout the protocol for 
consistency with these modifications.




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CINRYZE (C1 inhibitor [human])
11.0-11.2
Adverse events will be collected from the time informed consent is signed
Schedule 1 and Sections 6.2 and 9.1
Angioedema attacks will not be reported as adverse events unless the 
attack meets the definition of a serious adverse event
Protocol Synopsis and Sections 3.0, 
6.12, 6.12.2, 9.1, and 9.1.4
An inclusion criterion was added to stipulate that all subjects must be of 
Japanese descent
Protocol Synopsis and Section 4.1
An inclusion criterion was added to define a minimum body weight 
requirement for study entry (per PMDA request)
Protocol Synopsis and Section 4.1
If functional C1 INH testing is not performed as standard of care to 
diagnose HAE, a blood sample will be collected at screening to confirm a 
functional C1 INH concentration less than 50% of normal
Protocol Synopsis, Schedule 1, and 
Section 4.1
References to a second study diary were removed because the data 
collected were redundant with data captured by other study procedures
Protocol Synopsis, Schedule 1, 
Schedule 2, and Sections 3.0, 6.0, 
and 6.11
Treatment of breakthrough attacks is recommended to occur at the 
investigational site whenever possible so that clinical assessments can be 
completed as specified in the protocol
Protocol Synopsis and Sections 3.0 
and 6.12.1
Other treatments for angioedema attacks (eg, another C1 INH product, 
tranexamic acid, fresh frozen plasma) are not permitted at the 
investigational site unless a subject does not adequately respond following 
treatment with CINRYZE
Protocol 
Synopsis 
and 
Section 6.12.1
The CINRYZE utilized in this study will be manufactured using US source 
plasma, and CINRYZE
will be reconstituted with United States 
Pharmacopeia (USP) Sterile Water for Injection
Protocol Synopsis and Sections 5.3 
and 8.2
Other administrative and clarifying revisions have been made throughout the protocol for 
consistency with these modifications.


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CINRYZE (C1 inhibitor [human])
APPENDIX 2
RECOMMENDED PROCEDURES FOR THE MANAGEMENT OF SUSPECTED 
VENOUS THROMBOEMBOLISM OR OTHER THROMBOTIC OR 
THROMBOEMBOLIC EVENTS

SAP_001.pdf: 
St ati sti c al A n al y si s Pl a n
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A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S P L A N
P R O T O C OL : 0 6 2 4 -2 0 9
A P H A S E 3, O P E N -L A B EL, SI N GL E-P E RI O D S T U D Y T O E V AL U A T E T H E S A F E T Y A N D 
T R E A T M E N T E F F E C T O F IN T R A V E N O U S A D MI NI S T R A TI O N 
O F CI N R Y Z E ®
( C 1
IN HI BI T O R [ HU M A N ]) F O R T H E P R E V E N TI O N O F A N GI O E D E M A A T T A C K S
A N D 
T R E A T M E N T 
O F 
B R E A K T H R O U G H 
A T T A C K S 
I N JA P A N E S E 
S U BJ E C T S 
WI T H
H E R E DI T A R Y A N GI O E D E M A ( H A E)
A U T H O R :
V E R SI O N N U M B E R A N D D A T E :
P P D
V 1. 0, 2 1J UL 2 0 1 7
P P D






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A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
M O DI FI C A TI O N H I S T O R Y
U ni q u e 
I d e ntifi e r 
f o r t hi s 
V e r si o n
D at e of t h e 
D o c u m e nt 
V e r si o n
A ut h o r
Si g nifi c a nt C h a n g e s f r o m 
P r e vi o u s A ut h o ri z e d V e r si o n
1. 0
2 1J U L 2 0 1 7
N ot A p plic a bl e – First V ersi o n
P P D
P P D


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A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T A BL E O F C O N T E N T S
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ..........................................................6
1.
I N T R O D U C TI O N ...............................................................................................................................7
1. 1.
B ac k gr o u n d ................................................................................................................................... 7
1. 2.
St u d y R ati o n al e .............................................................................................................................7
2.
S T U D Y O BJ E C TI V E S ........................................................................................................................8
3.
S T U D Y D E SI G N ................................................................................................................................. 9
3. 1.
G e n er al D escri pti o n ......................................................................................................................9
3. 2.
D et er mi n ati o n of S a m pl e Siz e .......................................................................................................9
4.
E F FI C A C Y A N D S A F E T Y V A RI A B L E S ........................................................................................1 0
4. 1.
Sc h e d ul e of E v al u ati o ns .............................................................................................................. 1 0
4. 2.
Effic ac y V ari a bl es ........................................................................................................................ 1 0
4. 2. 1.
Pr e v e nti o n of A n gi o e d e m a Att ac ks ................................................................................................1 0
4. 2. 2.
Tr e at m e nt of Br e a kt hr o u g h A n gi o e d e m a Att ac ks ..........................................................................1 0
4. 3.
S af et y Ass ess m e nts ..................................................................................................................... 1 1
5.
S T A TI S TI C A L A N A L Y SI S ..............................................................................................................1 2
5. 1.
G e n er al M et h o d ol o g y ................................................................................................................. 1 2
5. 2.
A n al ysis P o p ul ati o ns ................................................................................................................... 1 2
5. 3.
S u bj ect Dis p ositi o n ...................................................................................................................... 1 2
5. 4.
Pr ot oc ol D e vi ati o ns ..................................................................................................................... 1 2
5. 5.
D e m o gr a p hic a n d Ot h er B as eli n e C h ar act eristics ........................................................................ 1 3
5. 6.
E xt e nt of E x p os ur e ...................................................................................................................... 1 4
5. 7.
A n al ysis of Effic ac y ...................................................................................................................... 1 4
5. 7. 1.
Pr e v e nti o n of A n gi o e d e m a Att ac ks ................................................................................................1 4
5. 7. 2.
Tr e at m e nt of Br e a kt h r o u g h A n gi o e d e m a Att ac ks ..........................................................................1 7
5. 7. 3.
A n gi o e d e m a Q u alit y of Lif e ( A E -Q oL) Q u esti o n n air e ......................................................................1 8
5. 7. 4.
S e nsiti vit y A n al ysis ..........................................................................................................................2 0
5. 8.
A n al ysis of S af et y ........................................................................................................................ 2 0
P P D
5. 8. 1.
A d v ers e E v e nts ................................................................................................................................2 0
5. 8. 2.
Cli nic al L a b or at or y E v al u ati o n .........................................................................................................2 1
5. 8. 3.
E C G E v al u ati o ns ..............................................................................................................................2 3
5. 8. 4.
Vit al Si g ns P ar a m et ers ....................................................................................................................2 3
5. 8. 5.
P h ysic al Ex a mi n ati o n .......................................................................................................................2 3
5. 8. 6.
M e dic al Hist or y ...............................................................................................................................2 4


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A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
5. 8. 7.
Pri or a n d C o nc o mit a nt M e dic ati o n .................................................................................................2 4
5. 8. 8.
Tr e at m e nt C o m pli a n c e ...................................................................................................................2 4
5. 9.
I m m u n o g e nicit y ( C 1-I N H a nti b o d y) a n d P h ar m ac o ki n etic C o nc e ntr ati o ns a n d 
P h ar m ac o d y n a mics L e v els ........................................................................................................... 2 5
6.
C H A N G E S I N T H E C O N D U C T O F T H E S T U D Y O R P L A N N E D A N A L Y S E S ........................2 6
6. 1.
C h a n g es i n t h e C o n d uct of t h e St u d y ........................................................................................... 2 6
6. 2.
C h a n g es fr o m t h e A n al ys es Pl a n n e d i n t h e Pr ot oc ol ................................................................... 2 6
7.
S T A TI S TI C A L / A N A L Y TI C I S S U E S .............................................................................................2 7
7. 1.
H a n dli n g of Dr o p o uts or Missi n g D at a ......................................................................................... 2 7
7. 2.
I nt eri m A n al ys es a n d D at a M o nit ori n g........................................................................................ 2 7
8.
R E F E R E N C E S ...................................................................................................................................2 8
9.
A P P E N DI C E S ....................................................................................................................................2 9
9. 1.
A p p e n di x I – List of St atistic al O ut p uts ........................................................................................ 2 9
9. 1. 1.
List of Pl a n n e d T a bl es .....................................................................................................................2 9
9. 1. 2.
List of Pl a n n e d Fi g ur es ....................................................................................................................3 0
9. 1. 3.
List of Pl a n n e d Listi n gs ....................................................................................................................3 0
9. 2.
A p p e n di x II - Pr o gr a m mi n g C o n v e nti o ns ..................................................................................... 3 1
D at es & Ti m es ............................................................................................................................................... 3 1
S p elli n g F or m at ............................................................................................................................................. 3 2
Pr es e nt ati o n of Tr e at m e nt Gr o u ps ............................................................................................................... 3 2
Pr es e nt ati o n of Visits .................................................................................................................................... 3 2
Listi n gs
.................................................................................................................................................... 3 2
9. 3.
A p p e n di x III - P arti al D at e C o n v e nti o ns ....................................................................................... 3 2
Al g orit h m f or Tr e at m e nt E m er g e nc e of A d v ers e E v e nts ............................................................................... 3 3
Al g orit h m f or Pri or / C o nc o mit a nt M e dic ati o ns ............................................................................................ 3 4
L I S T O F T A BL E S
P P D
T a bl e 1:  P ot e nti all y i m p ort a nt l a b v al u es ............................................................................................................ 2 2


