A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age With Hereditary Angioedema
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

CI N R Y Z E/ P R O T O C O L 0 6 2 4 -3 0 1
( C o m p o u n d N u m ber V P 2 0 6 2 4)
A P H A S E 3, M U L TI C E N T E R, R A N D O MI Z E D, SI N G L E -B LI N D , D O S E-R A N GI N G, 
C R O S S O V E R S T U D Y T O E V A L U A T E T H E S A F E T Y A N D E F FI C A C Y O F 
I N T R A V E NO U S A D MI NI S T R A TI O N O F CI N R Y Z E ® ( C 1 E S T E R A S E I N HI BI T O R
[ H U 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 I N C HI L D R E N 
6 T O 1 1 Y E A R S O F A G E WI T H H E R E DI T A R Y A N GI O E D E M A
U S I N D 1 1 8 3 8
E u dr a C T N u m ber 2 0 1 3- 0 0 2 4 5 3 - 2 9
S hire V I R OP H A R M A IN C O R P O R A T E D
3 0 0 S hire Wa y
Le xi n gt o n , M A   0 2 4 2 1-2 1 0 1
U S A
M E DI C A L M O NI T O R
, M D, F R C P( C)
Office p h o ne:  
M o bile p h o ne: 
E mail:  
Ori gi n al D ate:   0 7 A u g ust 2 0 1 3
A m e n d me nt 1:  0 9 Oct o ber 2 0 1 3
A m e n d me nt 2:  1 1 Dece m ber 2 0 1 3
A m e n d me nt 3:  0 2 J u ne 2 0 1 4
A m e n d me nt 4:  2 6 Ja n uar y  2 0 1 5
C O N FI D E N TI A LI T Y S T A T E M E N T
T his d oc u me nt is t he c o nfi de ntial pr o pert y of S hire V I R OP H A R M A IN C O R P O R A T E D
(Vir o P har ma a n d its affiliates are w h oll y -o w ne d s u bsi diaries of S hire plc) .  N o part of it ma y  
be tra ns mitte d, re pr o d uce d, p u blis he d, or use d b y ot her pers o ns wit h o u t pri or writte n 
a ut h orizati o n fr o m S hire V I R OP H A R M A
P P D
.
P P D
P P D
P P D

C!NRYZE®(Cl esterase inhibitor [human]) 
Protocol 0624-301 with Amendments 1, 2, 3, and 4 
PROTOCOL REVIEW AND APPROVAL FORM 
SUBMISSION OF PROTOCOL 0624-301 WITH AMENDMENTS 1, 2, 3, AND 4 
PRODUCT NAME (CODE): CINRYZE (VP 20624) 
Title: A PHASE 3, MULTICENTER, RANDOMIZED, SINGLE-BLIND, DOSE-RANGING, 
CROSSOVER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
INTRA VENOUS ADMINISTRATION OF CINRYZE® [C1 ESTERASE INHIBITOR 
(HUMAN)] FOR THE PREVENTION OF ANGIOEDEMA ATTACKS IN CHILDREN 6 TO 
11 YEARS OF AGE WITH HEREDITARY ANGIOEDEMA 
DEPARTMENT 
Clinical Operations 
Regulatory Affairs 
Medical Monitor/ 
Clinical Research 
26 January 2015 
26 January 2015 
NAME 
, MS 
, MBA 
, MD, 
FRCP(C) 
2 
DATE 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
TABLE OF CONTENTS
Page
26 January 2015
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PROTOCOL REVIEW AND APPROVAL FORM .................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................6
AMENDMENT 4:  26 JANUARY 2015 ..................................................................................8
AMENDMENT 3:  02 JUNE 2014 .........................................................................................11
AMENDMENT 2:  11 DECEMBER 2013 .............................................................................13
AMENDMENT 1:  09 OCTOBER 2013 ................................................................................14
PROTOCOL SYNOPSIS ........................................................................................................16
SCHEDULE 1:
CLINICAL STUDY ASSESSMENTS –
SCREENING AND 
BASELINE OBSERVATION PERIOD .........................................................25
SCHEDULE 2:
CLINICAL STUDY ASSESSMENTS – TREATMENT PERIOD 1.....26
SCHEDULE 3:
CLINICAL STUDY ASSESSMENTS – TREATMENT PERIOD 2.....28
SCHEDULE 4:
CLINICAL 
STUDY 
ASSESSMENTS 
–
EARLY 
DISCONTINUATION, 1-WEEK POST-TREATMENT, AND 1-MONTH 
POST-TREATMENT FOLLOW-UP VISITS ................................................30
SCHEDULE 5:
BLOOD SAMPLE COLLECTION FOR PK/PD AND POST-
TREATMENT IMMUNOGENICITY ASSESSMENTS ...............................31
1.0
INTRODUCTION...........................................................................................32
1.1
CINRYZE® (C1 esterase inhibitor [human])...................................................33
1.1.1
Nonclinical Experience with Intravenous Administration ..............................34
1.1.2
Clinical Experience with Intravenous Administration ....................................34
1.1.3
Pediatric Experience with Intravenous Administration...................................36
1.2
Study Rationale................................................................................................42
2.0
STUDY OBJECTIVES ...................................................................................44
3.0
INVESTIGATIONAL PLAN..........................................................................44
4.0
STUDY POPULATION..................................................................................49
4.1
Inclusion Criteria .............................................................................................49
4.2
Exclusion Criteria............................................................................................50
5.0
STUDY DRUG ADMINISTRATION............................................................50

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
TABLE OF CONTENTS
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5.1
Dose Selection .................................................................................................50
5.2
Randomization.................................................................................................51
5.3
Study Drug.......................................................................................................51
5.4
Blinding ...........................................................................................................52
5.5
Stopping Rules.................................................................................................52
5.5.1
Anaphylactic Reaction.....................................................................................52
5.5.2
Thrombotic or Thromboembolic Event...........................................................53
6.0
STUDY PROCEDURES.................................................................................53
6.1
Medical History and Physical Examination ....................................................53
6.1.1
HAE History....................................................................................................54
6.2
Vital Signs .......................................................................................................55
6.3
Prior and Concomitant Medications................................................................55
6.3.1
Prior Medications.............................................................................................55
6.3.2
Concomitant Medications................................................................................56
6.3.3
Prohibited Medications....................................................................................56
6.4
Nonpharmacologic Treatments and Procedures..............................................56
6.5
Clinical Laboratory Parameters.......................................................................56
6.6
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses .........57
6.7
Total Blood Volume Collected........................................................................58
6.8
Restrictions ......................................................................................................59
6.9
Electronic Study Diary (eDiary)......................................................................59
6.10
Angioedema Attacks........................................................................................60
6.10.1
Recording of Angioedema Attacks..................................................................60
6.10.2
Management of Acute Angioedema Attacks...................................................61
6.10.3
Angioedema Attacks During Treatment Periods.............................................61
6.11
Quality of Life Measurements.........................................................................62
6.11.1
Health-related Quality of Life (EQ-5D-Y)......................................................62
6.12
Discontinuation From Treatment and/or Study...............................................62
6.12.1
Discontinuation From Treatment.....................................................................63
6.12.2
Discontinuation From Study............................................................................64
7.0
STATISTICAL METHODOLOGY................................................................64
7.1
Sample Size .....................................................................................................64
7.2
Populations ......................................................................................................64
7.3
Efficacy Analysis.............................................................................................65
7.4
Safety Analysis................................................................................................66

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
TABLE OF CONTENTS
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CONFIDENTIAL
7.5
Other Endpoints...............................................................................................66
7.6
Pharmacokinetic and Pharmacodynamic Analyses .........................................66
8.0
DRUG SUPPLIES...........................................................................................67
8.1
How Supplied ..................................................................................................67
8.1.1
Reconstitution of CINRYZE for Intravenous Infusion ...................................67
8.2
Drug Accountability ........................................................................................68
8.3
Drug Labels .....................................................................................................68
9.0
ADVERSE EVENTS ......................................................................................68
9.1
Severity (Intensity) Assessment ......................................................................69
9.2
Relationship to Study Drug .............................................................................69
9.3
Serious Adverse Events...................................................................................70
9.3.1
Reference Safety Information..........................................................................71
9.4
Other Reportable Events..................................................................................72
9.5
Recording Adverse Events ..............................................................................72
10.0
STUDY MONITORING .................................................................................73
11.0
DATA HANDLING........................................................................................73
12.0
ETHICAL CONDUCT OF THE STUDY.......................................................74
13.0
SUBJECT CONFIDENTIALITY ...................................................................74
14.0
INFORMED CONSENT.................................................................................74
15.0
INDEPENDENT REVIEWING AUTHORITY APPROVAL .......................75
16.0
PUBLICATION POLICY ...............................................................................76
17.0
INVESTIGATOR'S STATEMENT (PROTOCOL 0624-301).......................77
18.0
LIST OF REFERENCES.................................................................................79
APPENDIX I: PROCESSING OF SAMPLES FOR ANALYSES OF C1 INH ANTIGEN, 
C1 INH FUNCTION, C4 COMPLEMENT, AND C1 INH ANTIBODIES 
IN HUMAN PLASMA....................................................................................82
APPENDIX II:
RECOMMENDED PROCEDURES FOR SUSPECTED VENOUS 
THROMBOEMBOLISM 
OR 
OTHER 
THROMBOTIC 
OR 
THROMBOEMBOLIC EVENTS...................................................................84

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-versus-time curve
AUC0-
Area under the plasma concentration-versus-time curve from time 0 to infinity
AUC0-τ
Area under the plasma concentration-versus-time curve from time 0 to selected 
time point
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C
Centigrade
C1 INH
C1 esterase inhibitor or C1 inhibitor
Cavg
Average concentration at steady state
CBC
Complete blood count
CHO
Chinese hamster ovary
CL
Clearance
CL/F
Apparent plasma clearance
Cmax
Maximum concentration
Cmin
Minimum concentration
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRA
Clinical research associate
CRU
Clinical Research Unit
CT
Computer axial tomography
CTA
Clinical Trial Agreement
DC
Discontinuation
DNA
Deoxyribonucleic acid
DVT
Deep venous thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form
eDiary
Electronic study diary
EDTA
Ethylenediaminetetraacetic acid
ER
Emergency room
EU
European Union
F
Fahrenheit; Bioavailability 
FDA
Food and Drug Administration
h, hr
Hour(s)
HAE
Hereditary angioedema
HIV
Human immunodeficiency virus
HR
Heart rate
ICH
International Conference on Harmonisation
ID
Intradermal
IEC
Independent Ethics Committee
INR
International normalized ratio
IRA
Independent Reviewing Authority (e.g., Institutional Review Board or 
Independent Ethics Committee)

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
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CONFIDENTIAL
Abbreviation
Definition
ISR
Incurred sample reproducibility
ISS
Incurred sample stability
ITT-E
Intent-to-Treat Efficacy (population)
ITT-S
Intent-to-Treat Safety (population)
IUD
Intrauterine device
IV
Intravenous
IXRS
Interactive voice and web response system
Kel
Elimination rate constant
MedDRA
Medical Dictionary for Regulatory Activities
mM
Millimolar
mOsmol
Milliosmole
n, N
Sample size
NA
Not applicable
NDA
New Drug Application
PD
Pharmacodynamic(s)
PE
Pulmonary embolism
PEG
Polyethylene glycol
Ph. Eur.
European Pharmacopeia
PK
Pharmacokinetic(s)
PT
Prothrombin time
QoL
Quality of life
RBC
Red blood cells
Rmax
Maximum pharmacodynamic response
RSI 
Reference safety information
SAE
Serious adverse event
SC
Subcutaneous
SD
Standard deviation
SOP
Standard operating procedure
SPC, SmPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reaction
SWFI
Sterile water for injection
T/TE
Thrombotic/thromboembolic
t1/2
Terminal elimination half-life
TEAE
Treatment-emergent AE
tmax
Time to maximum concentration or maximum pharmacodynamic response
TX
Treatment
U
Unit(s)
US
United States
USP
United States Pharmacopeia
USPI
United States Package Insert
VAS
Visual analogue scale
V/Q
Ventilation/perfusion scan
VTE
Venous thromboembolism
Vz/F
Apparent volume of distribution
WBC
White blood cell
WHO
World Health Organization
NOTE: Table includes comprehensive list of abbreviations used in CINRYZE regulatory documents.

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
8
C O N FI D E N TI A L
A M E N D M E N T 4: 2 6 J A N U A R Y 2 0 1 5
A me n d me nt 4 t o Pr ot oc ol 0 6 2 4 -3 0 1 i nc or p orates re visi o ns relate d t o st u d y  dr u g rec o nstit uti o n 
a n d a d mi nistrati o n .  A n a d mi nistrati ve l o o k will occ ur f oll o wi n g t he c o m pleti o n of t he first 6 
s u bjects.  Safet y, efficac y an d p har mac o ki netics res ults will be re vie we d, s u m marize d a n d 
prese nte d i n a cli nical st u d y re p ort.  This st u d y re p ort will ser ve as t he basis f or a re g ulat ory 
s u b missi o n t o satisf y the E U Pe diatric I nvesti gati o n Pla n .  I n ad diti o n, te xt has bee n a d de d t o 
Secti o n 3. 0
P P D
(In vesti gati o nal Pla n) , t o all o w t he fle xi bilit y of a d di n g c o u ntries or re gi o ns if 
necessar y  to c o m plete e nr oll me nt.  T his a me n d me nt
als o i nc or p orates A d mi nistrati ve 
Re visi o n 1 ( date d 2 5 Se pte m ber 2 0 1 4) w hic h u p date d t he pr ot oc ol title pa ge wit h t he c o ntact 
i nf or mati o n of t he ne w me dical m o nit or (
, M D) f or t his st u d y.
1.
St u d y  Dr u g A d mi nistrati o n:
E ur o pea n I n vesti gat ors rec o m me n de d re visi n g t he pr ot oc ol la n g ua ge t o all o w m ore fle xibilit y
re gar di n g st u d y dr u g a d mi nistrati o n . A me n d me nt 3 s pecifies t hat CI N R Y Z E treat me nts will 
be pre pare d a n d a d mi nistere d b y  qual ifie d site pers o n nel or q ualifie d h o me healt hcare 
pr ofessi o nals. P h y sicia ns ha ve s hare d t heir e x perie nce i n t he pe diatric p o p ulati o n a n d ha ve
i n dicate d t hat pe diatric patie nts a ge d 6 - 1 1 wh o t he y see i n r o uti ne practice ofte n self-
a d mi nister (after trai ni ng) or ha ve a pare nt ad mi nister C 1 I nhi bit or ( C 1 I NH) treat me nt (after 
trai ni n g). T hese I n vesti gat ors ha ve i n dicate d t hat pe diatric patie nts w h o c urre ntl y self-
a d mi nister, or w h o are r o uti nel y a d mi nistere d treat me nt b y  a n o n- healt hcare pr ofessi o nal 
(e. g., pare nt), will n ot a gree t o e nter a st u d y re q uiri n g t hat st u d y site pers o n nel or h o me 
healt hcare pr ofessi o nals a d mi nister t he treat me nt f or t he st u d y.
T heref ore, A me n d me nt 4 i nc or p orates t he f oll o wi n g c ha n ges:
-
Clarifies t hat h o me healt hcare pr ofessi o nals ma y pre pare st u d y dr u g at t he s u bject’s 
h o me .
-
A ll o ws self-a d mi nistrati o n of st u d y dr u g f or s u bjects w h o self-a d mi nister C 1 I NH i n 
r o uti ne practice a n d w h o wa nt t o c o nti n ue t o d o s o i n t his st u d y. If a s u bject w h o d oes 
n ot r o uti nel y self-a d mi nister w o ul d li ke t o be gi n t his practice, t his will be per mitte d 
a n d a p pr o priate trai ni n g will be pr o vi de d b y  t he st u d y site pers o n nel.  
-
All o ws a d mi nistrati o n of st u d y dr u g b y  trai ne d n o n- healt hcare pr ofessi o nals (e. g.,
pare nt, le gal g uar dia n ) f or s u bjects i n w h o m t his o cc urs i n r o uti ne practice a n d w here 
t he prefere nce is t o c o nti n ue t o d o s o. If a n o n- healt hcare pr ofessi o nal (e. g., pare nt, 
le gal g uar dia n) w h o d oes n ot r o uti nel y ad mi nister C 1 I NH
w o ul d li ke t o be gi n t his 
practice, it will be per mitte d a n d a p pr o priate trai ni n g will be pr o vi de d b y t he site .  