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A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
P P D
A E
a d v ers e e v e nt
A E -Q o L
A n gi o e d e m a Q u alit y of Lif e
A T C
A n at o mic al T h er a p e utic Cl assific ati o n
E C G
el ectr oc ar di o gr a m
C 1 -I N H
C 1 est er as e i n hi bit or or C 1 i n hi bit or
CI
c o nfi d e nc e i nt er v al
e C R F
el ectr o nic cas e re p ort for m 
H A E
h er e dit ar y a n gi o e d e m a
H R
h e art r at e
I T T- S
int e nt -t o-tr e at s af et y
I V
i ntr a v e n o us
M e d D R A
M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es
N N A
n or m ali z e d n u m b er of a n gi o e d e m a att ac ks
P CI
p ot e nti all y cli nic all y i m p ort a nt
P D
p h ar m ac o d y n a mics
P K
p h ar m ac o ki n etics
P T
pr ef err e d t er m
S A P
St atistic al A n al ysis Pl a n
S O C
s yst e m or g a n cl ass
V A S
v is u al a n al o g u e sc al e


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 7 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1. IN T R O D U C TI O N
T his St atistic al A n al ysis Pl a n ( S A P) pr o vi d es a t ec h nic al a n d d et ail e d el a b or ati o n of t h e st atistic al a n al ys es 
of effic ac y, s af et y, p h ar m ac o ki n etic ( P K), p h ar m ac o d y n a mic ( P D), a n d a n gi o e d e m a q u alit y of lif e ( A E -Q o L) 
p ar a m et ers as d escri b e d i n t h e fi n al st u d y pr ot oc ol A m e n d m e nt 5 d at e d 3 0 A u g ust 2 0 1 6. S p ecific ati o ns f or 
t a bl es, fi g ur es, a n d listi n gs ar e als o c o nt ai n e d i n t his d oc u m e nt.  
1. 1.
B A C K G R O U N D
H er e dit ar y a n gi o e d e m a ( H A E) is a r ar e, a ut os o m al d o mi n a nt dis e as e c a us e d b y a n i n h erit e d or 
s p o nt a n e o us g e n e m ut ati o n o n c hr o m os o m e 1 1 t h at r es ults i n a q u a ntit ati v e or f u ncti o n al d efici e nc y of C 1 
i n hi bit or ( C 1-I N H) pr ot ei n ( B er nst ei n 2 0 1 1 ). P ati e nts wit h H A E ar e s usc e pti bl e t o r ec urr e nt e pis o d es of 
d e bilit ati n g s w elli n g t hr o u g h o ut t h e b o d y. R e pl ac e m e nt of C 1 -I N H t hr o u g h i ntr a v e n o us (I V) a d mi nistr ati o n 
of CI N R Y Z E ® ( C 1 i n hi bit or [ h u m a n]) i ncr e as es s er u m c o nc e ntr ati o ns of C 1-I N H a nti g e n ( pr ot ein v ol u m e) 
a n d f u ncti o n al C 1 -I N H acti vit y ( p ot e nc y), t e m p or aril y r est ori n g t h e n at ur al r e g ul ati o n of t h e c o m pl e m e nt, 
c o nt act ( br a d y ki ni n-f or mi n g), a n d fi bri n ol ytic s yst e ms. C 1 i n hi bit or r e pl ac e m e nt t h er a p y c a n pr e v e nt t h e 
occ urr e nc e of a n gi o e d e m a att ac ks as s oci at e d wit h H A E or st o p a n d c o ntr ol t h e m ec h a nis m t h at c a us es 
s w elli n g if a n att ac k d o es occ ur.
C I N R Y Z E® is a hi g hl y p urifi e d, vir al-i n acti v at e d, n a n ofilt er e d c o nc e ntr at e of C 1-I N H pr o d uc e d fr o m h u m a n 
pl as m a.
1. 2.
S T U D Y R A TI O N AL E
C urr e ntl y, t h er e is n o pr o d uc t a p pr o v e d i n J a p a n f or b ot h pr e v e nti o n of a n gi o e d e m a att ac ks a n d tr e at m e nt 
of a n gi o e d e m a att ac ks ass oci at e d wit h H A E. I n cli nic al tri als c o n d uct e d o utsi d e of J a p a n, CI N R Y Z E® w as 
pr o v e n t o b e s af e, w ell t ol er at e d, a n d eff ecti v e f or t h e pr e v e nti o n a n d tr e atm e nt of a n gi o e d e m a att ac ks i n a 
br o a d a g e r a n g e of p ati e nts wit h H A E ( p e di atrics t hr o u g h p ati e nts ≥6 5 y e ars ol d). O v ers e as st u di es h a v e 
s h o w n t h at s elf-a d mi nistr ati o n all o ws p ati e nts t o m a n a g e t h eir dis e as e s y m pt o ms wit h mi ni m al disr u pti o n 
t o t h eir d ail y a cti viti es r es ulti n g i n r e d uc e d a bs e nc es fr o m w or k or sc h o ol a n d o v er all i m pr o v e m e nt i n  
q u alit y of lif e (Cic ar di et al. 2 0 1 3 ; C a b all er o et al. 2 0 1 3 ). It is e x p ect e d t h at CI N R Y Z E®
P P D
will f ulfill a n u n m et
m e dic al n e e d f or J a p a n es e p ati e nts wit h H A E, a n d t h e pr es e nt st u d y is b ei n g p erf or m e d t o c o nfir m its s af et y 
a n d effic ac y i n t his p ati e nt p o p ul ati o n.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 8 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
2. S T U D Y O BJ E C TI V E S
T h e o bj ecti v es of t h e st u d y ar e t o ass ess:

T h e s af et y a n d t ol er a bilit y of C I N R Y Z E® a d mi nist er e d b y I V i nf usi o n i n J a p a n es e s u bj ects wit h H A E;

T h e p h ar m a c o ki n etics (P K ) a n d p h ar m ac o d y n a mics ( P D ) of C I N R Y Z E® a d mi nist er e d b y I V i nf usi o n i n t his 
s u bj ect p o p ul ati o n; a n d

T h e tr e at m e nt eff ect of C I N R Y Z E
P P D
® a d mi nist er e d b y I V i nf usi o n f or t h e pr e v e nti o n of a n gi o e d e m a att ac ks 
a n d tr e at m e nt of br e a kt hr o u g h att ac ks i n t his s u bj ect p o p ul ati o n.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 9 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
3. S T U D Y D E SI G N
3. 1.
G E N E R AL D E S C RI P TI O N
T his si n gl e -p eri o d, o p e n -l a b el st u d y will b e c o n d uct e d at m ulti pl e i n v esti g ati o n al sit es i n J a p a n. T his is a n 
o ut p ati e nt st u d y ; h o w e v er, s u bj ects m a y r e q uir e a n o v er ni g ht st a y at t h e sit e f or t h os e d a ys o n w hic h s eri al 
P K / P D bl o o d s a m pl es ar e c oll ect e d. S u bj ects w o ul d b e disc h ar g e d t h e f oll o wi n g d a y aft er c oll ecti o n of t h e 
2 4 -h o ur P K / P D bl o o d s a m pl e.
S u bj ects will b e a d mi nist er e d C I N R Y Z E® b y I V i nf usi o n t wic e w e e kl y ( e v er y 3 or 4 d a ys) f or 1 2 w e e ks. St u d y 
dr u g will b e a d mi nist er e d t o all s u bj ects at t h e i n v esti g ati o n al sit e f or D osi n g Visits 1 t hr o u g h 8, 1 6, a n d 2 4; 
d uri n g t h es e visits, s u bj ects m a y als o h a v e p h ysic al e x a mi n ati o ns a n d ot h er pr oc e d ur es p erf or m e d ( s e e 
Sc h e d ul e 1 of t h e pr ot oc ol ). Ot h er d os es of st u d y dr u g m a y b e a d mi nist er e d at t h e i n v esti g ati o n al sit e or at 
t h e s u bj ect’s h o m e.
3. 2.
D E T E R MI N A TI O N O F S A M PL E S I Z E
P P D
A s uffici e nt n u m b er of s u bj ects will b e e nr oll e d t o e ns ur e t h at a mi ni m u m of 6 s u bj ects c o m pl et e t h e st u d y. 
W h e n 6 s u bj ects h a v e c o m pl et e d t h e 1 2 -w e e k tr e at m e nt p eri o d, n o f urt h er s u bj ects will b e e nr oll e d; 
h o w e v er, all s u bj ects alr e a d y e nr oll e d i n t h e st u d y will b e f oll o w e d t o st u d y c o m pl eti o n.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 0 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
4. E F FI C A C Y A N D S A F E T Y V A RI A BL E S
4. 1.
S C H E D UL E O F E V AL U A TI O N S
Sc h e d ul e of e v al u ati o n s c a n b e f o u n d i n Sc h e d ul e 1 of t h e pr ot oc ol.
4. 2.
E F FI C A C Y V A RI A BL E S
4. 2. 1.
P R E V E N TI O N O F A N GI O E D E M A A T T A C K S
T h e f oll o wi n g effic ac y e n d p oi nts f or pr e v e nti o n of a n gi o e d e m a att ac ks will b e ass ess e d:

T h e n or m aliz e d n u m b er of a n gi o e d e m a att ac ks ( N N A) r ec or d e d d uri n g t h e tr e at m e nt p eri o d, n or m aliz e d 
f or t h e n u m b er of d a ys t h e s u bj ect p artici p at e d i n t h e p eri o d; a n d t h e N N A f or hist oric al d at a n or m aliz e d 
f or 3 m o nths pri or t o st u d y dr u g a d mi nist r ati o n.

S u m m ar y of all att ac ks d uri n g t h e tr e at m e nt p eri o d a n d hist oric al 3 m o nt h d at a , i ncl u di n g:
o
A n at o mic l oc ati o n.
o
S e v erit y (i nt e nsit y).
o
A v er a g e d ur ati o n of att ac ks .
o
N u m b er of a n gi o e d e m a att ac ks tr e at e d wit h C I N R Y Z E® , n o n - CI N R Y Z E® C 1 -I N H or n ot tr e at e d wit h C 1 -I N H 
(i ncl u di n g att ac k s tr e at e d wit h a n y m e dic ati o ns ot h er t h a n C 1 -I N H or u ntr e at e d att ac ks).

Eff ects of t h er a p y o n q u alit y of lif e (r es ults of A E -Q oL q u esti o n n air e).
4. 2. 2.
T R E A T M E N T O F B R E A K T H R O U G H A N GI O E D E M A A T T A C K S
T h e f oll o wi n g effic ac y e n d p oi nts f or tr e at m e nt of br e a kt hr o u g h a n gi o e d e m a att ac ks will b e ass ess e d b y ;
C I N R Y Z E® tr e at e d att ac ks , n o n-C I N R Y Z E® C 1 -I N H tr e at e d att ac ks a n d ot h er att ac ks (i ncl u di n g a n y 
m e dic ati o ns ot h er t h a n C 1 -I N H a n d u ntr e at e d att ac ks):

T h e n u m b er of s u bj ects wit h br e a kt hr o u g h a n gi o e d e m a att ac ks.

T h e n u m b er of s u bj ects wit h 1, 2, 3 or m or e a n gi o e d e m a att ac ks.

T h e n u m b er of s u bj ects w h o ac hi e v e i niti al i m pr o v e m e nt a n d C o m pl et e R es ol uti o n. C o m pl et e R es ol uti o n 
is d efi n e d as t h e c ess ati o n of all s y m pt o ms of t h e br e a kt hr o u g h a n gi o e d e m a att ac k si nc e o ns et of att ac k.

P P D
Ti m e t o i niti al i m pr o v e m e nt a n d ti m e t o C o m pl et e R es ol uti o n.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 1 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A d diti o n al a n al ysis f or br e a kt hr o u g h a n gi o e d e m a att ac ks tr e at e d wit h C I N R Y Z E® will als o b e pr es e nt e d f or:

T h e n u m b er of s u bj ects wit h br e a kt hr o u g h a n gi o e d e m a att ac ks.

T h e n u m b er of s u bj ects wit h 1, 2, 3 or m or e a n gi o e d e m a att ac ks.

Ti m e fr o m o ns et of att ac k t o ti m e tr e at e d b y C I N R Y Z E®.

T h e n u m b er of s u bj ects w h o ac hi e v e i niti al i m pr o v e m e nt a n d C o m pl et e R es ol uti o n. C o m pl et e R es ol uti o n 
is d efi n e d as t h e c ess ati o n of all s y m pt o ms of t h e br e a kt hr o u g h a n gi o e d e m a att ac k si nc e o ns et of att ac k.

Ti m e fr o m t h e st art of st u d y dr u g a d mi nistr ati o n , C I N R Y Z E®, f or t h e p artic ul ar att ac k t o t h e ti m e of i niti al 
i m pr o v e m e nt a n d ti m e t o C o m pl et e R es ol uti o n.
4. 3.
S A F E T Y A S S E S S M E N T S
T h e f oll o wi n g will b e ass ess e d:

A d v ers e e v e nts (i ncl u di n g tr e at m e nt -e m er g e nt a d v ers e e v e nts).

S u m m ar y st atistics a n d c h a n g es fr o m b as eli n e t o p ost -b as eli n e f or l a b or at or y t esti n g, vit al si g ns, a n d, if 
a p plic a bl e, a n y el ectr oc ar di o gr a m ( E C G) fi n di n gs will b e pr es e nt e d.

P P D
R es ults of C 1 -I N H a nti b o d y t esti n g will b e r e p ort e d f or i n di vi d u al s u bj ects a n d s u m m ariz e d as a p pr o pri at e.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 2 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
5. S T A TI S TI C AL A N AL Y SI S
5. 1.
G E N E R AL M E T H O D OL O G Y
E x p eri m e nt al r es ults will b e s u m m ari z e d usi n g d escri pti v e st atistics acc or di n g t o d at a t y p e ( n, m e a n, 
st a n d ar d d e viati o n or st a n d ar d err or, m e di a n, a n d r a n g e f or c o nti n u o us e n d p oi nts; n u m b er a n d p erc e nt of 
s u bj ects i n e ac h c at e g or y f or c at e g oric al e n d p oi nts) .
T h e esti m at e d m e di a n ti m e t o e v e nt a n d its 9 5 % c o nfi d e nc e i nt er v al ( CI) will b e c alc ul at e d (if at l e ast 5 0 % 
of s u bj ects i n t h e F ull A n al ysis S et ac hi e v e d t h e e v e nt) usi n g t h e K a pl a n-M ei er esti m at or. T h e K a pl a n -M ei er 
esti m at es will als o b e dis pl a y e d gr a p hic all y.
All a n al ys es will b e pr es e nt e d b y C 1 I n hi bit or 1 0 0 0 U o nl y. St u d y dr u g a d mi nistr ati o ns w er e pl a n n e d 
acc or di n g t o s u bj ects a g e ; 5 0 0 U f or S u bj ects 2 t o 5 y e ars of a g e a n d 1 0 0 0 U f or S u bj ects 6 y e ars of a g e a n d 
ol d er.   H o w e v er, o nl y t h e hi g h er d os e of 1 0 0 0 U w er e a d mi nist er e d.   
U nsc h e d ul e d visits d at a will n ot b e i ncl u d e d i n a n al ysis, ot h er wis e s p ecifi e d. U nsc h e d ul e d visits d at a will 
m er el y b e pr es e nt e d i n listi n gs.
5. 2.
A N AL Y SI S P O P UL A TI O N S
E nr oll e d s u bj ects ar e all s u bj ects w h o si g n e d si g n e d i nf or m e d c o ns e nt a n d c o m pl et e d scr e e ni n g. 
All tr e at e d s u bj ects (i e, I nt e nt -t o-Tr e at S af et y [I T T -S] P o p ul ati o n: s u bj ect s w h o r ec ei v e a n y a m o u nt of st u d y 
dr u g) will b e i ncl u d e d i n t h e s af et y a n al ys es.
F ull A n al ysis S et P o p ul ati o n ( d efi n e d as s u bj ects w h o h a v e at l e ast o n e p ost b as eli n e effic ac y ass ess m e nt ) 
will b e i ncl u d e d i n t h e effic ac y a n al ys es.
All s u bj ects wit h e v al u a b l e P K / P D pr ofil es (i e, P K / P D P o p ul ati o n) will b e i ncl u d e d i n P K / P D a n al ys es as 
a p pr o pri at e.
5. 3.
S U BJ E C T D I S P O SI TI O N
A s u m m ar y t a bl e of s u bj ect dis p ositi o n will b e pr o vi d e d, t o s h o w t h e n u m b er of s u bj ects scr e e n e d, e nr oll e d, 
a n d t h e n u m b er of s u bj ects i n t h e I TT- S p o p ul ati o n. 
T h e n u m b er of s u bj ects c o m pl eti n g t h e st u d y a n d wit h dr a wi n g fr o m t h e st u d y will als o b e t a b ul at e d. 
Wit h dr a w als will b e c at e g ori z e d b y pri m ar y r e as o n f or wit h dr a w al.
5. 4.
P R O T O C OL D E VI A TI O N S
P P D
N u m b er of s u bj ects wit h p r ot oc ol d e vi ati o ns will b e s u m m aris e d f or t h e f oll o wi n g c at e g ori es:


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 3 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.