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
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CONFIDENTIAL
Regardless of self-administration or administration by a non-healthcare professional, all 
study drug will be administered under the supervision of qualified healthcare personnel
(i.e., if study drug is self-administered, or administered by a non-healthcare professional, a 
qualified healthcare professional will always be present). Investigators will use their 
clinical judgment and knowledge of the home situation to determine whether self-
administration or administration by a non-healthcare professional is in the best interest of 
the pediatric subject.  
Added text is bolded and deleted text is struck through, as applicable.
All protocol sections affected by the amendment are noted below, and the synopsis and 
schedules of procedures have been updated accordingly.
3.0
INVESTIGATIONAL PLAN
This multicenter, randomized, single-blind, dose-ranging, crossover study will be conducted 
in multiple countries including the US, EU, and Latin America. Other countries/regions
may be added if necessary to complete enrollment.
Subjects and parents/caregivers will be blinded to treatment sequence and dose.  Study site 
personnel, qualified home healthcare professionals, and the Sponsor will not be blinded to 
treatment assignment and the dose of study drug administered. Study drug will be prepared 
and administered intravenously by qualified personnel at the investigational site, or by 
qualified home healthcare professionals at the subject’s home or other agreed upon location.  
Alternatively, if allowed per local regulations, subjects who have been trained to self-
administer C1 INH or who have a non-healthcare provider (e.g., parent) who has been 
trained to administer C1 INH will be permitted to do so based upon the request of the 
subject (and with approval of the parent(s)/legal guardian and the Investigator.  Note: 
self-administration will always occur under the supervision of a qualified healthcare 
professional at the study site or the subject’s home (or other agreed upon location).
Supervision by a qualified healthcare professional will include real time direct visual 
observation of the following: selection of the injection site, preparation of the injection 
site, insertion of the infusion device into the vein, study drug infusion, removal of 
infusion device, compression and applying a bandage to the injection site, and disposal 
of all infusion materials.

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
10
CONFIDENTIAL
For those subjects who are administered study drug at a location other than the study site
by home healthcare professionals, study personnel will contact the parent/caregiver by 
telephone twice during each treatment period (Week 3 after Dose 6 [Visits 6a and 6b] and 
Week 9 after Dose 18 [Visits 18a and 18b]).
5.3
Study Drug
See Section 8.0 for a complete description of study drug.  Instructions for the reconstitution of 
CINRYZE are provided in a separate Pharmacy Manual.  CINRYZE treatments will be 
prepared and administered by qualified study site personnel or qualified home healthcare 
professionals. Home healthcare professionals may prepare and administer CINRYZE 
treatments at the subject’s home. Alternatively, if allowed per local regulations, subjects 
who have been trained to self-administer C1 INH or who have a non-healthcare 
provider (e.g., parent) who has been trained to administer C1 INH will be permitted to 
do so based upon the request of the subject (and with approval of the parent(s)/legal 
guardian and the Investigator).  Note: self-administration will always occur under the 
supervision of a qualified healthcare professional at the study site or the subject’s home 
(or other agreed upon location). Supervision by a qualified healthcare professional will 
include real time direct visual observation of the following: selection of the injection site, 
preparation of the injection site, insertion of the infusion device into the vein, study drug 
infusion, removal of infusion device, compression and applying a bandage to the 
injection site, and disposal of all infusion materials.
7.0
STATISTICAL METHODOLOGY
An administrative look will occur following completion of the first 6 subjects.  Safety,
efficacy and pharmacokinetic results will be reviewed, summarized and presented in a 
clinical study report.  This study report will serve as the basis for a regulatory 
submission to satisfy the EU Pediatric Investigation Plan.  A final CSR will be completed 
after 12 subjects finish the study.

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
11
CONFIDENTIAL
AMENDMENT 3:  02 JUNE 2014
Amendment 3 to Protocol 0624-301 incorporates 2 revisions:  
1. European Investigators recommended that a modification be made to the angioedema 
attack criteria qualifying subjects for study inclusion.  Physicians may opt to provide 
early intervention with acute treatment when the attack is considered mild to minimize 
the risk of subsequent complications with ongoing severity.  Therefore to allow 
angioedema attacks that require acute treatment to qualify, inclusion criteria #3 and #6 
have been modified. 
2. Investigators requested clarification of the analytical tests performed on blood samples 
collected from subjects when they present to the investigator site with an angioedema 
attack.
Added text is bolded and deleted text is struck through, as applicable.
All protocol sections affected by the amendment are noted below, and the synopsis and 
schedules of procedures have been updated accordingly.
Section 4.1, Inclusion Criteria
Inclusion Criteria 
3. Have a history of ≥1.0 angioedema attacks per month (average) that are
moderate1 or severe2 or require acute treatment3 angioedema attacks per 
month (average) during the 3 consecutive months prior to screening.
Additional Inclusion Criteria (Qualifying for Randomization)
6. Have experienced ≥1.0 angioedema attacks per month (average) that are
moderate1 or severe2 or require acute treatment3 angioedema attacks per 
month (average) during the 12-week baseline observation period.
                                                
1
Moderate:  Angioedema attack sign/symptom(s) interferes with the subject’s ability to attend school or 
participate in family life and social/recreational activities.
2
Severe:  Angioedema attack sign/symptom(s) significantly limits the subject’s ability to attend school or 
participate in family life and social/recreational activities.
3
‘Treatment’ refers specifically to standard of care therapies used to treat an angioedema attack (e.g., 
C1 INH, kallikrein inhibitor, bradykinin receptor antagonist).  Products used for the treatment of attack 
symptoms (e.g., analgesics, anti-emetics) do not qualify for this study inclusion criterion.

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
12
CONFIDENTIAL
Section 6.6, Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
NOTE:  If a subject presents to the site with an angioedema attack, every effort should be 
made to obtain a PK blood sample prior to any treatment.  In addition, if the subject is treated 
with commercial C1 INH, every effort should be made to obtain a 1-hour post-treatment 
sample.  These samples will be analyzed for C1 INH antigen and functional C1 INH 
activity.
Other administrative revisions (e.g., updating Sponsor’s contact information) and editorial 
revisions have been made throughout the protocol for consistency.

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
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CONFIDENTIAL
AMENDMENT 2:  11 DECEMBER 2013
Amendment 2 to Protocol 0624-301 encompasses three revisions.  Added text is bolded and 
deleted text is struck through, as applicable.

Exclusion Criterion #7 (Synopsis and Section 4.2), has been revised since some of the 
temperature conversions were incorrect:
7. Have any active infectious illness or fever defined as an oral temperature 
>38C (100.4F) tympanic >38.5C (101. 23F), axillary >38.1C (100.6F) 
or rectal/core >398.5C (101.23F) within 24 hours prior to the first dose of 
study drug in Treatment Period 1. 

In Section 8.1, the storage conditions for CINRYZE have been corrected to be 
consistent with the US product label:
The US sourced vials of CINRYZE and SWFI will be stored at 20oC–25oC (68oF–
77oF) 2oC–25oC (36oF–77oF) in the original carton and protected from light.  Do 
not freeze.

Appendix I (Reconstitution of CINRYZE) and all references throughout the protocol 
to this Appendix have been removed.  Subsequent appendices were renumbered.  
Instructions for the reconstitution of CINRYZE will be detailed in a separate 
Pharmacy Manual.  

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
26 January 2015
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AMENDMENT 1:  09 OCTOBER 2013
Amendment 1 to Protocol 0624-301 encompasses nine substantive revisions:

In Schedule 3 (Clinical Study Assessments – Treatment Period 2), footnote “h” has 
been added to clarify that if an angioedema attack is ongoing at Visit 24b, then 
recording of signs and symptoms and completing the EQ-5D-Y should continue daily 
in the eDiary until the attack resolves.

In Schedule 5
(Blood Sample Collection for PK/PD and Post-treatment 
Immunogenicity Assessments), two blood sampling time points have been corrected; 
the Post-dose time point was incorrectly noted as Dose 1 rather than Dose 12.
Treatment Period 1 – Visit 12a / Dose 12
Post-dose time point should be 1 h post Dose 12 (± 15 min)
Treatment Period 2 – Visit 12b / Dose 12
Post-dose time point should be 1 h post Dose 12 (± 15 min)

In the Synopsis, Section 6.9 (Electronic Study Diary), and Section 6.11.1 (Health-
related Quality of Life), text has been revised to state that the EQ-5D-Y (QoL 
assessment) is to be completed by subjects and not by parents or caregivers, as was 
stated in the original protocol.  The EQ-5D-Y is designed to be a self-reported 
questionnaire for children and adolescents.

In the Synopsis and Section 6.10 (Angioedema Attacks), the definition of an 
angioedema attack has been revised to clarify that there must be a “full symptom-free 
calendar day” preceding the onset of symptoms for an attack to be considered a new 
attack.  The original protocol stated that there was to be a “24-hr symptom-free 
interval”, however only the date (not time) of symptom onset and resolution for an 
angioedema attack is to be recorded.

In Sections 3.0 (Investigational Plan), 6.9 (Electronic Study Diary), and 6.11.1
(Health-related Quality of Life), information about integration of eDiary/QoL data into 
the eCRF has been deleted; details about handling of these data will be provided in a 
separate Data Management Plan.

In Section 6.3.2 (Concomitant Medication), the requirement for study personnel to 
record the start and stop “time” of medications administered in the management of 
angioedema attacks has been deleted.

In Section 6.9 (Electronic Study Diary), the details on all questions contained 
within the eDiary have been deleted.  Instead there is a general high level 
description of the information to be collected and the responsibility of the 
parent/caregiver and subject to complete this information in the eDiary. At the 

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screening visit, study personnel will instruct subjects and parents/caregivers how 
to complete the eDiary.

In Section 6.10.1 (Recording of Angioedema Attacks), “Other (describe)” has been 
deleted as option for the location (site) of the swelling or pain associated with an 
angioedema attack. 

In Section 6.12 (Discontinuation From Treatment and/or Study), the sentence referring
to the possibility of enrolling additional subjects to replace subjects who withdraw or 
discontinue has been removed.  This referred to a scenario when the plan was to enroll 
a sufficient number of subjects (8) to ensure that 6 would complete the study.  Per 
request from the FDA, the protocol now states that the target enrollment is 12 subjects 
and the Sponsor believes that it would be neither necessary nor realistic to address the 
issue of replacing subjects who drop out of the study.
Other editorial revisions have been made to the schedules of clinical assessments to clarify 
study procedures and also throughout the protocol for consistency with the nine revisions 
noted above.  In addition, CINRYZE recently received marketing authorization in Israel 
(August 2013); this information has been added to Sections 1.1 and 1.2.

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PROTOCOL SYNOPSIS
Study Title:  A phase 3, multicenter, randomized, single-blind, dose-ranging, crossover study 
to evaluate the safety and efficacy of intravenous administration of CINRYZE® (C1 esterase 
inhibitor [human]) for the prevention of angioedema attacks in children 6 to 11 years of age 
with hereditary angioedema (Protocol 0624-301). 
Study Objectives:  
Primary Objective

To assess the relative efficacy of two dose levels of CINRYZE (500 U and 
1000 U) administered by intravenous (IV) injection every 3 or 4 days to prevent 
angioedema attacks in children 6 to 11 years of age.
Secondary Objectives

To assess the safety and tolerability of two dose levels of CINRYZE administered 
by IV injection in children 6 to 11 years of age with hereditary angioedema 
(HAE).

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of 
CINRYZE administered by IV injection in children 6 to 11 years of age.

To assess the immunogenicity of CINRYZE following IV administration.
Other Objective

To assess the impact of treatment on health status (quality of life) in children 6 to 
11 years of age with HAE.
Study Population:  
Number of Subjects
Twelve subjects will be randomized in this study.  
Inclusion Criteria
To be eligible for this protocol, a subject must:
1. Be a child (male or female), ≥6 to <12 years of age at the time of screening.
2. Have a confirmed diagnosis of Type I or Type II HAE and have a functional 
C1 inhibitor (C1 INH) level less than 50% of normal.

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3. Have a history of ≥1.0 angioedema attacks per month (average) that are moderate1
or severe2 or require acute treatment3 during the 3 consecutive months prior to 
screening.
4. Agree to adhere to the protocol-defined schedule of assessments and procedures.
5. Have a parent(s)/legal guardian who is informed of the nature of the study provide 
written informed consent for the child to participate in the study before any study-
specific procedures are performed (with assent from the child when appropriate).  
Additional Inclusion Criteria (Qualifying for Randomization)
6. Have experienced ≥1.0 angioedema attacks per month (average) that are moderate1
or severe2 or require acute treatment3 during the 12-week baseline observation 
period.
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 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. Be pregnant or breastfeeding. 
5. Have received an investigational drug other than those required for prevention or 
treatment of angioedema attacks within 30 days prior to screening.
6. Have, as determined by the Investigator and the Sponsor’s medical monitor, any 
surgical or medical condition that could interfere with the administration of study 
drug or interpretation of study results.
Additional Exclusion Criteria (Disqualifying from Randomization)
7. Have any active infectious illness or fever defined as an oral temperature >38C
(100.4F), tympanic >38.5C (101.3F), axillary >38C (100.4F), or rectal/core 
>38.5C (101.3F) within 24 hours prior to the first dose of study drug in 
Treatment Period 1. 
                                                
1
Moderate:  Angioedema attack sign/symptom(s) interferes with the subject’s ability to attend school or 
participate in family life and social/recreational activities.
2
Severe:  Angioedema attack sign/symptom(s) significantly limits the subject’s ability to attend school or 
participate in family life and social/recreational activities.
3
‘Treatment’ refers specifically to standard of care therapies used to treat an angioedema attack (e.g., 
C1 INH, kallikrein inhibitor, bradykinin receptor antagonist).  Products used for the treatment of attack 
symptoms (e.g., analgesics, anti-emetics) do not qualify for this study inclusion criterion.

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8. Have had signs or symptoms of an angioedema attack within 2 days prior to the 
first dose of study drug in Treatment Period 1.
Duration of Study:  Individual participation from screening through the completion of 
1-month safety follow-up visit will be approximately 10 months (1-day screening visit, 
12-week baseline observation period, two 12-week treatment periods [consecutive without 
any washout between treatment periods], and 1-month post-treatment safety follow-up visit).  
Drug Product: CINRYZE is supplied as a lyophilized powder of 500 Units (U) C1 INH per 
vial.  Each vial of CINRYZE will be reconstituted for IV infusion with 5 mL of sterile water.  
Each infusion will require reconstitution of one (1) or two (2) 500 U vials depending on the 
treatment scheduled (Treatment A [500 U] or Treatment B [1000 U]).  The solution must be 
used within 3 hours of reconstitution.
Study Drug Administration:  CINRYZE (500 U or 1000 U) will be administered by IV 
injection twice weekly (every 3 or 4 days) for 12 weeks in two crossover treatment periods.  
Study drug will be administered intravenously by qualified healthcare personnel at the 
investigational site or at a location outside of the investigative site (e.g., home). Alternatively,
if allowed per local regulations, subjects who have been trained to self-administer C1 INH or 
who have a non-healthcare provider (e.g., parent) who has been trained to administer C1 INH 
will be permitted to do so based upon the request of the subject (and with approval of the 
parent(s)/legal guardian and the Investigator).  Note: self-administration will always occur 
under the supervision of a qualified healthcare professional at the study site or the subject’s 
home (or other agreed upon location). Supervision by a qualified healthcare professional will 
include real time direct visual observation of the following: selection of the injection site, 
preparation of the injection site, insertion of the infusion device into the vein, study drug 
infusion, removal of infusion device, compression and applying a bandage to the injection 
site, and disposal of all infusion materials.
Treatment Sequences:  Participants in this crossover study are expected to receive both 
treatments (A = 500 U and B = 1000 U), assigned in random order, in sequential treatment 
periods.  Each treatment period will be 12 weeks, without a washout between the two periods.  
Eligible subjects will be randomized to one of two treatment sequences, A/B or B/A.
Study Design:
This multicenter, randomized, single-blind, dose-ranging, crossover study 
will be conducted in multiple countries including the United States, Europe and Latin
America.  Other countries/regions may be added if necessary to complete enrollment.