Pr oc e d ur es/t ests

Dis all o w e d m e dic ati o ns

I ncl usi o n/ excl usi o n crit eri a

I n v esti g ati o n al pr o d uct a d mi nistr ati o n/st u d y tr e at m e nt

Ot h er
T h e d at e pr ot oc ol d e vi ati o ns w er e i d e ntifi e d t o g et h er wit h t h e pr ot oc ol d e vi ati o n d escri pti o n will als o b e 
pr es e nt e d i n a listi n g.
5. 5.
D E M O G R A P HI C A N D O T H E R B A S ELI N E C H A R A C T E RI S TI C S
D e m o gr a p hics ( a g e, a g e gr o u p of < 1 8, b et w e e n 1 8 – 6 4, ≥ 6 5, s e x,et h nic it y a n d r ac e ) will b e s u m m ari z e d.
I n a d diti o n, t h e f oll o wi n g b as eli n e c h ar act eristics will b e als o b e t a b ul at e d:

W ei g ht
( k g) at scr e e ni n g

H ei g ht (c m) at scr e e ni n g

B MI ( k g/ m2) at scr e e ni n g
I n a s e p ar at e t a bl e, s u m m ar y of H A E hist or y will als o b e t a b ul at e d f or t h e f oll o wi n g:

T y p e of H A E

F a mil y hist or y of H A E 

Ti m e si nc e l ast a n gi o e d e m a a tt ac k ( d a ys)

T ot al n u m b er of a n gi o e d e m a att ac ks d uri n g 3 c o ns ec uti v e m o nt hs pri or t o st u d y dr u g a d mi nistr ati o n

T y pic al V A S sc or e ( m m) d uri n g 3 c o ns ec uti v e m o nt hs pri or t o st u d y dr u g a d mi nistr ati o n

A v er a g e o v er all d ur ati o n ( d a ys) of a n gi o e d e m a att ac ks d uri n g 3 c o ns ec uti v e m o nt hs pri or t o st u d y dr u g 
a d mi nistr ati o n , as c oll ect e d i n t h e M e dic al/ A n gi o e d e m a Hist or y el ectr o nic C as e R e p ort F or m ( e C R F)

A v er a g e o v er all s e v erit y of a n gi o e d e m a att ac ks d uri n g 3 c o ns ec uti v e m o nt hs pri or t o st u d y dr u g 
a d mi nistr ati o n , as c oll ect e d i n t h e M e dic al/ A n gi o e d e m a Hist or y e C R F

P P D
T y pic al l oc ati o n(s) of a n gi o e d e m a att ac k d uri n g t h e 3 c o ns ec uti v e m o nt hs pri or t o st u d y dr u g 
a d mi nistr ati o n


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 4 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
D eri v ati o ns will b e c o nstr uct e d as f oll o w:
B o d y m ass i n d e x ( k g/ m 2)
...
=
ℎ ( 
)
ℎ 
ℎ( 
)
1 0 0
2
pr es e nt e d t o o n e d eci m al pl ac e .
Ti m e si nc e l ast a n gi o e d e m a att ac k ( d a ys)
ti m e = first d os e  d at e − o ns et  d at e  of  l ast a n gi o e d e m a  att ac k  pri or  t o first d os e
5. 6.
E X T E N T O F E X P O S U R E
T h e a v er a g e d ail y d os e, t ot al d os e a n d d ur ati o n of e x p os ur e will b e s u m m ari z e d f or st u d y dr u g t a k e n as 
‘ L o n g-t er m pr e v e nti o n’.
D eri v ati o ns will b e c o nstr uct e d as f oll o w:
D ur ati o n of e x p os ur e ( w e e ks)
d ur ati o n = ( l ast d os e  d at e −first d os e  d at e + 1) / 7
T ot al d os e ( U)
T h e s u m of all st u d y dr u g a d mi nist er e d. 
A v er a g e d ail y d os e ( U/ d a y)
a v er a g e =
  
 (
)
  
  
− 
  
  
+ 1 ( 
)
5. 7.
A N AL Y SI S O F E F FI C A C Y
5. 7. 1.
P R E V E N TI O N O F A N GI O E D E M A A T T A C K S
A n a n gi o e d e m a att ac k is d efi n e d a s a n y s u bj ect-r e p ort e d ( or c ar e gi v er-r e p ort e d) i n dic ati o n of s w elli n g or 
p ai n at a n y l oc ati o n f oll o wi n g a r e p ort of n o s w elli n g or p ai n o n t h e pr e vi o us d a y (i e, t h er e m ust b e a f ull 
s y m pt o m-fr e e c al e n d ar d a y pr ec e di n g t h e o ns et of s y m pt o ms f or a n att ac k t o b e c o nsi d er e d a n e w att ac k). 
T h er ef or e,

P P D
Att ac ks t h at pr o gr ess fr o m 1 sit e t o a n ot h er will b e c o nsi d er e d a si n gl e att ac k;


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 5 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.

Att ac ks t h at b e gi n t o r e gr ess a n d t h e n w ors e n b ef or e c o m pl et e r es ol uti o n will b e c o nsi d er e d 1 att ac k; a n d

Att ac ks t h at b e gi n, a p p e ar t o r es ol v e, a n d t h e n r e a p p e ar wit h o ut a s y m pt o m -fr e e c al e n d ar d a y r e p ort e d 
aft er t h e a p p e ar a nc e of r es ol uti o n will b e c o nsi d er e d 1 att ac k.
A n a n gi o e d e m a att ac k d o es N O T i ncl u d e s w elli n g d u e t o tr a u m a or art hritis, or s y m m etric al n o n-p ai nf ul 
s w elli n g of t h e l o w er e xtr e miti es.
T h e f oll o wi n g effic ac y e n d p oi nts f or pr e v e nti o n of a n gi o e d e m a att ac ks will b e t a b ul at e d .

T h e N N A d uri n g t h e tr e at m e nt p eri o d, c o m p ar e d t o t h e N N A f or hist oric al d at a f or 3 m o nt hs pri or t o 
st u d y dr u g a d mi nistr ati o n .

S u m m ar y of all att ac ks d uri n g t h e tr e at m e nt p eri o d, i ncl u di n g:
o
A n at o mic l oc ati o n.
o
S e v erit y (i nt e nsit y).
o
A v er a g e d ur ati o n of att ac ks .
o
N u m b er of a n gi o e d e m a att ac ks tr e at e d wit h C I N R Y Z E® , n o n - CI N R Y Z E® C 1 -I N H or n ot tr e at e d wit h C 1 -I N H 
(i ncl u di n g att ac k s tr e at e d wit h a n y m e dic ati o ns ot h er t h a n C 1 -I N H or u ntr e at e d att ac ks). 

T h e n u m b er of s u bj ects wit h pr e - a n d p ost -tr e at m e nt N N A v al u es will als o b e pr es e nt e d f or t h e f oll o wi n g:
o
N u m b er of s u bj ects ac hi e vi n g > = 5 0 % r e d ucti o n i n N N A r el ati v e t o N N A f or Hist otic al d at a 
o
N u m b er of s u bj ects ac hi e vi n g > = 7 0 % r e d ucti o n i n N N A r el ati v e t o N N A f or Hist otic al d at a
o
N u m b er of s u bj ects ac hi e vi n g > = 9 0 % r e d ucti o n i n N N A r el ati v e t o N N A f or Hist otic al d at a

Eff ects of t h er a p y o n q u alit y of lif e (r es ults of A E -Q oL q u esti o n n air e).
D eri v ati o ns will b e c o nstr uct e d as f oll o w:
N u m b er of a n gi o e d e m a att ac ks ( p er m o nt h )
T h e N N A d uri n g t h e tr e at m e nt p eri o d is t h e n u m b er of a n gi o e d e m a att ac ks n or m ali z e d f or t h e n u m b er of 
d a ys t h e s u bj ect p artici p at e d i n t h e p eri o d a n d m ulti pli e d b y 3 0. 4 :
  
 
 
  
  
− 
  
  
+ 1 3 0 . 4
pr es e nt e d t o t w o d eci m al pl ac e.
T h e N N A f or hist oric al d at a is t h e n u m b er of a n gi o e d e m a att ac ks d uri n g 3 m o nt hs pri or t o st u d y dr u g 
a d mi nistr ati o n , di vi d e d by 3.
 
  
 
  
  
 
 ℎ  
 
  
 
3
P P D


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 6 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A n at o mic l oc ati o n
T h e s u m m ar y of a n at o mic l oc ati o n will b e c o u nt e d f or e ac h of t h e f oll o wi n g l oc ati o n w h e r e t h er e is a 
pr es e nc e of p ai n or s w elli n g of a n y l e v el of s e v erit y; mil d, m o d er at e or s e v er e at a n y d a y d uri n g t h e att ac k.

A b d o mi n al/ G astr oi nt esti n al

G e nit al/ Uri n ar y (i ncl u d es scr ot u m or v ul v a)

U p p er air w a y (i ncl u d es l ar y n g e al or p h ar y n g e al)

C ut a n e o us – f aci al

C ut a n e o us – extr e mit y or p eri p h er al
T h e hist oric al d at a of t h e t y pic al l oc ati o n of s u bj ects a n gi o e d e m a att ac ks c a n b e o bt ai n e d fr o m t h e 
M e dic al / A n gi o e d e m a Hist or y e C R F p a g e.
S e v erit y (i nt e nsit y)
T h e s e v erit y of a n att ac k will b e t h e hi g h est v al u e assi g n e d b y t h e s u bj ect t o a n y l oc ati o n at a n y d a y d uri n g 
t h e att ac k. I n or d er t o c alc ul at e t h e a v er a g e s e v erit y of att ac ks,e ac h mil d, m o d er at e, a n d s e v er e att ac k will 
b e assi g n e d a sc or e of 1, 2, or 3, r es p ecti v el y. T h e t ot al s e v erit y sc or e wi ll b e c alc ul at e d f or m ulti pl yi n g t h e 
t ot al n u m b er of mil d att ac ks b y 1, t ot al n u m b er of m o d er at e att ac ks b y 2, a n d t h e t ot al n u m b er of s e v er e 
att ac ks b y 3, t h e n a d di n g t h e r es ults of t h es e t hr e e c alc ul ati o ns.
T h e a v er a g e s e v erit y of att ac k will b e s u m m ari z e d. T h e a v er a g e s e v erit y is d eri v e d b y di vi di n g t h e 
c u m ul ati v e s e v erit y sc or e b y t h e t ot al n u m b er of att ac ks.
F or hist oric al d at a, t h e a v er a g e o v er all s e v erit y of s u bj ects a n gi o e d e m a att ac k ar e c oll ect e d i n t h e 
M e dic al / A n gi o e d e m a Hist or y e C R F p a g e.  T h e s i mil ar sc ori n g s yst e m as i n dic at e d a b o v e will b e a p pli e d t o 
t h e a v er a g e s e v erit y l e v el.
A v er a g e d ur ati o n of att ac ks ( d a ys)
T h e d ur ati o n of a n att ac k will b e m e as ur e d fr o m t h e o ns et of att ac ks u ntil c o m pl et e r es ol uti o n . 
T h e a v er a g e d ur ati o n of att ac ks is c alc ul at e d b y di vi di n g t h e c u m ul ati v e d ur ati o n of att ac ks b y t h e t ot al 
n u m b er of att ac ks d uri n g t h e tr e at m e nt p eri o d. 
F or t h e hist oric al d at a, t h e a v er a g e d ur ati o n of att ac ks r ec or d e d o n t h e M e dic al / A n gi o e d e m a Hist or y e C R F 
p a g e will b e us e d.
N u m b er of a n gi o e d e m a att ac ks tr e at e d wit h r esc u e m e dic ati o n ( p er m o nt h )
P P D


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 7 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T h e N N A tr e at ed wit h r esc u e m e dic ati o n will b e s u m m ari z e d f or C I N R Y Z E® , n o n - CI N R Y Z E® C 1 -I N H or n ot 
tr e at e d wit h C 1-I N H (i ncl u di n g att ac ks tr e at e d wit h a n y m e dic ati o n s ot h er t h a n C 1 -I N H or u ntr e at e d 
att ac ks ), a n d is d efi n e d as b el o w .
  
 
  
  
  
 
  
  
− 
  
  
+ 1
3 0 . 4
F or o n tr e at m e nt att ac ks, o nl y m e dic ati o n t a k e n aft er st u d y dr u g a d mi nistr ati o n a n d h a d a n i n dic ati o n of 
‘ H A E M a n a g e m e nt – Ac ut e Tr e at m e nt’ s el ect e d o n t h e Pri or a n d C o nc o mit a nt M e dic ati o ns a n d T h er a p y
e C R F p a g e will b e c o nsi d er e d as r esc u e m e dic ati o ns.  C I N R Y Z E® will o nl y b e c o nsi d er e d as a r esc u e 
m e dic ati o n w h e n tr e at e d f or ‘ Br e a kt hr o u g h Att ac k Tr e at m e nt’. 
F or hist oric al d at a, o nl y m e dic ati o n pri or t o t h e st art of st u d y dr u g a d mi nistr ati o n a n d h a d a n i n dic ati o n of 
‘ H A E M a n a g e m e nt – Ac ut e Tr e at m e nt’ s el ect e d o n t h e Pri or a n d C o nc o mit a nt M e dic ati o ns a n d T h er a p y
e C R F p a g e will b e c o nsi d er e d as r esc u e m e dic ati o ns.  
5. 7. 2.
T R E A T M E N T O F B R E A K T H R O U G H A N GI O E D E M A A T T A C K S
A br e a kt hr o u g h att ac k is d efi n e d as a n a n gi o e d e m a att ac k t h at occ urs d uri n g l o n g -t er m pr e v e nti o n t h er a p y
wit h C I N R Y Z E® (i. e, b et w e e n first st u d y dr u g a n d l ast st u d y dr u g d os e).
T h e f oll o wi n g effic ac y e n d p oi nts f or tr e at m e nt of br e a kt hr o u g h a n gi o e d e m a att ac ks will b e ass ess e d b y 
C I N R Y Z E® tr e at e d att ac ks, n o n-C I N R Y Z E® C 1 -I N H tr e at e d att ac ks a n d all ot h er att ac ks (i ncl u di n g a n y 
m e dic ati o n s ot h er t h a n C 1-I N H a n d u ntr e at e d att ac ks):

T h e n u m b er of s u bj ects wit h br e a kt hr o u g h a n gi o e d e m a att ac ks .

T h e n u m b er of s u bj ects wit h 1, 2, 3 or m or e a n gi o e d e m a att ac ks.

T h e n u m b er of s u bj ects w h o ac hi e v e i niti al i m pr o v e m e nt a n d C o m pl et e R es ol uti o n. 

Ti m e t o i niti al i m pr o v e m e nt a n d ti m e t o C o m pl et e R es ol uti o n.
A d diti o n al a n al ysis f or br e a kt hr o u g h a n gi o e d e m a att ac ks tr e at e d wit h C I N R Y Z E® will als o b e pr es e nt e d f or:

T h e n u m b er of s u bj ects wit h br e a kt hr o u g h a n gi o e d e m a att ac ks .

T h e n u m b er of s u bj ects wit h 1, 2, 3 or m or e a n gi o e d e m a att ac ks.

Ti m e fr o m o ns et of att ac k t o ti m e tr e at e d b y C I N R Y Z E®.

T h e n u m b er of s u bj ects w h o ac hi e v e i niti al i m pr o v e m e nt a n d C o m pl et e R es ol uti o n. C o m pl et e R es ol uti o n 
is d efi n e d as t h e c ess ati o n of all s y m pt o ms of t h e br e a kt hr o u g h a n gi o e de m a att ac k si nc e o ns et of att ac k.

Ti m e fr o m t h e st art of st u d y dr u g a d mi nistr ati o n , C I N R Y Z E®
P P D
, f or t h e p artic ul ar att ac k t o t h e ti m e of i niti al 
i m pr o v e m e nt a n d ti me t o C o m pl et e R es ol uti o n.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 8 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
D eri v ati o ns will b e c o nstr uct e d as f oll o w:
C o m pl et e R es ol uti o n
C o m pl et e R es ol uti o n is d efi n e d as t h e c ess ati o n of all s y m pt o ms of t h e br e a kt hr o u g h a n gi o e d e m a att ac k
si nc e o ns et of att ac k.
Ti m e t o C o m pl et e R es ol uti o n
Ti m e t o c o m pl et e r es ol uti o n is d efi n e d as t h e ti m e fr o m t h e o ns et of att ac k t o c o m pl et e r es ol uti o n of 
s y m pt o ms. 
T h e a n al ysis of t h e ti m e t o e v e nt e n d p oi nt i ncl u d es o nl y t h e first att ac k fr o m e ac h s u bj ect m e eti n g t h e 
tr e at m e nt crit eri o n si nc e att ac ks e x p eri e nc e d b y t h e s a m e s u bj ect ar e d e p e n d e nt. M e di a n ti m e t o c o m pl et e 
r es ol uti o n a n d t h e c orr es p o n di n g 9 5 % CI esti m at e d usi n g t h e K a pl a n -M ei er m et h o d will b e s u m m ari z e d .  
K a pl a n M ei er pl ots f or ti m e fr o m CI N R Y Z E® t o i niti al i m pr o v e m e nt a n d t o c o m pl et e r es ol uti o n will als o b e 
pr es e nt e d.
5. 7. 3.
A N GI O E D E M A Q U ALI T Y O F L I F E ( A E- QO L) Q U E S TI O N N AI R E
T h e A n gi o e d e m a Q u alit y of Lif e ( A E -Q o L) is a q u esti o n n air e o n t h e q u alit y of lif e of p ati e nts s uff eri n g fr o m 
r ec urr e nt a n gi o e d e m a. It c o nsists of 1 7 s p ecific q u esti o ns t h at ar e ass oci at e d wit h w or k, p h ysic al acti vit y, 
fr e e ti m e, s oci al r el ati o ns, a n d di et. E ac h q u esti o n is t h e n a ns w er e d wit h N e v er, R ar el y, Occ asi o n all y, Oft e n 
a n d V er y Oft e n, w hic h will b e sc or e d as 1, 2, 3, 4 a n d 5 r es p ecti v el y. T h e 1 7 q u esti o ns will b e gr o u p e d i nt o 
f o ur c at e g ori es as f oll o w, a n d a t ot al sc or e will als o b e c alc ul at e d:

F u nct i o ni n g
o
1. I m p air m e nt of wor k
o
2. I m p air m e nt of ph ysic al acti vit y
o
3. I m p air m e nt of s p ar e ti m e acti viti es
o
4. I m p air m e nt of soci al r el ati o ns

F ati g u e/ M o o d
o
6. Diffic ult i es of f alli n g asl e e p
o
7. W a k i n g u p d uri n g t h e ni g ht
o
8. F e eli n g tir e d d uri n g t h e d a y
o
9. Diffic u lti es i n c o nc e ntr ati n g
o
1 0. F e el i n g d o w n h e art e d

P P D
F e ars/ S h a m e
o
1 2. F e eli n g b ur d e n at h a vi n g s w elli n gs
o
1 3. F e ar of n e w s u d d e nl y a p p e ari n g s w elli n gs
o
1 4. F e ar of i ncr e as e d fr e q u e nc y of s w elli n gs
o
1 5. A s h a m e d t o visit p u blic pl ac es


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 1 9 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
o
1 6. E m b arr ass e d b y t h e a p p e ar a nc e of s w elli n gs
o
1 7. F e ar of l o n g-t er m n e g ati v e dr u g eff ects

N utriti o n
o
5. G e n er al li mit ati o ns i n f o o ds a n d e ati n g
o
1 1. Li mitati o ns i n t h e s el ecti o n of f o o d or b e v er a g es ?