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Potential subjects (≥6 to <12 years of age) will have a screening evaluation the day prior to 
entering the study’s baseline observation period.  Subjects with qualifying angioedema attack 
rates, and who meet all other eligibility criteria, will be enrolled and enter the observation 
period for at least 12 weeks.  
Throughout the study, an electronic study diary (eDiary) will be used to collect specific 
information regarding the subject’s symptoms of HAE.  The eDiary will consist of two 
sections:  
(a) Section to record daily if any elective procedures have been performed, signs and 
symptoms of angioedema attacks, triggers for angioedema attacks, medications used for the 
management of angioedema attacks, and interruptions in activities of daily living due to an 
angioedema attack.  Section (a) is to be completed by the parent/caregiver, and when possible, 
the same parent/caregiver should be responsible for completing this section of the eDiary 
throughout the study.
(b) Section to record the impact of HAE on quality of life (EQ-5D-Y).  Section (b) is to be 
completed by the subject at specified time points throughout the study and on each day the 
subject experiences signs or symptoms of an angioedema attack.  
Study personnel will contact the parent/caregiver by telephone bi-weekly (Weeks 2, 4, 6, 8, 
10, and 12) during the baseline observation period to discuss study compliance (completion of
the eDiary daily) and to evaluate the subject’s angioedema attack frequency (Schedule 1).
During the baseline observation period, subjects are allowed to remain on any prophylactic 
HAE therapy they were receiving prior to study enrollment, if clinically indicated.  However, 
it is recommended that consideration by the Investigator be given to discontinuing subjects 
from any prophylactic antifibrinolytic or androgen therapy during the first 6 weeks of the 
observation period.  If these medications cannot be discontinued, stable doses should be used 
during Treatment Periods 1 and 2.  At least 3 days prior to first dose of study drug, subjects 
receiving commercial C1 INH for prevention of attacks must discontinue this therapy.  

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In the event that during the 12 weeks of baseline observation subjects do not meet the attack 
criteria qualifying for randomization (≥1.0 angioedema attacks per month [average] that are 
moderate or severe or require acute treatment), despite having met this same criteria 
historically for study enrollment, additional weeks of observation will be considered at the 
discretion of the Investigator and Sponsor to allow qualification for randomization and entry 
into the treatment periods of the study.  In this case, subjects will maintain the same schedule 
of assessments by beginning at Week 1 again for the additional weeks of observation 
(Schedule 1).
After the completion of the baseline observation period, subjects who remain eligible per 
study criteria will be randomized to one of two treatment sequences, with each sequence 
consisting of two treatment periods.  In Treatment Period 1, subjects will receive CINRYZE 
at a dose of either 500 U or 1000 U IV twice weekly (every 3 or 4 days), depending upon their 
randomized assignment.  After completion of the first treatment period, subjects will 
immediately crossover to the alternate CINRYZE dose and begin Treatment Period 2.
This is a single-blind study.  Subjects and parents/caregivers will be blinded to the treatment 
administered.  Study site personnel, home healthcare professionals, and the Sponsor will not 
be blinded to dose and treatment sequence.  Study drug will be administered intravenously by 
qualified personnel at the investigational site, or by qualified home healthcare professionals at 
the subject’s home or other agreed upon location.  Alternatively if allowed per local 
regulations, subjects who have been trained to self-administer C1 INH or who have a non-
healthcare provider (e.g. parent) who has been trained to administer C1 INH will be permitted 
to do so based upon the request of the subject (and with approval of the parent(s)/legal 
guardian and the Investigator).  Note: self-administration will always occur under the 
supervision of a qualified healthcare professional at the study site or the subject’s home (or 
other agreed upon location). Supervision by a qualified healthcare professional will include 
real time direct visual observation of the following: selection of the injection site, preparation 
of the injection site, insertion of the infusion device into the vein, study drug infusion, 
removal of infusion device, compression and applying a bandage to the injection site, and 
disposal of all infusion materials.
The Investigator or designee will monitor and document study compliance, tolerability of 
each CINRYZE dose, and adverse events.  The following doses of study drug in each 
treatment period must be administered at the investigational site:  Dose 1 (Visits 1a and 1b, 
where a=treatment period 1 and b=treatment period 2), Dose 12 (Visits 12a and 12b) and 
Dose 24 (Visits 24a and 24b).  At these visits, subjects will also have other scheduled 
procedures performed (Schedules 2 and 3).  For those subjects who are administered study 
drug at a location other than the study site, study personnel will contact the parent/caregiver
by telephone twice during each treatment period (Week 3 after Dose 6 [Visits 6a and 6b] and 
Week 9 after Dose 18 [Visits 18a and 18b]).  If study drug is administered at the site (Doses 6 
and 18), no telephone contact is necessary.

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To the extent possible, subjects will postpone elective procedures (e.g., dental work) while 
participating in the study.  In the event a procedure cannot be postponed, parents/caregivers 
will notify the Investigator and the information will be recorded in the subject’s eCRF.
A post-treatment visit will be performed at the investigative site 1 week (±2 days) after the 
last dose of study drug for follow-up safety assessments.  In addition, subjects will have a 
blood sample for C1 INH antibody testing collected 30 (±2) days after the last dose of study 
drug.  If a subject discontinues prematurely from treatment and/or the study, the Investigator 
will perform the early discontinuation visit safety procedures as soon as possible
(Schedule 4).  For those subjects who discontinue prematurely from treatment, every effort 
should be made to complete protocol evaluations for the 1-month post-treatment follow-up 
visit. 
The schedules of study procedures are provided immediately following the synopsis:

Schedule 1:  Clinical study assessments – Screening and Baseline Observation 
Period (Weeks 1 to 12).

Schedule 2:  Clinical study assessments –Treatment Period 1 (Visits 1a to 24a).

Schedule 3:  Clinical study assessments – Treatment Period 2 (Visits 1b to 24b).

Schedule 4: Clinical study assessments – Early Discontinuation, 1-week Post-
treatment, and 1-month Post-treatment Follow-up Visits.

Schedule 5:  Blood sample collection – PK/PD and post-treatment 
immunogenicity assessments.
Definition of an Angioedema Attack
An angioedema attack will be defined as any subject-reported (or parent/caregiver-reported) 
indication of swelling or pain at any location following a report of no swelling or pain on the 
previous day (i.e., 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 one site to another will be considered a single attack, 

Attacks that begin to regress and then worsen before complete resolution will be 
considered one attack, and

Attacks that begin, appear to resolve, and then reappear without a symptom-free 
calendar day reported after the appearance of resolution will also be considered 
one attack.
NOTE:  An angioedema attack does NOT include swelling due to trauma or symmetrical 
non-painful swelling of the lower extremities.
Management of Angioedema Attacks
If a subject experiences an angioedema attack that in the opinion of the healthcare provider 
requires medical intervention, the choice of acute treatment will be left to the Investigator’s 

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discretion.  Where appropriate, CINRYZE can be provided for acute treatment of angioedema 
attacks.  
If a subject has an angioedema attack at any time during any study treatment period, 
study drug administration and study procedures will continue for that subject adhering 
to the study schedule, regardless of whether C1 INH therapy or other products were 
administered to treat the attack.  
NOTE:  If a subject presents to the site with an angioedema attack, every effort should be 
made to obtain a PK blood sample prior to any treatment.  In addition, if the subject is treated 
with commercial C1 INH, every effort should be made to obtain a 1-hour post-treatment 
sample.  These samples will be analyzed for C1 INH antigen and functional C1 INH activity.
To the extent possible during the study, subjects should avoid any stimuli (e.g., foods, 
activities, environments) known to trigger their angioedema attacks.  Otherwise, subjects may 
maintain their normal diets, medications, and activities of daily living.
Safety Monitoring
Safety will be monitored through the recording of adverse events (AEs) and any changes in
medical history, physical examinations, vital signs, and clinical safety laboratory testing 
(hematology, chemistry, and coagulation).  Testing of blood samples for clinical laboratory 
parameters will be performed at a Central Laboratory.
Investigators will report all serious adverse events (SAEs) occurring up to 30 days after the 
last dose of study drug to Shire VIROPHARMA and their respective IRA according to local 
reporting requirements.  In addition, SAEs with an onset more than 30 days after the last dose 
of study drug should be reported if considered by the Investigator to be related to study drug.  
Stopping Rules
If an anaphylactic reaction or a thrombotic or thromboembolic event occurs in any subject, 
pre-specified stopping rules for individual subjects and for the study as a whole are detailed in 
Section 5.5 of the protocol.
Monitoring for C1 INH Antibodies
Blood samples will be obtained from subjects prior to the first dose of study drug in each 
treatment period, 1 week post-treatment (or if prematurely discontinued), and at the 1-month 
post-treatment follow-up visit to monitor for C1 INH antibodies (see Schedules 2, 3, 4, and 5).
Pharmacokinetics and Pharmacodynamics
Blood samples for PK (functional and antigenic C1 INH) and PD (complement C4) 
assessments will be collected at pre-specified time points in both treatment periods (see 
Schedule 5).

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Quality of Life Measurements
EQ-5D-Y1 (Youth version of EQ-5D) is a descriptive system of youth health-related quality 
of life states consisting of five dimensions each of which can have one of three responses.  
The responses record the level of severity within a particular EQ-5D dimension.  EQ-5D-Y is 
not intended for use in children 6 years of age; however in this study all subjects (6 to 11 
years of age and where translated language version is available) will be assessed.  The 
EQ-5D-Y will be completed by the subject at the time points specified in Schedules 1, 2, 3, 
and 4, as well as on each day that a subject experiences signs or symptoms of an angioedema
attack.
Statistical Considerations:  
Sample Size:  Twelve subjects will be randomized in this study.  Subjects will be randomized 
to one of two treatment sequences so that upon completion of the study, each subject will 
have received both dose levels of CINRYZE (500 U and 1000 U). Based on the EU Pediatric 
Investigation Plan, an administrative look for regulatory purpose may be completed after 6 
patients have finished the study.  A final CSR will be completed after 12 subjects finish the 
study.  
Primary efficacy endpoint:  The primary efficacy endpoint is the number of angioedema 
attacks normalized to a 12-week treatment period.  This endpoint will be measured for each 
subject in each treatment period.  
Secondary efficacy endpoints:
The following will be measured for each subject in each treatment period:

Cumulative Attack Severity.  This score is the sum of the maximum symptom 
severity recorded for each angioedema attack in a treatment period.  

Cumulative Daily Severity.  This score is the sum of the severity scores recorded 
for every day of reported symptoms in a treatment period.  

Time (measured in days from the first dose of study drug in a treatment period) to 
the first angioedema attack reported in that treatment period.

Change from pre- to post-dose in C1 INH functional activity, C1 INH antigen, and 
C4 levels.

Number of angioedema attacks requiring acute treatment during each treatment 
period.
Analysis of efficacy endpoints will employ descriptive statistics and will include all subjects 
randomized and treated with study drug.
If warranted by the data, the comparison of CINRYZE doses will employ a paired t-test to 
perform a two-sided test of superiority (1000 U vs. 500 U) conducted at α=0.10.  
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.

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Safety Endpoints:
The following will be assessed during the study:

Safety and tolerability, including:

adverse events by dose group

adverse events by exposure (dose normalized to body weight [U/kg])

adverse events by time of onset (e.g., during administration of study drug 
or within 24 hours after the end of injection of study drug) 

Summary statistics and changes from baseline to post-baseline for safety 
laboratory testing and vital signs by dose group.

Results of C1 INH antibody testing will be reported for individual subjects and 
summarized as appropriate. 
PK/PD Endpoints:

Concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 
for individual subjects will be determined using validated analytical methods.  Results 
will be summarized using descriptive statistics for values at each time point and for 
change from baseline at each post-injection time.
Other Endpoints:

Results of the EQ-5D-Y health status questionnaire will be presented in 
accordance with the EQ-5D-3L User Guide (version 4.01), and adapted as 
appropriate for the youth version.
                                                
1
EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L questionnaire.  Version 4.0, April 
2011.  Published by the EuroQol Group Executive Office on behalf of the EuroQol Group.

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SCHEDULE 1:
CLINICAL STUDY ASSESSMENTS – SCREENING AND BASELINE OBSERVATION 
PERIOD
Procedures
Screening a
BASELINE OBSERVATION PERIOD (BY STUDY WEEK) b
1
2
3
4 
5 
6 
7
8
9
10
11
12
Informed consent (written 
permission and assent)
X
Medical/HAE history
X
Prior/current medications c
X
X---------------------------------------------------------------------------------------------------------------------------------------------X
Telephone contact d
X
X
X
X
X
X
Daily angioedema attack 
monitoring/eDiary e
X---------------------------------------------------------------------------------------------------------------------------------------------X
EQ-5D-Y/eDiary f
X
X
X
eDiary=electronic study diary; EQ-5D-Y (Youth version of EQ-5D)=health-related quality of life descriptive system for youth
a:
All subjects will have a screening evaluation the day prior to entering Week 1 of the baseline observation period.  
b:
Additional weeks of observations will be considered at the discretion of the Investigator and Sponsor to allow a subject to qualify for randomization and entry into the 
treatment periods of the study.  In this case, subjects will maintain the same schedule of assessments by beginning at Week 1 again for the additional weeks of observation
(i.e., Week 13 = schedule of assessments for Week 1, Week 14 = schedule of assessments for Week 2, etc).
c:
Parents/caregivers should record in the eDiary any medications taken by the subject for the management of angioedema attacks during the baseline observation period.
d:
Study personnel will contact the parent/caregiver by telephone on Weeks 2, 4, 6, 8, 10, and 12 to discuss study compliance (completion of the eDiary daily) and to evaluate
the subject’s angioedema attack frequency.  Telephone contacts will be documented in the source notes at the clinical site.
e:
During the baseline observation period, parents/caregivers will use an eDiary to record the subject’s symptoms or occurrences of angioedema attacks.
f:
In addition, subjects should complete the EQ-5D-Y on each day that they experience signs or symptoms of an angioedema attack.

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SCHEDULE 2:
CLINICAL STUDY ASSESSMENTS – TREATMENT PERIOD 1
Procedures
TREATMENT PERIOD 1 (BY STUDY WEEK) a
1
2
3
4
5
6
7
8
9
10
11
12
DOSING VISITS (1a to 24a)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
Confirm eligibility
X b
Randomization
X c
Medical history update /Physical 
exam d
X b
X
X
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
Height and Body Weight
X b
Vital signs (BP, HR) e
X f
X
X
X
X
X
X
X
X
X
X
X
Clinical safety lab testing. 
(hematology, chemistry, 
coagulation)
X b
X
Virology screening g
X b
Pregnancy testing h
X b
Study drug administration
X i
X
X
X
X
X
X
X
X
X
X
X i
X
X
X
X
X
X
X
X
X
X
X
X i
Telephone contact j
X
X
EQ-5D-Y/eDiary k
X b
X
X
Daily angioedema attack 
monitoring/eDiary
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Adverse events
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
PK/PD assessments
Details on timing of blood sample collection for PK/PD assessments is provided in Schedule 5.
Immunogenicity testing (C1 INH 
antibody)
X.b

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eDiary=electronic study diary; EQ-5D-Y (Youth version of EQ-5D)=health-related quality of life descriptive system for youth
a:
Study drug administration and scheduled procedures will occur twice weekly (every 3 or 4 days) during the 12-week treatment period (Treatment Period 1, Visits 1a-24a).
b:
Specified study procedures and blood samples should be performed/collected prior to study drug administration, on the same day.  
c:
Randomization will occur on Dosing Day 1 (Visit 1a) prior to the first dose of study drug in Treatment Period 1.
d:
Medical history will be updated prior to randomization at Visit 1a.  Physical examinations will be targeted based on reporting of adverse events and performed in accordance with standards at the site.
e:
Vital signs will be measured using standard methods at each study site.  On dosing days, vital signs should be obtained prior (within 60 minutes) to the injection of study drug and between 10 to 30 
minutes after completion of the injection of study drug.  Additional vital signs measurements may be performed if clinically indicated.
f:
Body temperature should be measured prior to randomization at Visit 1a.
g:
HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
h:
Pregnancy testing (urine) will be performed on females who have reached menarche. 
i:
Study drug will be administered by/under supervision of qualified personnel to all subjects at the investigational site for Dosing Visits 1a, 12a, and 24a.
j:
For those subjects who are administered study drug at a location other than the study site, study personnel will contact the parent/caregiver by telephone on Weeks 3 and 9 (after Dosing Visits 6a and 
18a, respectively) to discuss and document study compliance, tolerability of CINRYZE dose, and adverse events.  All telephone contacts will be documented in the source notes at the clinical site.
k:
In addition, subjects should complete the EQ-5D-Y on each day that they experience signs or symptoms of an angioedema attack.
See Schedule 4 for details regarding clinical assessments at early discontinuation (if applicable), 1-week post-treatment, and 1-month post-treatment follow-up visits.  
In the event a subject prematurely discontinues from treatment and/or the study, Early Discontinuation Visit procedures will be performed as soon as possible.
NOTE:  Investigators will report all SAEs to Shire VIROPHARMA Drug Safety through 30 days after the last dose of study drug and SAEs considered related to study drug >30 days after the last dose of study 
drug.