P P D
T ot al Sc or e
o
Q u esti o n 1 t o Q u esti o n 1 7


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 0 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S u m m ar y a n d c h a n g e fr o m b as eli n e f or t h e t ot al sc or e will b e pr es e nt e d f or all visits.
5. 7. 4.
S E N SI TI VI T Y A N AL Y SI S
T h e f oll o wi n g s e nsiti vit y a n al ys es will b e p erf or m e d f or effic ac y a n al ysis o n N N A d escri b e d i n S ecti o n 5. 7. 1 .
T h e first s e nsiti vit y a n al ysis i ncl u d es o nl y s u bj ects wit h tr e at m e nt c o m pli a nc e. T h e d efi niti o n of tr e at m e nt 
c o m pli a nc e will b e gi v e n i n S ecti o n 5 . 8. 8. T h at is, o nl y s u bj ects w h o h a v e n o d os e i nt err u pti o n a n d r ec ei v e 
2 4 c o m pl et e i nf usi o ns ar e i ncl u d e d i n t h e a n al ysis.
I n t h e s ec o n d s e nsiti vit y a nl a ysis, all FA S s u bj ects will b e i ncl u d e d i n t his s e nsiti vit y a n al ysis, h o w e v er d at a 
will o nl y i ncl u d e u p t o t h e p oi nt w h e n n o n -tr e at m e nt c o m pli a nc e occ urr e d .    
5. 8.
A N AL Y SI S O F S A F E T Y
5. 8. 1.
A D V E R S E E V E N T S
P P D
A d v ers e E v e nts ( A Es) will b e c o d e d usi n g M e dic al Dicti o n ar y f or R e g ul at o r y Acti viti es ( M e d D R A) c e ntr al 
c o di n g dicti o n ar y v ersi o n 1 9. 0 .E v e nts will b e cl assifi e d b y s yst e m or g a n cl ass ( S O C) a n d pr ef err e d t er m 
( P T).  O nl y tr e at m e nt e m er g e nt a d v ers e e v e nts ( T E A Es) will b e s u m m ari z e d.
Tr e at m e nt -e m er g e nt e v e nts i ncl u d e all A Es t h at st art d uri n g t h e tr e at m e nt p eri o d  a n d w er e n ot s e e n at 
b as eli n e, or w er e s e e n at b as eli n e b ut w ors e n e d i n fr e q u e nc y a n d / or s e v erit y d uri n g t h e tr e at m e nt p eri o d.
T h e i nci d e nc e of i nj ecti o n sit e r e acti o n A Es will als o b e s u m m ari z e d at P T a n d S O C l e v el .I njecti o n sit e 
r e acti o n A Es ar e a n y P T t h at i ncl u d e t h e t er m ‘i nj ecti o n sit e r e acti o n’. 
T h e i nci d e nc e of T E A Es will b e s u m m ari z e d b y i nt e nsit y (' Mil d', ' M o d er at e' or ' S e v er e') at P T a n d S O C l e v el.  
F or e ac h s u bj ect a n d P T , o nl y t h e m ost s e v er e A E will b e c o u nt e d.
T h e i nci d e nc e of A Es r el at e d t o st u d y dr u g will b e s u m m ari z e d at P T a n d S O C l e v el. E v e nts wit h a 
r el ati o ns hi p t o st u d y dr u g cl assifi e d as 'P ossi bl y R el at e d ', ' Pr o b a bl y R el at e d ', a n d ‘ D efi nit el y R el at e d ' will b e 
c at e g ori z e d as ' R el at e d'. If a s u bj ect e x p eri e nc es t h e s a m e e v e nt ( at P T l e v el) o n m or e t h a n o n e occ asi o n, 
t h e n o nl y o n e e v e nt will b e c o u nt e d, a n d t his e v e nt will b e c at e g ori z e d as ' R el at e d' if a n y of t h e e v e nts 
u n d er t h at P Ts ar e c at e g ori z e d as ' R el at e d'. 
T h e i nci d e nc e of A E b y P T, t h e i n ci d e nc e of s eri o us A E b y P T a n d S O C, a n d t h e i nci d e nc e of s eri o us A E b y P T 
will als o b e pr es e nt e d.
A d v ers e e v e nts will b e s ort e d b y S O C i n al p h a b etic al or d er, t h e n wit hi n S O C, s ort P T i n d esc e n di n g 
fr e q u e nc y.
All A Es f or e ac h s u bj ect, i ncl u di n g t h e s a m e e v e nt o n s e v er al occ asi o ns will b e list e d, gi vi n g b ot h pr ef err e d 
t er m a n d t h e ori gi n al t er m us e d b y t h e i n v esti g at or.  S eri o us A Es will b e pr es e nt e d s e p ar at el y o n a n 
a d diti o n al listi n g.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 1 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
5. 8. 2.
C LI NI C AL L A B O R A T O R Y E V AL U A TI O N
L a b or at or y v al u es will b e o bt ai n e d f or h e m at ol o g y, cli nic al c h e mistr y, c o a g ul ati o n, vir ol o g y a n d uri n al ysis
at t h e ti m e p oi nts s p ecifi e d i n Sc h e d ul e 1 a n d Sc h e d ul e 3 of t h e pr ot oc ol . T h e l a b or at or y t ests will b e 
p erf or m e d b y a c e ntr al l a b or at or y. 
D escri pti v e st atistics will b e pr o vi d e d h e m at ol o g y, cli nic al c h e mistr y a n d c o a g ul ati o n d at a at ti m e p oi nts 
s p ecifi e d i n Sc h e d ul e 1 a n d Sc h e d ul e 3 of t h e pr ot oc ol . D escri pti v e st atistics f or c h a n g e fr o m b as eli n e t o 
p ost -b as eli n e , a n d s hifts wit h r es p ect t o n or m al r a n g es f or t h e s a m e p eri o d will als o b e pr es e nt e d. D at a 
listi n gs will b e pr o vi d e d f or all s u bj ects. L a b or at or y v al u es o utsi d e t h e n or m al r a n g e will b e fl a g g e d. 
B as eli n e is d e n ot e d as Visit 1.
N u m b er of s u bj ects wit h p ot e nti all y cli nic all y i m p ort a nt ( P CI) l a b v al u es will als o b e pr es e nt e d. P ot e nti all y 
cli nic all y i m p ort a nt l a b v al u es ar e d efi n e d as p er T a bl e 1
P P D
 b el o w. 






St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 4 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
As p er g ui d a nc e i n C o m pl eti o n G ui d el i n es, a n y b as eli n e a b n or m al p h ysic al e x a mi n ati o ns will b e r ec or d e d i n 
t h e M e dic al Hist or y F or m.  An y p ost D osi n g Visit 1 cli nic all y si g nific a nt p h ysic al e x a mi n ati o n fi n di n gs or 
w ors e ni n g of pr e vi o us c o n diti o ns w ill b e r ec or d e d in t h e A d v ers e E v e nt f or m.”
5. 8. 6.
M E DI C AL H I S T O R Y
M e dic al hist or y will b e c o d e d acc or di n g t o M e d D R A v ersi o n 1 9. 0 c e ntr al c o di n g dicti o n ar y . M e dic al hist or y 
will b e pr es e nt e d b y S O C a n d P T, a n d will b e s ort e d b y S O C i n al p h a b etic al or d er, t h e n wit hi n S O C, P T will 
b e s ort e d i n d esc e n di n g fr e q u e nc y.
5. 8. 7.
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N
Pri or m e dic ati o ns ar e a n y m e dic ati o ns r ec ei v e d f or t h e m a n a g e m e nt of H A E wit hi n 1 2 m o nt hs b ef or e D a y 1
a n d a ll ot h er m e dic atio ns t a k e n wit hi n 1 w e e k b ef or e D osi n g Visit 1. 
C o nc o mit a nt m e dic ati o ns ar e a n y m e dic ati o ns t a k e n fr o m t h e st art of D osi n g Visit 1 t hr o u g h t h e 1 -M o nt h 
P ost -tr e at m e nt F oll o w -u p Visit. 
Pri or a n d c o nc o mit a nt m e dic ati o ns will b e c o d e d acc or di n g t o W orl d H e alt h Or g a ni z ati o n ( W H O) dr u g 
dict i o n ar y v ersi o n 0 1J U N 2 0 1 6 . S u m m ar y of m e dic ati o ns will b e di vi d e d i nt o m e dic ati o ns gi v e n f or H A E 
l o n g-t er m pr e v e nti o n, H A E s h ort-t er m pr e v e nti o n, H A E ac ut e tr e at m e nt w hic h i ncl u d e d eit h er C 1 I n hi bit or 
or Tr a n e x a mic Aci d ,H A E s y m pt o m m a n a g e m e nt w hic h i n dic ati o n i ncl u d e d ac ut e tr e at m e nt a n d m e dic ati o n 
is n ot C 1 I n hi bit or or Tr a n e x a mic Aci d,a n d all ot h er m e dic ati o ns us e d .  T hiswill b e pr es e nt e d b y A T C L e v el 
1 a n d P T . P r ef err e d T er m is d efi n e d as b as e n a m e fr o m W H O dr u g dicti o n ar y. T a bl e will b e s ort e d b y 
i n dic ati o ns a n d A T C L e v el 1 i n al p h a b etic al or d er, t h e n wit hi n A T C L e v el 1 , P T will b e s ort e d i n d esc e n di n g 
fr e q u e nc y. D et ails of pri or a n d c o nc o mit a nt m e dic ati o ns us e d will b e pr o vi d e d i n o n e listi n g.
5. 8. 8.
T R E A T M E N T C O M PLI A N C E
T r e at m e nt c o m pli a nc e is d efi n e d by 2 4 c o m pl et e i nf usi o ns, a n d n o d os e i nt err u pti o n. D os e i nt err u pti o n 
m e a ns t h at t h e g a p b et w e e n a n y t w o c o ns ec uti v e d os es is at l e ast 6 d a ys.
T h e c o m pli a nc e f or s u bj ects w h o h a v e n o d os e i nt err u pti o n or s u bj ects w h os e tr e at m e nt d ur ati o n is l ess 
t h a n 1 2 w e e ks ( 8 4 d a ys ) is c alc ul at e d as:
 ( %) =
(
  
  
  
  
  
 
)
2 4
x 1 0 0
T h e c o m pli a nc e f or s u bj ects w h o h a v e d os e i nt err u pti o n a n d t h e tr e at m e nt d ur ati o n is gr e at er t h a n 1 2 
w e e ks ( 8 4 d a ys) is c alc ul at e d as:
 ( %) =
(
  
 act u al   
  
  
 
)
(
  
  
− 
  
  
+ 1)/ 3. 5
x 1 0 0
P P D
w h er e 3. 5 is t h e a v er a g e n u m b er of d a ys b et w e e n 2 i nf usi o ns i n o n e w e e k.   


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 5 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
5. 9.
I M M U N O G E NI CI T Y ( C 1-I N H A N TI B O D Y ) A N D P H A R M A C O KI N E TI C 
C O N C E N T R A TI O N S A N D P H A R M A C O D Y N A MI C S L E V EL S
P P D
T h e c o nc e ntr ati o ns of C 1 -I N H a nti g e n ( pr ot ei n v ol u m e), f u ncti o n al C 1-I N H acti vit y ( p ot e nc y), a n d 
c o m pl e m e nt C 4 a n d C 1 q f or i n di vi d u al s u bj ects will b e d et er mi n e d usi n g f ull y v ali d at e d bi o a n al ytic al 
m et h o ds , a n d will b e list e d a n d s u m m ari z e d usi n g d escri pti v e st atistics at e ac h ti m e p oi nt .C 1 q 
c o nc e ntr ati o ns will b e ass ess e d at b as eli n e o nl y (i e, pr e -i nf usi o n, D osi n g Visit 1).
T h e A nti b o d y r es ul ts will b e list e d a n d s u m m ari z e d usi n g d escri pti v e st atistics at e ac h n o mi n al ti m e p oi nt .


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 6 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
6. C H A N G E S I N T H E C O N D U C T O F T H E S T U D Y O R PL A N N E D A N AL Y S E S
6. 1.
C H A N G E S I N T H E C O N D U C T O F T H E S T U D Y
N o c h a n g es i n t h e c o n d uct of t h e st u d y.
6. 2.
C H A N G E S F R O M T H E A N AL Y S E S P L A N N E D I N T H E P R O T O C OL
P P D
D u e t o i ns uffici e nt d at a c oll ecti o n, t h e a n al ysis of cli nic al r eli ef h as n ot b e e n c o n d uct e d as pl a n n e d.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 7 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
7. S T A TI S TI C AL/ A N AL Y TI C I S S U E S
7. 1.
H A N DLI N G O F D R O P O U T S O R M I S SI N G D A T A
O nl y t h e f oll o wi n g missi n g d at a will b e i m p ut e d a n d a n al y z e d i n t a bl es s u m m ari es.  I m p ut e d d at a will n ot 
b e pr es e nt e d i n listi n g.  All ot h er m issi n g d at a will n ot b e i m p ut e d.
S e v erit y of A E
If s e v erit y of A E is missi n g, ‘ S e v er e’ A E will b e i m p ut e d f or a n al ysis .
C a us alit y of A E
If t h e r el ati o ns hi p of A E t o i n v esti g ati o n al pr o d uct is missi n g, ‘ R el at e d’ will b e i m p ut e d f or a n al ysis .
7. 2.
I N T E RI M A N AL Y S E S A N D D A T A M O NI T O RI N G
P P D
N o i nt eri m a n al ys es or d at a m o nit ori n g ar e pl a n n e d f or t his st u d y.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 8 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
8. R E F E R E N C E S
B er nst ei n J A. U p d at e o n a n gi o e d e m a: e v al u ati o n, di a g n osis, a n d tr e at m e nt. All er g y Ast h m a Pr oc. 2 0 1 1; 
3 2( 6): 4 0 8 -4 1 2.
C a b all er o T, S al a -C u nill A, C a nci a n M, et al. C urr e nt st at us of i m pl e m e nt ati o n of s elf -a d mi nistr ati o n tr ai ni n g 
i n v ari o us r e gi o ns of E ur o p e, C a n a d a a n d t h e U S A i n t h e m a n a g e m e nt of h er e dit ar y a n gi o e d e m a. I nt Arc h 
All er g y I m m u n ol. 2 0 1 3; 1 6 1( S u p pl 1): 1 0 -1 6.
Cic ar di M, Cr ai g TJ, M arti n e z -S a g u er I, et al. R e vi e w of r ec e nt g ui d eli n es a n d c o ns e ns us st at e m e nts o n 
h er e dit ar y a n gi o e d e m a t h er a p y wit h f o c us o n s elf-a d mi nistr ati o n. I nt Arc h All er g y I m m u n ol. 
P P D
2 0 1 3; 
1 6 1( S u p pl 1): 3 -9.


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 2 9 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
9. A P P E N DI C E S
9. 1.
A P P E N DI X I – LI S T O F S T A TI S TI C AL O U T P U T S
9. 1. 1.
L I S T O F P L A N N E D T A BL E S
P P D
T a bl e 1 4. 1. 1. 1 S u bj ect Dis p ositi o n ( All Scr e e n e d S u bj ects)
T a bl e 1 4. 1. 2. 1 Pr ot oc ol D e vi ati o ns (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 1. 4. 1 D e m o gr a p hic a n d B as eli n e C h ar act eristics (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 1. 4. 3. 1 S u m m ar y of H A E Hist or y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 1. 4. 3. 2 S u m m ar y of M e dic al Hist or y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 1. 4. 4 Pri or M e dic ati o ns a n d T h er a p y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 1. 4. 5 C o nc o mit a nt M e dic ati o ns a n d T h er a p y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 2. 1. 1 S u m m ar y of A n gi o e d e m a Att ac ks d uri n g Tr e a t m e nt P eri o d ( F ull A n al ysis S et)
T a bl e 1 4. 2. 1. 2. 1 S e nsiti vit y A n al ysis C o m pl et e d Sc h e d ul es - S u m m ar y of A n gi o e d e m a Att ac ks d uri n g 
Tr e at m e nt P eri o d ( F ull A n al ysis S et)
T a bl e 1 4. 2. 1. 2. 2 S e nsiti vit y A n al ysis Tr e at m e nt C o m pli a nc e - S u m m ar y of A n gi o e d e m a Att ac k s d uri n g 
Tr e at m e nt P eri o d ( F ull A n al ysis S et)
T a bl e 1 4. 2. 1. 3 A n al ysis of Cli nic al R es p o n d er R at e – Ac hi e vi n g at l e ast 5 0 %, 7 0 % or 9 0 % R e d ucti o n 
R el ati v e t o Hist oric al D at a i n N N A ( F ull A n al ysis S et)
T a bl e 1 4. 2. 2. 1. 1 S u m m ar y of Br e a kt hr o u g h A n gi o e d e m a Att ac ks Tr e at e d B y CI N R Y Z E ( F ull A n al ysis S et)
T a bl e 1 4. 2. 2. 1. 2 S u m m ar y of Br e a kt hr o u g h A n gi o e d e m a Att ac ks Tr e at e d B y N o n -CI N R Y Z E C 1 -I N H ( F ull 
A n al ysis S et)
T a bl e 1 4. 2. 2. 1. 3 S u m m ar y of Ot h er Br e a kt hr o u g h A n gi o e d e m a Att ac ks N ot Tr e at e d wit h C 1 -I N H ( F ull 
A n al ysis S et)
T a bl e 1 4. 2. 2. 1. 4 S u m m ar y a n d C h a n g e fr o m B as eli n e o n A E -Q o L ( F ull A n al ysis S et)
T a bl e 1 4. 2. 3. 1 C 1 -I N H A nti g e n, F u ncti o n al C 1-I N H acti vit y, C o m pl e m e nt C 4 a n d C 1 q (I nt e nt-t o-Tr e at S af et y 
A n al ysis S et)
T a bl e 1 4. 2. 3. 2 A nti b o d y R es ults (I nt e nt-t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 1. 1 O v er all Tr e at m e nt -e m er g e nt A d v ers e E v e nts ( T E A Es) (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 1. 2. 1 Tr e at m e nt -e m er g e nt A d v ers e E v e nts b y S yst e m Or g a n Cl ass a n d Pr ef err e d T er m (I nt e nt -
t o-Tr e at S af et y A n al ysis S et)