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SCHEDULE 3:
CLINICAL STUDY ASSESSMENTS – TREATMENT PERIOD 2
Procedures
TREATMENT PERIOD 2 (BY STUDY WEEK) a
1
2
3
4
5
6
7
8
9
10
11
12
DOSING VISITS (1b to 24b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
Physical exam b
  X d
X
X
Body Weight
  X d
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
Vital signs (BP, HR) c
X
X
X
X
X
X
X
X
X
X
X
X
Clinical safety lab testing. 
(hematology, chemistry, 
coagulation)
  X d
X
X
Study drug administration
  X e
X
X
X
X
X
X
X
X
X
X
X e
X
X
X
X
X
X
X
X
X
X
X
X e
Telephone contact f
X
X
EQ-5D-Y/eDiary g, h
  X d
X
X
Daily angioedema attack 
monitoring/eDiary h
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Adverse events
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
PK/PD assessments
Details on timing of blood sample collection for PK/PD assessments is provided in Schedule 5.
Immunogenicity testing 
(C1 INH antibody)
  X d

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eDiary=electronic study diary; EQ-5D-Y (Youth version of EQ-5D)=health-related quality of life descriptive system for youth
a:
Study drug administration and scheduled procedures will occur twice weekly (every 3 or 4 days) during the 12-week treatment period (Treatment Period 2, Visits 1b-24b).  
b:
Physical examinations will be targeted based on reporting of adverse events and performed in accordance with standards at the site.
c:
Vital signs will be measured using standard methods at each study site.  On dosing days, vital signs should be obtained prior (within 60 minutes) to the injection of study drug and 
between 10 to 30 minutes after completion of the injection of study drug.  Additional vital signs measurements may be performed if clinically indicated.
d:
Specified study procedures and blood samples should be performed/collected prior to study drug administration, on the same day.  
e:
Study drug will be administered by/under supervision of qualified personnel to all subjects at the investigational site for Dosing Visits 1b, 12b, and 24b.
f:
For those subjects who are administered study drug at a location other than the study site, study personnel will contact the parent/caregiver by telephone on Weeks 3 and 9 (after Dosing 
Visits 6b and 18b, respectively) to discuss and document study compliance, tolerability of CINRYZE dose, and adverse events.  All telephone contacts will be documented in the source 
notes at the clinical site.
g:
In addition, subjects should complete the EQ-5D-Y on each day that they experience signs or symptoms of an angioedema attack.
h:
If an angioedema attack is ongoing at Visit 24b, then recording of signs and symptoms and completing the EQ-5D-Y should continue daily until the attack resolves. 
See Schedule 4 for details regarding clinical assessments at early discontinuation (if applicable), 1-week post-treatment, and 1-month post-treatment follow-up visits.  
In the event a subject prematurely discontinues from treatment and/or the study, Early Discontinuation Visit procedures will be performed as soon as possible.
NOTE:  Investigators will report all SAEs to Shire VIROPHARMA Drug Safety through 30 days after the last dose of study drug and SAEs considered related to study drug >30 days after the 
last dose of study drug.

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SCHEDULE 4:
CLINICAL STUDY ASSESSMENTS – EARLY 
DISCONTINUATION, 1-WEEK POST-TREATMENT, 
AND 1-MONTH POST-TREATMENT FOLLOW-UP 
VISITS
Procedures
Early 
Discontinuation 
Visit a
1-Week 
Post-treatment 
Visit b
1-Month 
Post-treatment
Follow-up Visit c
Concomitant medications
X
X
Brief physical examination d
X
X
Vital signs (BP, HR) e
X
X
Clinical safety lab testing (hematology, 
chemistry, coagulation)
X
X
Pregnancy testing f
X
X
EQ-5D-Y
X
X
Adverse events
X
X
Immunogenicity testing (C1 INH antibody)
X
X
X
Virology testing g
X
X
EQ-5D-Y (Youth version of EQ-5D)=health-related quality of life descriptive system for youth
a:
Early discontinuation visit will be performed as soon as possible in the event a subject prematurely discontinues 
from treatment and/or the study.  For those subjects who discontinue prematurely from treatment, every effort 
should be made to complete protocol evaluations for the 1-month post-treatment follow-up visit. 
b:
1-Week post-treatment visit will be performed at the investigational site 1 week (±2 days) after the last dose of 
study drug.
c:
1-Month post-treatment follow-up visit will be performed 30 (±2) days after the last dose of study drug.  
d:
Physical examinations will be targeted based on reporting of adverse events and performed in accordance with 
standards at the site.
e:
Vital signs will be measured using standard methods at each investigational site.  
f:
Pregnancy testing (urine) will be performed on females who have reached menarche. 
g:
HIV (single assay antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody).
NOTE:  Investigators will report all SAEs to Shire VIROPHARMA Drug Safety through 30 days after the last dose of 
study drug and SAEs considered related to study drug >30 days after the last dose of study drug.

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SCHEDULE 5:
BLOOD SAMPLE COLLECTION FOR PK/PD AND 
POST-TREATMENT IMMUNOGENICITY 
ASSESSMENTS
TREATMENT PERIOD 1
Visit / Dose #
Blood Sampling Time Points
C1 INH Antigen, C1 INH Function, Complement C4
1a / Dose 1
Pre Dose 1
1 h post Dose 1 (± 15 min)
12a / Dose 12
Pre Dose 12
1 h post Dose 12 (± 15 min)
24a / Dose 24
Pre Dose 24 
1 h post Dose 24 (± 15 min)
2 h post Dose 24 (± 15 min) – optional sampling time point
4 h post Dose 24 (± 15 min) – optional sampling time point
8 h post Dose 24 (± 15 min) – optional sampling time point
TREATMENT PERIOD 2
Visit / Dose #
Blood Sampling Time Points
C1 INH Antigen, C1 INH Function, Complement C4
1b / Dose 1  
Pre Dose 1 
1 h post Dose 1 (± 15 min)
12b/ Dose 12
Pre Dose 12 
1 h post Dose 12 (± 15 min)
24b / Dose 24
Pre Dose 24 
1 h post Dose 24 (± 15 min)
2 h post Dose 24 (± 15 min) – optional sampling time point
4 h post Dose 24 (± 15 min) – optional sampling time point
8 h post Dose 24 (± 15 min) – optional sampling time point
NOTE:  If a subject presents to the investigational site with an angioedema attack, every effort should be made 
to obtain a PK blood sample prior to any treatment.  In addition, if the subject is treated with commercial
C1 INH, every effort should be made to obtain a 1-hour post-treatment sample.  These samples will be analyzed 
for C1 INH antigen and functional C1 INH activity.
POST-TREATMENT
Visit 
Blood Sampling Time Points
Immunogenicity (C1 INH antibody)
1-week post-treatment
1 week (± 2 days) after the last dose of study drug
1-month post-treatment
30 (± 2) days after the last dose of study drug

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1.0
INTRODUCTION
Hereditary angioedema (HAE) is an autosomal dominant disease resulting from mutations of 
the C1 inhibitor (C1 INH) gene and deficient plasma C1 INH protein.  Nearly all affected 
individuals experience symptoms of the disease; however, the symptoms vary in both their 
frequency and severity (Gompels et al., 2005; Zuraw, 2003).  The diagnosis of a C1 INH 
deficiency is suggested by a history that includes recurrent attacks of angioedema, 
characterized by non-itching swelling of the skin or mucosa.  Serum C4, C1 INH antigen, and 
functional C1 INH levels can be measured to assist with the diagnosis of HAE.  A low level 
of C4 in combination with a low level of either C1 INH antigen (Type I HAE) or functional 
C1 INH (Type II HAE) are confirmatory for the diagnosis of HAE (Frank et al., 1976).  In 
rare instances, C4 levels may be normal in HAE patients between attacks, but are almost 
always decreased during episodes of HAE swelling (Frank et al., 1976).  In this circumstance, 
a low serum C4 level during an episode of idiopathic swelling can be used to confirm the 
diagnosis of HAE (Frank et al., 1976; Waytes et al., 1996). 
Attacks of HAE are usually self-limiting, but can be quite painful, disfiguring, disabling, and 
sometimes fatal.  Edema can involve the skin and visceral organs, but most frequently 
manifests in the extremities or bowel; the swelling generally lasts 2 to 5 days (Nzeako et al., 
2001; Zuraw, 2008).  Abdominal attacks have been reported to occur in >93% of patients and 
account for nearly 50% of all angioedema attacks (Zuraw, 2008).  Not infrequently, an 
abdominal HAE attack can imitate a surgical emergency.  Life-threatening laryngeal edema 
may also occur and this accounts for the majority of the 30% to 40% mortality rate reported 
for this disease (Agostoni and Cicardi, 1992; Bork et al., 2000).
Intravenous administration of C1 INH, the plasma protein that is deficient in patients with 
HAE, has been used in Europe for more than 30 years for the treatment of acute attacks of 
HAE (Wall and Frank, 1990; Gadek et al., 1980).  C1 INH concentrates are prepared from 
pooled human plasma.  The efficacy of purified C1 INH concentrates in the treatment of acute 
angioedema in HAE has previously been described (Agostoni et al., 1980; Bergamaschini et 
al., 1983; Logan and Greaves, 1984; Späth et al., 1984).  

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The median age at the onset of initial symptoms is reported to between 8 and 12 years;
however HAE can occur in the first year of life (Farkas et al., 2007; Farkas et al., 2002).  A 
large-scale study conducted by Bork et al. (2006) showed that the yearly number of attacks is 
approximately double in patients when the disease appeared before age 5 compared with those 
in whom HAE appeared after the age of 15.  Early diagnosis and early treatment are important 
as they allow efficient prevention and appropriate treatment of life-threatening complications. 
The HAE development program for IV CINRYZE included data in the pediatric population 
that is among the largest for any C1 INH therapy based on published literature.  However, 
further investigation is warranted to evaluate safety, tolerability, and treatment effect in 
children 6 to 11 years of age who require long-term C1 INH replacement therapy due to the 
morbidity imposed by frequent angioedema attacks.  
1.1
CINRYZE® (C1 esterase inhibitor [human])
CINRYZE® (C1 esterase inhibitor [human]) consists of a protein fraction prepared from 
human plasma.  The manufacturing process includes 3 virus inactivation/removal steps: 
polyethylene glycol precipitation, pasteurization, and nanofiltration.  CINRYZE is a normal 
human plasma protein that is not subject to Cytochrome P450 metabolism, excretion, or 
pharmacokinetic (PK) drug-drug interactions exhibited by low molecular weight compounds.  
CINRYZE was approved by the United States (US) Food and Drug Administration (FDA) for 
routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE in 
October 2008.  CINRYZE was approved throughout the European Union (EU), via the 
Centralized Procedure, in June 2011 for treatment and pre-procedure prevention of 
angioedema attacks in adults and adolescents with HAE, and 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 who are 
inadequately managed with repeated acute treatment.  CINRYZE has also received marketing 
authorization in Australia (2012), Canada (2012), India (2013), Switzerland (2013), and Israel 
(2013).

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1.1.1
Nonclinical Experience with Intravenous Administration
Acute and repeated-dose toxicity studies were performed in rats with IV administration of 
CINRYZE at dose levels of 20, 100, and 400 units (U)/kg/day.  The highest dose evaluated in 
animals without observable adverse effects (400 U/kg) represents a safety margin of 
approximately 10 to 28 times the recommended human dose for adults and pediatrics (1000 U 
in adults, adolescents, and children 6 years of age and above).  In the repeated-dose study, the 
signs of toxicity were limited to minor increases in inflammatory changes in the lungs and 
germinal center hypertrophy in the spleens of animals dosed at 400 U/kg/day for 14 days, as 
compared to control animals.  The amount of germinal center hypertrophy in the spleens of 
rats treated at 400 U/kg/day was within the normal background histopathological range in 
both incidence and severity, but did correlate with a small increase in splenic weights, which 
may have been a reflection of the inflammatory increase in the lungs.  Since CINRYZE is 
derived from human plasma, an immunological effect in rats is to be expected. 
Results of an ex vivo thrombogenicity study utilizing healthy human volunteer 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 physiologic concentration).  These 
findings were 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.  
No effects of C1 INH on embryo-fetal development were observed at dose levels up to 
400 U/kg.  No animal studies have been completed to evaluate the effects of CINRYZE on 
carcinogenesis, mutagenesis, or impairment of fertility.
1.1.2
Clinical Experience with Intravenous Administration
The HAE development program for IV CINRYZE in the US included 2 multicenter studies of 
CINRYZE for prevention of angioedema attacks (1 double-blind, placebo-controlled study; 1 
open-label study) and 2 multicenter studies of CINRYZE for treatment of angioedema attacks 
(1 double-blind, placebo-controlled study; 1 open-label study).  In the double-blind prevention 
study (LEVP 2005-1/B), CINRYZE was shown to reduce the incidence of HAE attacks in 22 
subjects analyzed (mean normalized 12-week HAE attack rate:  6.3 for CINRYZE vs. 12.7 for 

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placebo1; p<0.0001).  In the double-blind treatment study (LEVP 2005-1/A), subjects 
receiving CINRYZE achieved beginning of unequivocal relief of the defining HAE 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]).
More than 14,500 IV infusions of CINRYZE were administered to 262 unique subjects in 8
completed clinical studies in the HAE development program of IV CINRYZE.  The vast 
majority of infusions were CINRYZE doses of 1000 U.  In the clinical studies, local reactions 
(e.g., pain, bruising, or rash at the injection/catheter site, venous burning or phlebitis) 
occurred in association with approximately 0.2% of infusions.  No subjects were discontinued 
from CINRYZE due to an adverse event (AE) in any CINRYZE study completed to date
evaluating the IV formulation.  No serious adverse events (SAEs) were considered by the 
Investigator to be possibly, probably, or definitely related to treatment with CINRYZE.
Thrombotic and thromboembolic (T/TE) events have been reported following administration 
of IV CINRYZE 1000 U every 3 or 4 days as well as with higher than the recommended dose.  
Five subjects in the completed studies of the HAE development program for IV CINRYZE 
experienced SAEs that were thrombotic or thromboembolic in nature. The majority (4/5, 
80%) of these events occurred in subjects with thrombogenic risk factors and none of these 
events were considered by the Investigator to be related to CINRYZE.  
In a post-approval open-label study (0624-400) there were no systemic thrombotic events in 
subjects (n=20) who received IV CINRYZE up to 2500 U every 3 or 4 days for up to 
12 months.  One subject developed a blood clot in an intravenous central catheter, which was 
treated locally without systemic complication.  Nevertheless, patients with known risk factors 
for thrombotic events (including indwelling catheters) should be monitored closely.  
Evaluation of the clinical PK and pharmacodynamics (PD) following IV administration of 
CINRYZE in subjects with HAE was primarily based on the results of Protocol 
LEVP 2006-5.  After IV administration of CINRYZE 1000 U, functional C1 INH
                                                
1
Mean observed 12-week HAE attack rate:  6.1 for CINRYZE vs. 12.7 for placebo per CINRYZE US 
Package Insert (2012).

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concentrations 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 was approximately 60 hours using noncompartmental methods.  Mean clearance (CL) 
values for functional C1 INH were 0.85 and 1.17 mL/min for the single and double doses, 
respectively.  Mean Cmax values for C1 INH antigen 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 antigenic C1 INH was approximately 45 
to 47 hours and mean CL was 0.70 mL/min.
1.1.3
Pediatric Experience with Intravenous Administration
In the 2 multicenter studies of CINRYZE for prevention of angioedema attacks and 2 
multicenter studies of CINRYZE for treatment of angioedema attacks, 46 unique pediatric 
subjects (aged 2-17 years) received a total of 2,237 infusions of IV CINRYZE (see Table 1; 
Lumry et al., 2013).  There were 19 unique subjects 6-11 years old who received a total of 
1,056 infusions of CINRYZE.  The vast majority of infusions used CINRYZE doses of 
1000 U.  While the pediatric subsets in various studies had few subjects, analyses of efficacy 
by age showed that the clinical benefit of CINRYZE (as either HAE treatment or prevention) 
was generally comparable between children and adults.  

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Table 1.
Number of Pediatric Subjects Exposed to CINRYZE and Total 
Infusions by Age Group, Indication, and Study – ITT-S Population
Indication
Study a
2-5 years
Number of Subjects
(number of infusions)
6-11 years
Number of Subjects
(number of infusions)
12-17 years
Number of Subjects
(number of infusions)
Treatment
LEVP 2005-1/A
0
6 (19)
6 (11)
LEVP 2006-1
1 (2)
10 (116)
13 (75)
Prevention
LEVP 2005-1/B
0
1 (93)
3 (126)
LEVP 2006-4
2 (47)
9 (828)
12 (920)
Total b
3 (49)
26 (1,056)
34 (1,132)
a: Subjects may have been exposed to CINRYZE in one or more studies.
b: A subject may be counted more than once in the total if the subject participated in more than one study; 
therefore, this number represents the total number of subject exposures within each age subset.
CINRYZE had a favorable safety profile, with no clinically meaningful adverse trends 
observed among pediatric subjects.  An overall summary from the 4 studies of treatment-
emergent AEs in pediatric subjects that were considered by the Investigator to be related to 
study drug is provided in Table 2.  
Table 2.
Incidence of Treatment-Emergent Adverse Events Related to 
Study Drug Among Pediatric Subjects Exposed to CINRYZE by 
Age Group, Indication, and Study – ITT-S Population
Indication
Study a
2-5 years
6-11 years
12-17 years
n/N (%)
Treatment
LEVP 2005-1/A
---
0/6 (0%)
0/6 (0%)
LEVP 2006-1
0/1 (0%)
0/10 (0%)
0/13 (0%)
Prevention
LEVP 2005-1/B
---
1/1 (100%)
0/3 (0%)
LEVP 2006-4
0/2 (0%)
2/9 (22%)
2/12 (17%)
Total, n/N b
0/3 (0%)
3/26 (12%)
2/34 (6%)
n/N=number of subjects with ≥1 treatment-related AE/number of subjects in a given age group by study
a:  Subjects may have been exposed to CINRYZE in one or more studies.
b:  n/N=number of subjects with ≥1 treatment-related AE across studies (a given subject may be counted 
more than once in the total if the subject participated and had a treatment-related AE in more than one 
study)/total number of subject exposures within each age subset.

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
3 8
C O N FI D E N TI A L
T here were 5 pe diatric s u bjects wit h A Es c o nsi dere d t o be relate d t o st u d y  dr u g a n d t he e ve nts 
are descri be d bel o w :

St u d y  L E V P 2 0 0 5-1/ B: 
O ne c hil d
years of a ge), e x perie nce d m o derate p y re xia 
deter mi ne d b y  the I n vesti gat or t o be p ossi bl y relate d t o st u d y dr u g; t he e ve nt res ol ve d 
after a d urati o n of 1 da y.

St u d y  LE V P 2 0 0 6- 4:  F o ur c hil dre n re p orte d ≥1 treat me nt -relate d A E, as detaile d bel o w:

6 - 1 1 years of a ge:  2/ 9 ( 2 2 %) s u bjects re p orte d 4 relate d treat me nt-e mer ge nt A Es 
( dizzi ness, hea dac he, m o ut h ulcerati o n, a n d na usea)

1 2- 1 7 ye ars of a ge:  2/ 1 2 ( 1 7 %) s u bjects re p orte d 3 relate d treat me nt-e mer ge nt 
A Es (i nf usi o n site er y t he ma, metr orr ha gia, a n d p h ot ose nsiti vit y reacti o n)
Of n ote, se veral of t hese e ve nts are i ncl u de d a m o n g t he rel ate d treat me nt-e mer ge nt A Es o nl y 
beca use t he I n vesti gat or c o nsi dere d t he m t o be of “ u n k n o w n” relati o ns hi p t o CI N R Y Z E 
( dizzi ness, m o ut h ulcerati o n, metr orr ha gia, a n d p h ot ose nsiti vit y  reacti o n).  The o nl y e ve nts 
c o nsi dere d b y  the I n vesti gat or t o be p ossi bl y , pr o ba bl y , or defi nitel y relate d t o CI N R Y Z E 
were hea dac he, na usea, a n d i nf usi o n site er yt he ma, all of w hic h were mil d i n se verit y an d 
res ol ve d after a d urati o n of 1 t o 2 d a y s.  T here were 
n o s yste mic t hr o m b otic or 
t hr o m b oe m b olic e ve nts re p orte d i n pe diatric s u bjects.
Preve nti o n St u dies
St u dy L E V P 2 0 0 5 -1/ B
P P D
I n t he pi v otal st u d y of CI N R Y Z E 
f or t he pr e ve nti o n of H A E 
attac ks ( Pr ot oc ol 
L E V P 2 0 0 5 -1/ B), 4 pe diatric s u bjects were e nr olle d (ra n ge:
ye ars; me dia n: 1 5 ye ars), 
eac h of w h o m ha d pre vi o usl y  partici pate d i n St u d y  LE V P 2 0 0 5 -1/ A.  S u bjects were 
ra n d o mize d i n a 1: 1 rati o t o o ne of t w o pre ve nti o n t hera py se q ue nces:  12 wee ks of 
CI N R Y Z E 1 0 0 0 U e ver y 3 - 4 da y s f oll o we d b y  12 wee ks of place b o, or 1 2 wee ks of place b o 
f oll o we d b y  12 wee ks of CI N R Y Z E 1 0 0 0 U e ver y 3- 4 d a y s.  All 4 s u bjects c o m plete d b ot h 
peri o ds of t hera p y wit h CI N R Y Z E or place b o.  Si nce s u bjects i n t his st u d y were all o we d t o 
recei ve o pe n -la bel CI N R Y Z E f or t he treat me nt of ac ute attac ks, it is m ore a p pr o priate f or t he 
place b o ar m of t his st u d y t o be c o nsi dere d a n “ o n -de ma n d” c o m parat or.  
P P D

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
3 9
C O N FI D E N TI A L
A s u m mar y of the efficac y res ults fr o m t his st u d y is pr o vi de d i n Ta ble 3 .  CIN R Y Z E t hera p y 
was as efficaci o us i n t he pe diatric p o p ulati o n c o m pare d wit h t he o verall p o p ulati o n, wit h a n 
a p pr o xi mate 2 -f ol d re d ucti o n i n t he n u m ber of H A E attac ks c o m pare d t o place b o/ o n -de ma n d 
t hera py ( mea n n u m ber of attac ks per peri o d:  7. 0 vs. 1 3. 0).  
T a bl e 3 . S u m m ar y  of Effi c a c y R e s ult s f or P e di atri c S u bj e ct s ( N = 4) –
St u d y L E V P 2 0 0 5 -1/ B                                        
Me a n O bser ve d N o. of 
Att ac ks D uri n g 
T her a p y
Me a n Se verit y 
a
of Att ac ks D uri n g 
T her a p y
Me a n D ur ati o n
of Att ac ks D uri n g 
T her a p y ( D a ys)
Me a n N o. of O L 
CI N R Y Z E I nf usi o ns 
D uri n g T her a p y
Me a n T ot al D a ys
of S w elli n g D uri n g 
T her a p y
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
7 . 0
1 3. 0
1. 6
1. 6
2. 3
2. 6
6 . 8
1 5. 0
9. 0
2 0. 8
O L = o pe n -la bel
a: 1 = mil d; 2 = m o derate; 3 =se vere
Treat me nt - e mer ge nt A Es re p orte d i n c hil dre n i n t his st u d y are s u m marize d bel o w:

6- 1 1 ye ars of a ge:  1 su bject re p orte d 1 3 A Es (e xc oriati o n, hea dac he, H A E, i nfl ue nza, 
j oi nt i nj ur y, li m b i nj ur y, l ym p ha de n o pat h y , nasal c o n gesti o n, nas o p har y n gitis, p o or 
ve n o us access, p y re xia, varicella, a n d v o miti n g).  Onl y  1 eve nt ( pyr e xia) was c o nsi dere d 
b y  the I n vesti gat or t o be relate d t o st u d y dr u g; t his e ve nt res ol ve d after a d urati o n of 
1 da y .

1 2 - 1 7 ye ars of a ge:  3 su bjects re p orte d 9 A Es (c o u g h, viral gastr oe nteritis, hea dac he, 
nas o p har y n gitis, p har y n g olar y n geal pai n, ras h, u p per res pirat or y tract i nfecti o n, uri nar y 
tract i nfecti o n, a n d v o miti n g).  No ne of t hese e ve nts were c o nsi dere d relate d t o st u d y 
dr u g.
St u dy L E V P 2 0 0 6 -4
I n t he o pe n -la bel st u d y of CI N R Y Z E 
f or t he pre ve nti o n of H A E 
attac ks ( Pr ot oc ol 
L E V P 2 0 0 6 -4), 2 3 pe diatric s u bjects were e nr olle d (a ge ra n ge: 3 t o 1 7 ye ars).  All 2 3 s u bjects 
recei ve d at least 1 d ose of CI N R Y Z E f or pre ve nti o n t hera p y. 
A s u m mar y of t he efficac y 
res ults b y  pe diatric a ge gr o u p is pr o vi de d i n Ta ble 4 .
P P D
  Wit h t he e x ce pti o n of 2 s u bjects
a n d 
), all pr o p h ylactic d oses of CI N R Y Z E were a d mi nistere d t o pe diatric 
s u bjects per pr ot oc ol ( 1 0 0 0 U e ver y 3-7 da y s).  
P ri or t o e nr oll me nt, t he 2 3 c hil dre n i n t his st u d y re p orte d a me dia n m o nt hl y  HA E attac k rate 
of 3. 0 (ra n ge: 0. 5- 2 8. 0).  Duri n g t he st u d y while recei vi n g CI N R Y Z E pre ve nti o n t hera p y, 
pe diatric s u bjects e x perie nced a me dia n m o nt hl y  attac k rate of 0. 3 9 (ra n ge: 0 -3. 3 6), t he 
P P D
P P D

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
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CONFIDENTIAL
majority (87%, 20/23) experienced ≤1 HAE attack per month, and 22% (5/23) of children 
reported no attacks.  Thus, CINRYZE provided substantial clinical benefit in reducing the 
frequency of angioedema attacks in children and was comparable to that observed in adults. 
Table 4.
Summary of Efficacy Results for Pediatric Subjects (N=23) –
Frequency of Angioedema Attacks Age Group in Study 
LEVP 2006-4
CINRYZE
Age group
2-5 years
6-11 years
12-17 years
N by age group
2
9
12
Monthly attack rate per subject a
Mean (SD)
Median
Range
0.69 (0.977)
0.69
0-1.38
0.35 (0.453)
0.16
0-1.33
0.71 (0.897)
0.47
0-3.36
Distribution of monthly attack rate per subject, N (%) a
0 attacks
> 0 to ≤ 1 attack
> 1 to ≤ 2 attacks
> 2 to ≤ 3 attacks
> 3 to ≤ 4 attacks
> 4 attacks
1 (50.0%)
0
1 (50.0%)
0
0
0
3 (33.3%)
5 (55.6%)
1 (11.1%)
0
0
0
1 (8.3%)
10 (83.3%)
0
0
1 (8.3%)
0
a:  Monthly attack rate for each subject = 30.4 x (total # of attacks) / (last day of study drug – first day of 
study drug + 1).
In Study LEVP 2006-4, the proportion of pediatric subjects (N=23) reporting a TEAE during 
the study was 74% and similar to the proportion reported in adults (79%).  The most common 
TEAE in the study (and the most common TEAE in children) was upper respiratory tract 
infection (reported in 26% of children and 22% of adults).  Many of the TEAEs reported in 
children 6-17 years of age were associated with common childhood infections such as 
pharyngitis, tonsillitis, sinusitis, and other upper respiratory tract infections.  
Treatment-emergent AEs reported in children in this study are summarized below:

2-5 years of age:  1/2 (50%) subjects reported treatment-emergent AEs of HAE (severe 
abdominal HAE attack) and upper respiratory tract infection, both of which were 
considered to be not related to CINRYZE. 

6-11 years of age:  8/9 (89%) subjects reported 50 treatment-emergent AEs, 46 of which 
were considered to be not related to CINRYZE.  Two subjects reported 4 treatment-
related AEs (dizziness, headache, mouth ulceration, and nausea). 

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
4 1
C O N FI D E N TI A L

1 2 - 1 7 years of a ge:  8/ 1 2 ( 6 7 %) s u bjects re p orte d 6 0 treat me nt-e mer ge nt A Es, 5 7 of 
w hic h were c o nsi dere d t o be n ot relate d t o CI N R Y Z E.  T w o s u bjects re p orte d 3 treat me nt -
relate d A Es (i nf usi o n site er yt he ma, metr orr ha gia, a n d p h ot ose nsiti vit y reacti o n). 
Effic acy D at a f or P e di atric S u bjects A ge d 6 t o 1 1 Y e ars 
T here was o ne s u bject (
; 
fe male) e nr olle d i n St u d y  LE V P 2 0 0 5- 1/ B i n t he 
6 t o 1 1 years of a ge s u bset.  T his s u bject als o partici pate d i n St u d y  LE V P 2 0 0 6 - 4 ( pre ve nti o n) 
a n d St u d y LE V P 2 0 0 5 - 1/ A (treat me nt).  T he ra n d o mize d treat me nt assi g n me nt f or t his s u bject 
was Place b o/ CI N R Y Z E a n d all a d mi nistrati o ns of CI N R Y Z E were 1 0 0 0 U d oses.  As s h o w n 
i n Ta ble 5 , t his s u bject e x perie nce d a greater t ha n 2- f ol d re d ucti o n i n t he n u m ber of H A E 
attac ks wit h CI N R Y Z E c o m pare d t o place b o/ o n -de ma n d t hera p y  (8. 0 vs. 2 0. 0).  F urt her m ore, 
t he se verity of attac ks was less ( 1. 5 vs 1. 7), t he d urati o n of attac ks was s h orter ( 2.5 v s. 3. 1
da y s), a n d t he t otal da ys of s welli n g was c o nsi dera bl y l o wer ( 1 2. 0 vs 4 2) wit h CI N R Y Z E 
pre ve nti o n t hera p y co m pare d t o place b o/ o n -de ma n d t hera py.  Fe wer o pe n -la bel CI N R Y Z E 
i nf usi o ns f or treat me nt of ac ute H A E attac ks were a d mi nistere d t o t his s u bject w hile o n 
CI N R Y Z E c o m pare d wit h place b o/ o n -de ma n d t hera p y  ( 7. 0 vs. 2 8. 0).
T a bl e 5 .
D et ail e d Effi c a c y  R e s ult s f or P e di atri c S u bj e ct
–
St u d y L E V P 2 0 0 5 -1/ B                                        
O bser ve d N o. of 
Att ac ks D uri n g 
T her a p y
Me a n Se verit y 
a
of Att ac ks D uri n g 
T her a p y
Me a n D ur ati o n
of Att ac ks D uri n g 
T her a p y ( D a ys)
N o. of O L CI N R Y Z E 
I nf usi o ns D uri n g 
T her a p y
T ot al D a ys
of S w elli n g D uri n g 
T her a p y
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E
Pl ace b o
CI N R Y Z E 
Pl ace b o
8
2 0
1. 5 
1. 7 
2. 5 
3. 1
7
2 8 
1 2 
4 2
a: 1 = mil d; 2 = m o derate; 3 =se vere
Ta ble 6
P P D
descri bes t he de m o gra p hic, e x p os ure, a n d efficac y data fr o m St u d y  LE V P 2 0 0 6 - 4 f or 
t he 9 pe diatric s u bjects 6 t o 1 1 ye ars of a ge.  Pri or t o e nr oll me nt i n t he st u d y , t hese 9 s u bjects 
re p orte d a me dia n m o nt hl y  HA E attac k rate of 3 (ra n ge:  2-4).  Duri n g t he st u d y, t hese 
s u bjects e x perie nce d a me dia n m o nt hl y  attac k rate of 0. 1 6 (ra n ge:  0-1. 3 3); t he maj orit y of 
s u bjects ( 8/ 9, 8 9 %) e x perie nce d ≤1 H A E attac k per m o nt h, a n d 3 3 % ( 3/ 9) re p orte d n o attac ks.   
I n ter ms of safety, 8/ 9 ( 8 9 %) s u bjects re p orte d 5 0 treat me nt-e mer ge nt A Es, 4 6 of w hic h were 
c o nsi dere d t o be n ot relate d t o CI N R Y Z E.  As descri be d pre vi o usl y, tw o s u bjects re p orte d 4 
treat me nt-relate d A Es ( dizzi ness, hea dac he, m o ut h ulcerati o n, a n d na usea).
P P D
P P D