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 3 0 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T a bl e 1 4. 3. 1. 2. 2 S eri o us Tr e at m e nt -e m er g e nt A d v ers e E v e nts b y S yst e m Or g a n Cl ass a n d Pr ef err e d T er m 
(I nt e nt-t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 1. 3. 1 Tr e at m e nt -e m er g e nt A d v ers e E v e nts b y Pr ef err e d T er m (I nt e nt -t o-Tr e at S af et y A n al ysis 
S et)
T a bl e 1 4. 3. 1. 3. 2 S eri o us Tr e at m e nt -e m er g e nt A d v ers e E v e nts b y Pr ef err e d T er m (I nt e nt -t o-Tr e at S af et y 
A n al ysis S et 
T a bl e 1 4. 3. 2. 1 Tr e at m e nt -e m er g e nt A d v ers e E v e nts b y M a xi m u m S e v erit y, S yst e m Or g a n Cl ass a n d 
Pr ef err e d T er m  (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 2. 2 Tr e at m e nt -e m er g e nt A d v ers e E v e nts C o nsi d er e d R el at e d t o I n v esti g ati o n al Pr o d uct b y 
S yst e m Or g a n Cl ass a n d Pr ef err e d T er m (I nt e nt-t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 4. 1 Q u a ntit ati v e Cli nic al L a b or at or y R es ults: H e m at ol o g y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 4. 2 Q u a ntit ati v e Cli nic al L a b or at or y R es ults: Cli nic al C h e mistr y (I nt e nt -t o-Tr e at S af et y A n al ysis 
S et)
T a bl e 1 4. 3. 4. 3 Q u a ntit ati v e Cli nic al L a b or at or y R es ults: C o a g ul ati o n (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 4. 4 Q u a ntit ati v e Cli nic al L a b or at or y R es ults: Uri n al ysis (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 4. 5 S hift fr o m B as eli n e i n Cli nic al L a b or at or y R es ults: H e m at ol o g y (I nt e nt -t o-Tr e at S af et y 
A n al ysis S et)
T a bl e 1 4. 3. 4. 6 S hift fr o m B as eli n e i n Cli nic al L a b or at or y R es ults: Cli nic al C h e mistr y (I nt e nt-t o-Tr e at S af et y 
A n al ysis S et)
T a bl e 1 4. 3. 4. 7 S hift fr o m B as eli n e i n Cli nic al L a b or at or y R es ults: C o a g ul ati o n (I nt e nt -t o-Tr e at S af et y 
A n al ysis S et)
T a bl e 1 4. 3. 4. 8 S hift fr o m B as eli n e i n Cli nic al L a b or at or y R es ults: Uri n al ysis (I nt e nt -t o-Tr e at S af et y A n al ysis 
S et)
T a bl e 1 4. 3. 4. 9 S u bj ects wit h P ot e nti all y Cli nic all y I m p ort a nt ( P CI) L a b or at or y R es ults (I nt e nt -t o-Tr e at 
S af et y A n al ysis S et)
T a bl e 1 4. 3. 5. 1 Act u al V al u es a n d C h a n g e fr o m B as eli n e i n Vit al Si g ns (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 5. 2 P ot e nti all y Cli nic all y I m p ort a nt Vit al Si g ns R es ults (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
T a bl e 1 4. 3. 6 St u d y Dr u g E x p os ur e (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
9. 1. 2.
L I S T O F P L A N N E D F I G U R E S
Fi g ur e 1 4. 2. 2. 1. 1. 1 K a pl a n M ei er Pl ot - Ti m e fr o m Ci nr y z e t o I niti al I m pr o v e m e nt ( F ull A n al ysis S et) 
Fi g ur e 1 4. 2. 2. 1. 1. 2 K a pl a n M ei er Pl ot - Ti m e fr o m Ci nr y z e t o C o m pl et e R es ol uti o n ( F ull A n al ysis S et)
9. 1. 3.
L I S T O F P L A N N E D L I S TI N G S
P P D
Listi n g 1 6. 2. 1. 1 S u bj ect Dis p ositi o n ( All E nr oll e d S u bj ects)


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 3 1 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Listi n g 1 6. 2. 1. 2 S u bj ects W h o T er mi n at e d fr o m t h e St u d y ( All E nr oll e d S u bj ects)
Listi n g 1 6. 2. 2. 1 D e vi ati o ns fr o m I ncl usi o n / E xcl usi o n Crit eri a ( All E nr oll e d S u bj ects)
Listi n g 1 6. 2. 2. 2 Pr ot oc ol D e vi ati o ns ( All E nr oll e d S u bj ects)
Listi n g 1 6. 2. 4. 1 S u bj ect D e m o gr a p hic a n d B as eli n e C h ar act eristics (I nt e nt -t o-Tr e at S af et y A n al ysis S et )
Listi n g 1 6. 2. 4. 3. 1 H er e dit ar y A n gi o e d e m a ( H A E) Hist or y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 4. 3. 2 H er e dit ar y A n gi o e d e m a ( H A E) Hist or y D et a il (I nt e nt-t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 4. 3. 3 M e dic al Hist or y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 4. 4. 1 Pri or a n d C o nc o mit a nt M e dic ati o ns (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 4. 4. 2 C o nc o mit a nt M e dic al / S ur gic al Pr o c e d ur es (I nt e nt-t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 5. 2. 1 St u d y Dr u g A d mi nistr ati o n (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 5. 2. 2 St u d y Dr u g E x p os ur e (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 5. 3 C 1 -I N H A nti g e n, F u ncti o n al C 1-I N H acti vit y, C o m pl e m e nt C 4 a n d C 1 q (I nt e nt -t o-Tr e at 
S af et y A n al ysis S et)
Listi n g 1 6. 2. 5. 4 A nti b o d y R es ults (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 6. 1 S u bj ect D at a of A n gi o e d e m a Att ac k (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 6. 2 S u bj ect D at a of Br e a kt hr o u g h Att ac k (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 6. 3 I n v esti g at or Ass ess m e nt of Br e a kt hr o u g h Att ac k (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 6. 4 S elf- a d mi nistr ati o n S ur v e y (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 6. 5 Tr e at m e nt C o m pli a nc e (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 7. 1 A d v ers e E v e nts (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 7. 2 S eri o us A d v ers e E v e nts (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 8. 1. 2 Cli nic al L a b or at or y T est R es ults (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 8. 1. 3 S u bj ects wit h P ot e nti all y Cli nic all y I m p ort a nt L a b or at or y T est R es ults (I nt e nt -t o-Tr e at 
S af et y A n al ysis S et)
Listi n g 1 6. 2. 8. 2. 1 Vit al Si g ns (I nt e nt -t o-Tr e at S af et y A n al ysis S et)
Listi n g 1 6. 2. 8. 2. 2 S u bj ects wit h P ot e nti all y Cli nic all y I m p ort a nt Vit al Si g ns (I nt e nt -t o-Tr e at S af et y A n al ysis 
S et)
Listi n g 1 6. 2. 8. 3. 1 1 2 -l e a d E C G R es ults a n d I nt er pr et ati o n (I nt e nt-t o-Tr e at S af et y A n al ysis S et)
9. 2.
A P P E N DI X II- PR O G R A M MI N G C O N V E N TI O N S
D A T E S & T
P P D
I M E S


St ati sti c al A n al y si s Pl a n
P R O T O C O L : 0 6 2 4-2 0 9
P a g e 3 2 of 3 5
D o c u m e nt:
\\S W 2 0 R N D 0 1 \Vi st a T e m p Dir \T e m p 2 8 2 3 2 \S hir e _ 0 6 2 4 _ 2 0 9 _ S A P _ v 1 0. d o c x
A ut h or:
V er si o n N u m b er:
1. 0
V er si o n D at e:
2 1 J ul 2 0 1 7
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e vi si o n 4
R ef er e n c e:  C S _ W I _ B S 0 0 5
Eff e cti v e D at e: 0 1 A pr 2 0 1 6
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
D e p e n di n g o n d at a a v ail a bl e, d at es a n d ti m es will t a k e t h e f or m y y y y -m m -d d T h h: m m:ss.
S P ELLI N G F O R M A T
E n glis h U S .
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S
F or o ut p uts, tr e at m e nt gr o u ps will b e r e pr es e nt e d as f oll o ws a n d i n t h at or d er:
T r e at m e nt G r o u p
F o r T a bl e s , Li sti n g s a n d G r a p h s
Ci nr y z e 5 0 0 U
Ci nr y z e 5 0 0 U
Ci nr y z e 1 0 0 0 U
Ci nr y z e 1 0 0 0 U
P R E S E N T A TI O N O F V I SI T S
F or o ut p uts, visits will b e r e pr es e nt e d as f oll o ws a n d i n t h at or d er:
L o n g N a m e ( d ef a ult)
S h o rt N a m e 
Scr e e ni n g
Scr 
D osi n g Visit 1
V 1
D osi n g Visit 2
V 2
…
…
D osi n g Visit 2 4
V 2 4
L I S TI N G S
All listi n gs will b e or d er e d b y t h e f oll o wi n g : Ci nr y z e 5 0 0 U t h e n Ci nr y z e 1 0 0 0 U .
9. 3.
A P P E N DI X III - PA R TI AL D A T E C O N V E N TI O N S
P P D
I m p ut e d d at es will N O T b e pr es e nt e d i n t h e listi n gs.