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
4 2
C O N FI D E N TI A L
T a bl e 6 .
D e m o gr a p hi c s, E xt e nt of E x p o s ur e, a n d A tt a c k Fr e q u e n c y f or 
P e di atri c S u bj e ct s 6 -1 1 Y e ar s of A g e ( St u d y  L E V P 2 0 0 6-4)
S u bject I D
A ge/ Ge n der
Pre ve nti o n D ose
D a ys o n St u d y
Att ac ks per M o nt h
B aseli ne
O n St u d y
F
1 0 0 0 U
5 8 2
4
0. 1 6
F
1 0 0 0 U
2 4 6
2
0. 0 0
M
1 0 0 0 U
3 0 1
2
0. 3 0
F
1 0 0 0 U
6 9 7
4
0. 3 9
M
1 0 0 0 U
3 4 4
4
1. 3 3
F
1 0 0 0 U ( 7 5 0 da ys)
2 0 0 0 U ( 9 0 da ys)
1 0 0 0 U ( 8 3 da ys)
9 2 3
4
0. 8 2
F
1 0 0 0 U
1 3 6
2
0. 0 0
M
1 0 0 0 U
2 6 7
3
0. 1 1
F
1 0 0 0 U
6 4
3
0. 0 0
1. 2
St u d y R ati o n ale
C urre nt i nter nati o nal c o nse ns us rec o m me n dati o ns f or H A E t hera p y do n ot pr o vi de s ufficie nt 
gra n ularit y acr oss all a ge gr o u ps a nd ca n n ot be u nc o n diti o nall y  ad o pte d f or pe diatric patie nts 
i n vari o us c o u ntries, d ue t o me dical a n d le gal iss ues (Wa h n et al., 2 0 1 2 ).  F urt her st u dies i n 
pe diatric s u bjects wit h H A E t hera pies c urre ntl y ap pr o ve d f or a d ults o nl y , will pr o vi de 
pe diatricia ns wit h t hera pe utic o pti o ns f or treati n g t heir patie nts.  Re gar dless, e x perts i n dicate 
t hat plas ma-deri ve d C 1 IN H c o nce ntrate is t he first c h oice a n d best treat me nt o pti o n f or l o n g-
ter m pre ve nti o n i n pe diatric patie nts a n d atten uate d a n dr o ge ns a n d tra ne xa mic aci d are n ot 
rec o m me n de d (Wa h n et al., 2 0 1 2
P P D
).  
CI N R Y Z E I V (a d mi nistrati o n of 1 0 0 0 U e ver y 3 or 4 d a y s) was a p pr o ve d b y  t he U S F D A f or 
r o uti ne pr o p h yl a xis a gai nst a n gi oe de ma attac ks i n a d olesce nt a n d a d ult patie nts wit h H A E i n 
Oct o ber 2 0 0 8.  CI N RY Z E was als o a p pr o ve d t hr o u g h o ut t he E U, via t he Ce ntralize d 
Pr oce d ure, i n J u ne 2 0 1 1 f or treat me nt a n d pre -pr oce d ure pre ve nti o n of a n gi oe de ma attac ks i n 
a d ults a n d a d olesce nts wit h H A E, a n d r o uti ne pre ve nti o n of a n gi oe de ma attac ks i n a d ults a n d 
a d olesce nts wit h se vere a n d rec urre nt attac ks of H A E w h o are i nt olera nt t o or i ns ufficie ntly 
pr otecte d b y  oral pre ve nti o n treat me nts, or patie nts w h o are i na de q uatel y ma na ge d wit h 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

CINRYZE® (C1 esterase inhibitor [human])
Protocol 0624-301 with Amendments 1, 2, 3, and 4
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repeated acute treatment.  CINRYZE has also received marketing approval in Australia 
(March 2012), India (February 2013), Switzerland (May 2013), and Israel (August 2013) for 
all three indications (treatment, routine prevention, and pre-procedure prevention) in adults 
and adolescents (as well as children 6 years and above in India) with HAE.  CINRYZE was 
approved in Canada (October 2012) for routine prevention against angioedema attacks in 
adults and adolescents with HAE.  
The HAE development program for IV CINRYZE included data in the pediatric population
that is among the largest for any C1 INH therapy based on published literature.  However, 
further investigation is warranted to evaluate safety, tolerability, and treatment effect in 
children 6 to 11 years of age who require long term C1 INH replacement therapy due to the 
morbidity imposed by frequent angioedema attacks.  As of 07-Jun-2013, in the US a total of 
110 patients less than 18 years of age with HAE are actively receiving commercial 
CINRYZE.  Of 110 patients, 26 children are 6 to 11 years of age and 84 children are 12 to 17 
years of age (data on file).  
While CINRYZE has proven to be safe and effective in adults and adolescents, questions 
remain about the ideal pediatric dosing regimens, particularly for young and/or light-weight 
children.  Additional information with regards to the pharmacokinetics and dosing of 
CINRYZE in children (≥2 to <12 years of age) is currently being assessed in a study for the 
treatment of acute angioedema attacks (Protocol 0624-203).  Dosing in study 0624-203 is 
determined by subject weight category; 10 kg to 25 kg inclusive (500 U and 1000 U) and 
>25 kg (1000 U and 1500 U).
The aim of this study is to assess the safety and tolerability, relative efficacy, and PK/PD of 
two different doses (500 U and 1000 U) of CINRYZE administered by IV injection to further 
the knowledge of the management of HAE in children 6 to 11 years of age.  Consistent with 
the recent consensus on therapeutic strategies for children and adolescents with HAE (Wahn 
et al., 2012), the current study will account for differences in body weight by administering 2 
fixed doses of CINRYZE (500 U and 1000 U), and CINRYZE dosage will be related to 
plasma volume, body surface area, and body mass index.  The optimal dose for this age group

CINRYZE® (C1 esterase inhibitor [human])
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may be less than the IV dose of 1000 U every 3-4 days approved for adult and adolescent 
patients and the proposed study allows a within subject comparison of the effectiveness and 
tolerability of two dosing regimens.  In addition, the study will provide supportive data on 
potential immunogenicity and quality of life health status in this pediatric population, as well 
as prospective observational data on angioedema attack frequency in the “ultra-orphan” 6 to 
11 years of age subgroup.
Detailed considerations regarding CINRYZE doses selected for this study are presented in 
Section 5.1.
2.0
STUDY OBJECTIVES
The objectives of the study are as follows:
Primary Objective

To assess the relative efficacy of two dose levels of CINRYZE (500 U and 
1000 U) administered by IV injection every 3 or 4 days to prevent angioedema 
attacks in children 6 to 11 years of age.
Secondary Objectives

To assess the safety and tolerability of two dose levels of CINRYZE administered 
by IV injection in children 6 to 11 years of age with HAE.

To characterize the PK and PD of CINRYZE administered by IV injection in 
children 6 to 11 years of age. 

To assess the immunogenicity of CINRYZE following IV administration.
Other Objective

To assess the impact of treatment on health status (quality of life) in children 6 to 
11 years of age with HAE.
3.0
INVESTIGATIONAL PLAN
This multicenter, randomized, single-blind, dose-ranging, crossover study will be conducted 
in multiple countries including the US, EU, and Latin America. Other countries/regions may 
be added if necessary to complete enrollment. All study sites, irrespective of geographic 
location, will conduct the study in accordance with this study protocol and Good Clinical 
Practice (GCP) standards, including review and approval by independent ethics committee 

CINRYZE® (C1 esterase inhibitor [human])
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(IEC).  Data from all sites will be pooled for purposes of analysis and will be reported in the 
final clinical study report. 
Figure 1.
Study Design
Potential subjects (≥6 to <12 years of age) will have a screening evaluation the day prior to 
entering the study’s baseline observation period.  Subjects with qualifying angioedema attack 
rates, and who meet all other eligibility criteria, will be enrolled and baseline observation 
period for at least 12 weeks.  
Throughout the study, an electronic study diary (eDiary) will be used to collect specific 
information regarding the subject’s symptoms of HAE.  The eDiary will consist of two 
sections:  
(a) Section to record daily if any elective procedures have been performed, signs and 
symptoms of angioedema attacks, triggers for angioedema attacks, medications used for 
the management of angioedema attacks, and interruptions in activities of daily living due 
to an angioedema attack. Section (a) is to be completed by the parent/caregiver, and when 
possible, the same parent/caregiver should be responsible for completing this section of 
the eDiary throughout the study.

CINRYZE® (C1 esterase inhibitor [human])
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(b) Section to record the impact of HAE on quality of life (EQ-5D-Y).  Section (b) is to be 
completed by the subject at specified time points throughout the study and on each day 
the subject experiences signs or symptoms of an angioedema attack.  
Study personnel will contact the parent/caregiver by telephone bi-weekly (Weeks 2, 4, 6, 8,
10, and 12) during the baseline observation period to discuss study compliance (completion of 
the eDiary daily) and to evaluate the subject’s angioedema attack frequency (Schedule 1).
During the baseline observation period, subjects are allowed to remain on any prophylactic 
HAE therapy they were receiving prior to study enrollment, if clinically indicated.  However, 
it is recommended that consideration by the Investigator be given to discontinuing subjects 
from any prophylactic antifibrinolytic or androgen therapy during the first 6 weeks of the 
observation period.  If these medications cannot be discontinued, stable doses should be used 
during Treatment Periods 1 and 2.  At least 3 days prior to first dose of study drug, subjects 
receiving commercial C1 INH for prevention of attacks must discontinue this therapy.  
In the event that during the 12 weeks of baseline observation subjects do not meet the attack 
criteria qualifying for randomization (≥1.0 angioedema attacks per month [average] that are 
moderate or severe or require acute treatment), despite having met this same criteria 
historically for study enrollment, additional weeks of observations will be considered at the 
discretion of the Investigator and Sponsor to allow qualification for randomization and entry 
into the treatment periods of the study. In this case, subjects will maintain the same schedule 
of assessments by beginning at Week 1 again for the additional weeks of observation 
(Schedule 1).
After the completion of the baseline observation period, subjects who remain eligible per 
study criteria will be randomized to 1 of 2 treatment sequences prior to the first dose of study 
drug in Treatment Period 1 (i.e., Dosing Day 1).  Twelve subjects will be randomized in this 
study.  There is no washout period between Treatment Period 1 and Treatment Period 2.  
Subjects are required to maintain their twice weekly (every 3 or 4 days) schedule between the 
last dose of study drug in Treatment Period 1 and the first dose in Treatment Period 2.

CINRYZE® (C1 esterase inhibitor [human])
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Subjects and parents/caregivers will be blinded to treatment sequence and dose.  Study site 
personnel, qualified home healthcare professionals, and the Sponsor will not be blinded to 
treatment assignment and the dose of study drug administered. 
Study drug will be 
administered intravenously by qualified personnel at the investigational site, or by qualified 
home healthcare professionals at the subject’s home or other agreed upon location.  
Alternatively if allowed per local regulations, subjects who have been trained to self-
administer C1 INH or who have a non-healthcare provider (e.g., parent) who has been trained 
to administer C1 INH will be permitted to do so based upon the request of the subject (and 
with approval of the parent(s)/legal guardian and the Investigator.  Note: self-administration 
will always occur under the supervision of a qualified healthcare professional at the study site 
or the subject’s home (or other agreed upon location). Supervision by a qualified healthcare 
professional will include real time direct visual observation of the following: selection of the 
injection site, preparation of the injection site, insertion of the infusion device into the vein, 
study drug infusion, removal of infusion device, compression and applying a bandage to the 
injection site, and disposal of all infusion materials.
The Investigator or designee will monitor and document study compliance, tolerability of 
each CINRYZE dose, and adverse events.  The following doses of study drug in each 
treatment period must be administered at the investigational site:  Dose 1 (Visits 1a and 1b), 
Dose 12 (Visits 12a and 12b) and Dose 24 (Visits 24a and 24b).  At these visits, subjects will 
also have other scheduled procedures performed (Schedules 2 and 3).  For those subjects who 
are administered study drug at a location other than the study site, study personnel will 
contact the parent/caregiver by telephone twice during each treatment period (Week 3 after 
Dose 6 [Visits 6a and 6b] and Week 9 after Dose 18 [Visits 18a and 18b]).  If study drug is 
administered at the site (Doses 6 and 18), no telephone contact is necessary.  
To the extent possible, subjects will postpone elective procedures (e.g., dental work) while 
participating in the study.  In the event a procedure cannot be postponed, parents/caregivers 
will notify the Investigator and the information will be recorded in the subject’s eCRF (see 
Section 6.8).

CINRYZE® (C1 esterase inhibitor [human])
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Safety will be monitored through the recording of AEs and changes in medical history, 
physical examinations, vital signs, and clinical safety laboratory testing.  Stopping rules 
following an anaphylactic reaction or a thrombotic or thromboembolic event are provided in 
Section 5.5.  Details on the management of acute angioedema attacks are provided in Section 
6.10.  Study personnel will report any angioedema attacks that occur after the first dose of 
study drug as AEs (see Section 9.0).  
A post-treatment visit will be performed at the investigative site 1 week (±2 days) after the 
last dose of study drug in Treatment Period 2 for follow-up safety assessments.  In addition, 
subjects will have a blood sample for C1 INH antibody testing collected 30 (±2) days after the 
last dose of study drug.  If a subject discontinues prematurely from treatment and/or the study, 
the Investigator will perform the Early Discontinuation Visit safety procedures as soon as 
possible.  For those subjects who discontinue prematurely from treatment, every effort should 
be made to complete all applicable protocol evaluations for the 1-month post-treatment 
follow-up visit (see Schedule 4).  
Investigators will report all SAEs occurring up to 30 days after the last dose of study drug to 
Shire VIROPHARMA and their respective Independent Reviewing Authority (IRA) according 
to local reporting requirements.  In addition, SAEs with an onset more than 30 days after the 
last dose of study drug should be reported if considered by the Investigator to be related to 
study drug.  All suspected unexpected serious adverse reactions (SUSARs) will be reported 
by the Sponsor to the relevant competent authorities in accordance with the European 
Directive 2001/20/EC, as applicable.  
Subjects will remain outpatient throughout the study.  Individual participation from 
screening through the completion of follow-up will be approximately 10 months.  Subjects 
will adhere to the protocol-defined schedule of clinical assessments and procedures as 
outlined below:

Schedule 1 – Clinical study assessments during Screening and Baseline 
Observation Period (Weeks 1 to 12).

Schedule 2 – Clinical study assessments during Treatment Period 1 (Visits 1a to 
24a).

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
Schedule 3 – Clinical study assessments during Treatment Period 2 (Visits 1b to 
24b).

Schedule 4 – Clinical study assessments at Early Discontinuation, 1-week Post-
treatment, and 1-month Post-treatment Follow-up Visits.

Schedule 5 – Blood sample collection for PK/PD and post-treatment 
immunogenicity assessments.
4.0
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 a child (male or female), ≥6 to <12 years of age at the time of screening. 
2. Have a confirmed diagnosis of Type I or Type II HAE and have a functional 
C1 inhibitor (C1 INH) level less than 50% of normal.
3. Have a history of ≥1.0 angioedema attacks per month (average) that are moderate1
or severe2 or require acute treatment3 during the 3 consecutive months prior to 
screening. 
4. Agree to adhere to the protocol-defined schedule of assessments and procedures.
5. Have a parent(s)/legal guardian who is informed of the nature of the study provide
written informed consent  for the child to participate in the study before any study-
specific procedures are performed (with assent from the child when appropriate).  
Additional Inclusion Criteria (Qualifying for Randomization)
6. Have experienced ≥1.0 angioedema attacks per month (average) that are moderate1
or severe2 or require acute treatment3 during the 12-week baseline observation 
period.
                                                
1
Moderate:  Angioedema attack sign/symptom(s) interferes with the subject’s ability to attend school or 
participate in family life and social/recreational activities.
2
Severe:  Angioedema attack sign/symptom(s) significantly limits the subject’s ability to attend school or 
participate in family life and social/recreational activities.
3
‘Treatment’ refers specifically to standard of care therapies used to treat an angioedema attack (e.g., 
C1 INH, kallikrein inhibitor, bradykinin receptor antagonist).  Products used for the treatment of attack 
symptoms (e.g., analgesics, anti-emetics) do not qualify for this study inclusion criterion.

CI N R Y Z E ® ( C 1 esterase i n hi bit or [h u ma n] )
Pr ot oc ol 0 6 2 4 -3 0 1 w it h A me n d me nts 1 , 2, 3, a n d 4
2 6 Ja n uar y 2 0 1 5
5 0
C O N FI D E N TI A L
4. 2
E xcl usi o n Criteri a
T o be eli gi ble f or t his pr ot oc ol, a s u bject m ust n ot:
1.
Ha ve a hist or y  of h y perc oa g ula bilit y  (a b n or mal bl o o d cl otti n g).
2.
Ha ve a dia g n osis of ac q uire d a n gi oe de ma or k n o w n t o ha ve C 1 I N H a nti b o dies.
3.
Ha ve a hist or y  of aller gic reacti o n t o C 1 I NH pr o d ucts, i ncl u di n g CI N R Y Z E ( or 
a n y of t he c o m p o ne nts of CIN R Y Z E), or ot her bl o o d pr o d ucts.
4.
Be pre g na nt or breastfee di n g.
5.
Ha ve recei ve d a n i n vesti gati o nal dr u g ot her t ha n t h ose re q uire d f or pre ve nti o n or 
treat me nt of a n gi oe de ma attac ks wit hi n 3 0 da ys pri or t o scree ni n g.
6.
Ha ve, as deter mi ne d b y  t he I nvesti gat or a n d/ or t he S p o ns or’s me dical m o nit or, a n y 
s ur gical or me dical c o n diti o n t hat c o ul d i nterfere wit h t he a d mi nistrati o n of st u d y 
dr u g or i nter pretati o n of st u d y  res ults.
A d diti o n al E xcl usi o n Criteri a ( Dis q u alifyi n g fr o m R a n d o miz ati o n)
7.
Ha ve a n y acti ve i nfecti o us ill ness or fe ver defi ne d as a n oral te m perat ure > 3 8 C 
( 1 0 0. 4F), t ym pa nic > 3 8. 5 C ( 1 0 1. 3F), a xillar y >3 8 C ( 1 0 0. 4F), or rectal/c ore 
> 3 8. 5 C ( 1 0 1. 3F) wit hi n 2 4 h o urs pri or t o t he first d ose of st u d y dr u g i n 
Treat me nt Peri o d 1 . 
8.
Ha ve ha d si g ns or s ym pt o ms of a n a n gi oe de ma attac k wi t hi n 2 d a y s pri or t o t he 
first d ose of st u d y dr u g i n Treat me nt Peri o d 1. 
5. 0
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
As disc usse d i n Secti o n s 1. 1. 2 a n d 1. 1. 3 , t he vast maj orit y  of I V CI N R Y Z E
i nf usi o ns 
a d mi nistere d i n cli nical st u dies were d oses of 1 0 0 0 U f or b ot h a d ults a n d c hil dre n, alt h o u g h 
t he t w o yo u n gest s u bjects (a ges
a n d 
y ears ol d) recei ve d 5 0 0 U per I V d ose.   I n t he U S, t he 
a p pr o ve d d ose of CI N R Y Z E f or r o uti ne pr o p h y la xis a gai nst a n gi oe de ma attac ks i n a d olesce nt 
a n d a d ult patie nts wit h H A E is 1 0 0 0 U I V e ver y  3 or 4 d a y s.
T he effecti ve ness of t his d ose is s u p p orte d b y data fr o m S t u dies L E V P 2 0 0 5 -1/ B a n d
L E V P 2 0 0 6 -4, w here all pe diatric s u bjects ha d a cli nicall y si g nifica nt re d ucti o n i n t he n u m ber 
of a n gi oe de ma attac ks w hile recei vi n g 1 0 0 0 U of I V CI N R Y Z E e ver y 3-7 da y s (see Ta ble 5
a n d Ta ble 6 ). 
P P D
 This d osi n g re gi me n ha d a fa v ora ble safety pr ofile i n c hil dre n w he n 
a d mi nistered f or r o uti ne pre ve nti o n of a n gi oe de ma attac ks. 
P P D

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Although the data support that higher doses of CINRYZE are not necessary for subjects in the 
6 to 11 year age group, the efficacy of a lower dose (500 U every 3-4 days) has not been 
evaluated in this “ultra-orphan” subgroup.  The proposed study will provide additional data on 
a dosage range of CINRYZE for the prevention of angioedema attacks in children 6 to 11 
years of age.  
5.2
Randomization
Twelve subjects will be randomized to one of two treatment sequences, with each sequence 
consisting of two 12-week treatment periods.  Randomization will occur on Dosing Day 1 
(Visit 1a) of Treatment Period 1.  Each investigative site will receive a randomization 
schedule which will be used to assign subjects at that site to one of two sequences (A/B or 
B/A), with equal probability.
Treatment A will be 500 U CINRYZE administered 
intravenously twice weekly (every 3 or 4 days) for 12 weeks and Treatment B will be 1000 U 
CINRYZE administered intravenously twice weekly (every 3 or 4 days) for 12 weeks.
5.3
Study Drug
See Section 8.0 for a complete description of study drug.  Instructions for the reconstitution of 
CINRYZE are provided in a separate Pharmacy Manual.  CINRYZE treatments will be 
prepared and administered by qualified study site personnel or qualified home healthcare 
professionals. Home healthcare personnel may prepare and administer CINRYZE treatments 
at the subject’s home. Alternatively if allowed per local regulations, subjects who have been 
trained to self-administer C1 INH or who have a non-healthcare provider (e.g., parent) who 
has been trained to administer C1 INH will be permitted to do so based upon the request of 
the subject (and with approval of the parent(s)/legal guardian and the Investigator).  Note: 
self-administration will always occur under the supervision of a qualified healthcare 
professional at the study site or the subject’s home (or other agreed upon location). 
Supervision by a qualified healthcare professional will include real time direct visual 
observation of the following: selection of the injection site, preparation of the injection site, 
insertion of the infusion device into the vein, study drug infusion, removal of infusion device,

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compression and applying a bandage to the injection site, and disposal of all infusion 
materials.
For Treatment A (500 U CINRYZE dose), an additional vial of 5 mL sterile water for 
injection (SWFI) will be added to the 5 mL vial of reconstituted CINRYZE to make a total 
volume of 10 mL.  For Treatment B (1000 U CINRYZE dose), two 5 mL vials of 
reconstituted CINRYZE will make a total volume of 10 mL.  CINRYZE will be administered 
intravenously as a single 10-mL injection and at a rate of approximately 1 mL (50-100 U) per 
minute, as tolerated.
The following doses of study drug in each treatment period must be administered at the 
investigational site:  Dose 1 (Visits 1a and 1b), Dose 12 (Visits 12a and 12b) and Dose 24 
(Visits 24a and 24b).  At these visits, subjects will also have other scheduled procedures 
performed (Schedules 2 and 3).  For each dose administered, date and time at start of infusion 
and the date and time at completion of infusion will be recorded in the eCRF.  Any departure 
from the expected dosing regimen will be recorded in the eCRF.
5.4
Blinding
This is a single-blind study.  Subjects and parents/caregivers will be blinded to the treatment 
administered.  Study site personnel, qualified home healthcare professionals, and the Sponsor 
will not be blinded to dose and treatment sequence.  
To maintain the treatment blind (for subjects and parents/caregivers), each dose of study drug 
will consist of a single IV injection (total volume of 10 mL; see Section 5.3). 
5.5
Stopping Rules
5.5.1
Anaphylactic Reaction
If an anaphylactic reaction occurs in any subject, study drug will be discontinued.  The subject 
will follow the schedule of assessments for early discontinuation and complete the protocol 
evaluations for the 1-month post-treatment follow-up visit (see Schedule 4).  Other enrolled 
subjects will continue with study drug administration and procedures. 

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5.5.2
Thrombotic or Thromboembolic Event
If a 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 the medical monitor determines that the event was unrelated or 
unlikely to be 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 clinically appropriate.  
Investigators will comply with protocol-defined algorithms to assist in the diagnosis and 
management of all suspected T/TE events (see Appendix II).  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 in the treatment period that was interrupted.  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 early discontinuation (see 
Schedule 4).
6.0
STUDY PROCEDURES
Subjects meeting the eligibility criteria listed in Section 4.0 may be enrolled in the study after 
the nature and purpose of the protocol have been explained and written permission to 
participate has been voluntarily granted by the parent/legal guardian and assent has been 
provided by the subject (to the extent that is compatible with the subject’s understanding) (see 
Section 14.0).  Schedules 1, 2, 3, and 4 provide details of study procedures for clinical study 
assessments and Schedule 5 provides timing of blood sampling for PK/PD and post-treatment 
immunogenicity testing. 
6.1
Medical History and Physical Examination
A medical history will be taken at the screening visit, and updated prior to randomization on 
Day 1 of Treatment Period 1 to ensure that the subject remains eligible for study participation.  

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All medical history findings that have been present/active within 1 year prior to enrollment 
will be recorded in the eCRF regardless of clinical relevance or presence at study start.  
Medical history findings that have not been present within 1 year prior to enrollment will be 
recorded if deemed clinically relevant by the Investigator to the conduct of the study.  The 
medical history is to include any history of allergic reactions to drugs.  
The Investigator or designee will perform physical examinations at the time points specified 
in Schedules 2, 3, and 4.  General physical examinations will be performed in accordance 
with standard practices at the study site. 
Clinically significant physical examination 
abnormalities observed prior to dosing with study drug also will be recorded in the medical 
history section of the eCRF.  Any new or worsening clinically significant abnormality 
observed any time after the start of study drug administration should be recorded as an AE 
(see Section 9.0).  
Body weight and height will be measured at the time points specified in Schedules 2 and 3.  
Measurements should be performed without shoes and underclothes only and measured by the 
same individual at each assessment time point (if possible).
6.1.1
HAE History
The following information associated with HAE history will be recorded in the eCRF at the 
screening visit (NOTE:  the attack rate may be estimated based on subject or parent/caregiver
recall as well as the subject's medical records):  

HAE Type (I or II).

Any first-degree blood relative (i.e., mother, father, sibling) diagnosed with HAE.
(yes/no).  If yes, provide the relationship of first-degree blood relative(s).

Any therapy received during the 9 months prior to screening for management of 
HAE (yes/no) (see Section 6.3.1).

Total number, typical locations, average overall duration (days), and average 
overall severity of HAE attacks experienced during the 3 months prior to screening
(see Section 6.10.1 for definition of severity).

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6.2
Vital Signs
Blood pressure and heart rate will be measured at the time points specified in Schedules 2, 3
and 4.  Body temperature will be measured prior to randomization at Visit 1a.  During the 
study, additional vital signs measurements will be performed if clinically indicated.  Vital 
signs performed on dosing days should be obtained prior (within 60 minutes) to the start of 
the injection and between 10 to 30 minutes after completion of the injection of study drug.  
Every effort should be made to measure and record vital signs prior to any blood sample 
collection.  
6.3
Prior and Concomitant Medications
Prior and concomitant medications to be recorded will include prescription medications, 
blood products (e.g., 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 as treatment for an AE.
6.3.1
Prior Medications
A HAE medication history will be taken during the screening visit, and updated prior to study 
drug administration on Day 1 of Treatment Period 1 to ensure that the subject remains eligible 
for study participation.  Parents or caregivers should record in the eDiary any medications 
taken by the subject for the management of angioedema attacks during the baseline 
observation period. 
Any therapy received during the 9 months prior to screening for the management of 
angioedema attacks should be recorded, including overall start and stop dates if known, and 
the HAE indication (i.e., long-term prevention, acute treatment, short-term prevention).  For 
any medication used in the management of HAE that has a start date prior to Treatment 
Period 1 and is planned to be continued in the treatment periods of the study, a stop date prior 
to the first dose of study drug in Treatment Period 1 should be entered into the eCRF.  Any 
subsequent use of this medication should be recorded as a concomitant medication with a new 
start date.

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In addition, all medications taken within 1 week prior to Day 1 of Treatment Period 1 will be 
entered into the eCRF.
6.3.2
Concomitant Medications
Concomitant medications taken from the start of dosing through 1-week post-treatment will 
be recorded in the eCRF.  For medications associated with management of angioedema 
attacks, study personnel will record the start/stop dates, dose, unit, frequency, route of 
administration, and indication (if known) in the subject’s eCRF.  For medications not 
associated with the management of HAE, study personnel will record the start/stop dates, 
route of administration, and indication for which the medication was administered in the 
subject’s eCRF.
6.3.3
Prohibited Medications
Use of C1 INH therapy (other than study drug) for prophylaxis against angioedema attacks is 
prohibited during the study after completion of the baseline observation period. At least 3 
days prior to randomization, subjects receiving commercial C1 INH for prevention of attacks
must discontinue this therapy.  It is recommended that consideration by the Investigator be 
given to discontinuing subjects from any prophylactic antifibrinolytic or androgen therapy 
during the first 6 weeks of the observation period, if clinically indicated. If these medications 
cannot be discontinued, stable doses should be used during Treatment Periods 1 and 2. 
Details on the management of acute angioedema attacks are discussed in Section 6.10.
6.4
Nonpharmacologic Treatments and Procedures
Nonpharmacologic treatments and procedures (e.g., surgical, diagnostic, or dental) that occur 
during the baseline observation period through 1-week post-treatment will be recorded in the 
eCRF.
6.5
Clinical Laboratory Parameters
Subjects will have blood samples collected for routine clinical laboratory testing at the time 
points specified in Schedules 1, 2, 3 and 4.  Testing will be performed at a Central Laboratory, 

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except for the urine pregnancy test and for any other parameter that the Investigator will need 
to assess urgently for the acute care of any subject.  The following clinical laboratory 
parameters will be analyzed:

Hematology: 

Dosing Visits 1a (pre-dose), 12a, 1b (pre-dose), 12b, 24b, and 1-week 
post-treatment (or if prematurely discontinued):  CBC consisting of WBC 
and differential counts and percentages, RBC count, hemoglobin, 
hematocrit, and platelet count.

Clinical Chemistry:

Dosing Visits 1a (pre-dose), 12a, 1b (pre-dose), 12b, 24b, and 1-week 
post-treatment (or if prematurely discontinued):  Blood urea nitrogen 
(BUN), creatinine, glucose, sodium, potassium, chloride, carbon dioxide 
(CO2), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), creatine phosphokinase (CPK), total bilirubin, 
calcium, phosphorus, total protein, and albumin.

Coagulation:

Dosing Visits 1a (pre-dose), 12a, 1b (pre-dose), 12b, 24b, and 1-week 
post-treatment (or if prematurely discontinued):  Prothrombin time (PT), 
international normalized ratio (INR), and activated partial thromboplastin 
time (aPTT).

Virology:

Dosing Visit 1a (pre-dose) and 1-week post-treatment (or if prematurely 
discontinued): 
 
Human 
immunodeficiency 
virus 
(single 
assay 
antibody/Western Blot) and hepatitis (Hepatitis B Surface Antigen, 
Hepatitis C Antibody).
For all females who have reached menarche, urine pregnancy testing will be performed at 
the site at the time points specified in Schedules 2 and 4.
Additional clinical laboratory testing may be performed if clinically indicated, at the 
discretion of the Investigator, and may be sent to central laboratory or performed locally, and 
all results will be recorded.
6.6
Pharmacokinetic, Pharmacodynamic, and C1 INH Antibody Analyses
Blood samples for the determination of plasma concentrations of C1 INH antigen, functional 
C1 INH, and C4 complement will be collected from subjects during each treatment period as 

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shown in Schedule 5.  In addition, plasma samples collected prior to the dose of CINRYZE on 
Visit 1a (Dose 1 of Treatment Period 1), and Visit 1b (Dose 1 of Treatment Period 2), will be 
analyzed for C1 INH antibodies (see Schedules 2 and 3).  Additional blood samples for C1 
INH antibody testing will be collected 1 week post-treatment (or if prematurely discontinued) 
and 30 days after the last dose of study drug (see Schedules 4 and 5).  
NOTE:  If a subject presents to the site with an angioedema attack, every effort should be 
made to obtain a PK blood sample prior to any treatment.  In addition, if the subject is treated 
with commercial C1 INH, every effort should be made to obtain a 1-hour post-treatment 
sample.  These samples will be analyzed for C1 INH antigen and functional C1 INH activity.
The actual date and time of each sample collection will be recorded.  Plasma samples for the 
determination of antigenic C1 INH, functional C1 INH, complement C4 concentrations, and 
C1 INH antibodies will be analyzed using validated methodology.  All samples, except for 
incurred samples, will be processed according to the procedure outlined in Appendix I. 
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 antigenic C1 INH and functional C1 INH activity in study samples to investigate the 
stability of 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.
6.7
Total Blood Volume Collected
Subjects will have approximately 172 mL of blood collected for clinical safety laboratory 
testing (hematology, chemistry, and coagulation), PK/PD, and immunogenicity (C1 INH 
antibodies) assessments during the study.

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6.8
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. To the extent possible, subjects will postpone elective procedures (e.g., 
dental work) while participating in the study.  In the event a procedure cannot be postponed, 
the parent/caregiver will notify the Investigator and the information will be recorded in the 
eCRF (see Section 6.4).  
6.9
Electronic Study Diary (eDiary)
Throughout the trial, an eDiary will be used to collect specific information regarding the 
subject’s symptoms of HAE.  The eDiary will consist of two sections:
(a) Section to record daily if any elective procedures have been performed, signs and 
symptoms of angioedema attacks, triggers for angioedema attacks, medications used for 
the management of angioedema attacks, and interruptions in activities of daily living due 
to an angioedema attack.  Section (a) is to be completed by the parent/caregiver, and when 
possible, the same parent/caregiver should be responsible for completing this section of 
the eDiary throughout the study.
(b) Section to record the impact of HAE on quality of life (EQ-5D-Y, see Section 6.11.1).  
Section (b) is to be completed by the subject at specified time points throughout the study
and on each day the subject experiences signs or symptoms of an angioedema attack.  
At the screening visit, study personnel will instruct subjects and parents/caregivers how to 
complete the eDiary.  The diary will be completed on each day during the baseline 
observation period and Treatment Periods 1 and 2.
Study personnel will review each subject’s eDiary for completeness and accuracy at each 
visit.  The eDiary is intended to be used by study personnel in conjunction with direct subject 
interviews, inpatient records (if applicable), and any other study-specific records as source 
documentation.  
Details about the use of the eDiary are provided in a separate study manual.

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6.10
Angioedema Attacks
An angioedema attack will be defined as any subject-reported (or parent/caregiver-reported) 
indication of swelling or pain at any location following a report of no swelling or pain on the 
previous day (i.e., 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 one site to another will be considered a single attack,

Attacks that begin to regress and then worsen before complete resolution will be 
considered one attack, and

Attacks that begin, appear to resolve, and then reappear without a symptom-free 
calendar day reported after the appearance of resolution will also be considered 
one attack.
NOTE:  An angioedema attack does NOT include swelling due to trauma and symmetrical 
non-painful swelling of the lower extremities.
6.10.1
Recording of Angioedema Attacks
During the observation period and both treatment periods, parents/caregivers will use the 
eDiary each day to record any symptoms or occurrences of an angioedema attack experienced 
by the subject.  The Investigator will complete a separate angioedema attack eCRF for each 
attack based upon their review of the data in the eDiary and include:

Characterization of whether swelling or pain is (indicate all that apply):

Mucosal (pharyngeal, laryngeal, gastrointestinal, genitourinary)

Non-mucosal (truncal, external, facial)

Location (site) of the swelling or pain (indicate all that apply):

Upper airway (includes laryngeal or pharyngeal)
NOTE: pharyngeal or oral swelling that results in airway compromise will 
be classified as a laryngeal attack

Gastrointestinal/abdominal (including symptoms of pain, nausea, vomiting, 
swelling, and/or change in bowel habits)

Genitourinary (including scrotum or vulva)

Facial

Extremity or peripheral (e.g., buttocks, external head/neck, trunk)

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
Severity (intensity) of the sign/symptom at each location listed:

None

Mild:  the angioedema attack sign/symptom(s) is noticeable but is easily 
tolerated by the subject and does not interfere with routine activities.

Moderate:  angioedema attack sign/symptom(s) interferes with the 
subject’s ability to attend school or participate in family life and 
social/recreational activities.

Severe:  the angioedema attack sign/symptom(s) significantly limits the 
subject’s ability to attend school or participate in family life and 
social/recreational activities.

Angioedema attack trigger(s)

Answer the question, “Was treatment administered for the attack?”  If yes, record 
treatment administered.
In addition to recording the above information, study personnel will report any angioedema 
attack that occurs after the first dose of study drug as an AE (see Section 9.0).  
6.10.2
Management of Acute Angioedema Attacks
If a subject experiences an acute angioedema attack at any time during study that in the 
opinion of the healthcare care provider requires medical intervention, the choice of acute 
treatment will be left to the Investigator’s discretion.  Where appropriate, CINRYZE can be 
provided for acute treatment of angioedema attacks.
Acute treatment(s) for angioedema 
attacks should be recorded in the eCRF (see Sections 6.3.2 and 6.4).
6.10.3
Angioedema Attacks During Treatment Periods
If a subject has an angioedema attack at any time during the study treatment periods, study 
drug administration and study procedures will continue for that subject adhering to the study
schedule, regardless of whether C1 INH therapy or other products were administered to treat 
the attack.  

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6.11
Quality of Life Measurements
6.11.1
Health-related Quality of Life (EQ-5D-Y)
EQ-5D-Y1 (Youth version of EQ-5D) is a descriptive system of youth health-related quality 
of life states consisting of five dimensions, each of which can have one of three responses. 
The responses record the level of severity within a particular EQ-5D dimension.  EQ-5D-Y is 
not intended for use in children 6 years of age (Noyes and Edwards, 2011); however in this 
study all subjects (6 to 11 years of age and where translated language version is available)
will be assessed.  The EQ-5D-Y will be completed by the subject at the time points specified 
in Schedules 1, 2, 3 and 4, as well as on each day that a subject experiences signs or 
symptoms of an angioedema attack (see Section 6.9).  
Details about the use and administration of the EQ-5D-Y questionnaire are provided in a 
separate study manual.
6.12
Discontinuation From Treatment and/or Study
When a subject is discontinued from treatment and/or study, Early Discontinuation Visit 
procedures will be performed (see Schedule 4). 
For those subjects who discontinue 
prematurely from treatment, every effort should be made to complete protocol evaluations for 
the 1-month post-treatment follow-up visit.  
For those subjects who enter the observation period but discontinue prior to randomization or 
who discontinue after randomization but prior to receiving study drug, the following 
information will be recorded in the eCRF:

Demographic information

Inclusion/exclusion information

HAE history and HAE medications for the 9 months prior to the observation period 
and also for the duration of the observation period

Angioedema attack data (all attributes of the attacks such as location, severity, pain 
assessment, possible trigger, treatment received, missed school)
                                                
1
EQ-5D™ is a trade mark of the EuroQol Group.

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
EQ-5D-Y data

Reason for not receiving study drug (e.g., not randomized as subject failed to meet 
qualifying 
attack 
criteria
or
Investigator
concern 
regarding
subject’s 
or 
parent/caregiver’s compliance with study procedures) 
No additional study procedures or follow-up will be performed on subjects who discontinue 
prior to receiving a dose of study drug.
6.12.1
Discontinuation From Treatment
A subject may be discontinued prematurely from study drug treatment for the following 
reasons:

Withdrawal by subject (i.e., assent withdrawn) [specify reason in the eCRF]

Withdrawal by parent/guardian [specify reason in the eCRF]

Adverse event (which in the opinion of the Investigator, due to the nature and 
severity, requires discontinuation from treatment)

Lost to follow-up

Physician decision (i.e., Investigator decision based on protocol violation, 
assessment that it is not in the subject’s best interest to continue, or other reason) 
[specify reason in the eCRF]

Sponsor decision [specify reason in the eCRF]
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.

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6.12.2
Discontinuation From Study
A subject may be discontinued prematurely from the study for the following reasons:

Withdrawal by subject (i.e., assent withdrawn) [specify reason in the eCRF]

Withdrawal by parent/guardian [specify reason in the eCRF]

Lost to follow-up

Death

Physician decision (i.e., Investigator decision based on protocol violation, 
assessment that it is not in the subject’s best interest to continue, or other reason) 
[specify reason in the eCRF]

Sponsor decision [specify reason in the eCRF]
7.0
STATISTICAL METHODOLOGY
Based on the EU Pediatric Investigation Plan, an administrative look for regulatory purpose 
may be completed after 6 patients have finished the study.  This will facilitate timely 
reporting of study results to the European Medicines Agency’s Paediatric Committee after 6 
children have completed the study as agreed in the Pediatric Investigation Plan. A final CSR 
will be completed after 12 subjects finish the study.   
7.1
Sample Size
This study is designed to assess the safety, tolerability, and relative efficacy of two different 
doses (500 U and 1000 U) of CINRYZE as prevention therapy for angioedema attacks in 
children 6 to 11 years of age with HAE.  Twelve subjects will be randomized in this study.  
Given the limited number of pediatric subjects with HAE who will fall within this age 
category and have a history of angioedema attacks appropriate to meet study inclusion criteria
(Caballero, 2012), this number is considered a reasonable target with respect to the ability to 
enroll eligible subjects. 
7.2
Populations
Data will be collected and summarized for all subjects randomized and treated with study 
drug.

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7.3
Efficacy Analysis
All efficacy endpoints will be determined for each subject in each treatment period: 

Number of angioedema attacks, normalized to a 12-week treatment period

Cumulative Attack Severity.  This score is the sum of the maximum symptom 
severity recorded for each angioedema attack in a treatment period.  

Cumulative Daily Severity.  This score is the sum of the severity scores recorded 
for every day of reported symptoms in a treatment period.  

Time (measured in days from the first dose of study drug in a treatment period) to 
the first angioedema attack reported in that treatment period.

Change from pre- to post-dose in C1 INH functional activity, C1 INH antigen, and 
C4 levels.

Number of angioedema attacks requiring acute treatment during each treatment 
period.
The endpoints based on attack severity are further defined with the following example:
Study 
Day
Symptoms 
Present
Maximuma
Symptom 
Severity 
Symptom 
Severity 
Score
Attack 
Number
Maximumb
Attack 
Severity 
Daily 
Severity 
1
Yes
Moderate
2
1
-
2
2
Yes
Moderate
2
2
2
3
No
4
Yes
Mild
1
2
-
1
5
Yes
Severe
3
-
3
6
Yes
Moderate
2
3
2
7
No
8
Yes
Moderate
2
3
-
2
9
Yes
Severe
3
-
3
10
Yes
Moderate
2
-
2
11
Yes
Moderate
2
3
2
a:
Maximum Severity across all anatomic locations on the corresponding study day.
b:
Maximum Severity across all anatomic locations and days with symptoms for the corresponding attack.
In this hypothetical example, a patient recorded 9 days of symptoms in an 11-day study 
period.  Because individual attacks require at least one symptom-free calendar day between 
episodes, this diary fragment identifies three angioedema attacks.  The maximum severity of 
each attack is determined on the last day of symptoms and is derived as Mild, Moderate, or 
Severe.  Coding these categories as Mild=1, Moderate=2, and Severe=3 and summing over 
the three unique attacks, yields a Cumulative Attack Severity of 8.  Finally, summing the 

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reported severity scores over the 9 days with symptoms yields a Cumulative Daily Severity of 
19.  With respect to these defined endpoints, this hypothetical eleven-day symptom diary 
would be quantitatively described by:
Endpoint
Value
Number of Attacks
3
Cumulative Attack Severity
8
Cumulative Daily Severity
19
Analysis of efficacy endpoints will employ descriptive statistics and will include all subjects 
randomized and treated with study drug. 
If warranted by the data, the comparison of 
CINRYZE doses will employ a paired t-test to perform a two-sided test of superiority (1000 U 
vs. 500 U) conducted at α=0.10.  
7.4
Safety Analysis
The following will be assessed during the study:

Safety and tolerability, including:

adverse events by dose group

adverse events by exposure (dose normalized to body weight [U/kg])

adverse events by time of onset (e.g., during administration of study drug 
or within 24 hours after the end of injection of study drug) 

Summary statistics and changes from baseline to post-baseline for laboratory 
testing and vital signs by dose group will be presented.

Results of C1 INH antibody testing will be reported for individual subjects and 
summarized as appropriate. 
7.5
Other Endpoints
Results of the EQ-5D-Y health status questionnaire will be presented in accordance with the 
EQ-5D-3L User Guide (version 4.01), and adapted as appropriate for the youth version.
7.6
Pharmacokinetic and Pharmacodynamic Analyses
Concentrations of C1 INH antigen, functional C1 INH activity, and complement C4 for 
individual subjects will be determined.  Results will be summarized using descriptive 
                                                
1
EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L questionnaire.  Version 4.0, April 
2011.  Published by the EuroQol Group Executive Office on behalf of the EuroQol Group.

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statistics (number, mean, standard deviation, median, minimum, and maximum) for values at 
each time point and for change from baseline at each post-injection time.
PK/PD analyses will be performed based on correlation of plasma concentrations of C1 INH 
antigen, functional C1 INH, and C4 complement in conjunction with various safety 
parameters (e.g., selected AEs, clinical laboratory results, antibodies generation, frequency, 
severity, or anatomic location of the angioedema attack, etc.).  Correlations that will be 
analyzed will be determined based on observed data.
8.0
DRUG SUPPLIES
CINRYZE and supplies required for CINRYZE reconstitution will be provided by the 
Sponsor.
8.1
How Supplied
CINRYZE is supplied as a lyophilized powder of 500 U (C1 INH)/vial.  The vial of 
CINRYZE also contains the following inactive ingredients:  trisodium citrate, sodium 
chloride, L-Valine, L-Alanine, L-Threonine, and sucrose.
CINRYZE product and sterile water for injection(s) (SWFI) approved for commercial 
distribution in the US will be used at all sites.  The US sourced vials of CINRYZE will be 
stored at 2oC–25oC (36oF–77oF) and protected from light.  Do not freeze.
8.1.1
Reconstitution of CINRYZE for Intravenous Infusion
Each vial of CINRYZE will be reconstituted with 5 mL of 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.  
Each infusion will require reconstitution of one (1) or two (2) 500 U vials depending on 
treatment scheduled (Treatment A [500 U] or Treatment B [1000 U]; see separate Pharmacy 
Manual).  The solution must be used within 3 hours of reconstitution.

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8.2
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 eCRF.  In addition, 
records must be kept on when and how many study drug vials were dispensed for each 
individual subject in the trial.  Reasons for departure from the expected dosing regimen must 
also be recorded in both source documents and the eCRF.  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. 
8.3
Drug Labels 
Drug will be labeled in accordance with applicable regulatory requirements.
9.0
ADVERSE EVENTS
An AE is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, 
disease, or laboratory or physiological observations occurring in a subject participating in a 
clinical study with study drug, regardless of causal relationship.  An AE includes any 
condition that (1) was not present prior to study therapy but appeared following initiation of 
study therapy or (2) was present prior to study therapy, but worsened in severity and/or 
frequency following initiation of study therapy.  NOTE:  In this study, angioedema attacks 
after the first dose of study drug will be reported as AEs.  
Adverse events will be monitored from the first dose of study drug in Treatment Period 1 
through 1-week post-treatment.  The Investigator will follow a subject with any AE until the 
event is either resolved or assessed as stable and, where appropriate, additional written reports 

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will be provided.  The Investigator will evaluate and report the onset date, outcome, end date, 
duration (if <24 hours), severity (intensity), relationship to study drug, actions taken, and 
determination of seriousness for each AE.  In addition, the Investigator will report if the AE 
onset occurred during study drug administration or within 24 hours following completion of 
study drug administration.  
9.1
Severity (Intensity) Assessment
The severity (intensity) of AEs will be assessed according to the following definitions:

Mild:  The AE is noticeable to the subject but is easily tolerated and does not 
interfere with routine activity.  The AE may or may not require medication therapy 
or other therapy.

Moderate:  The AE interferes with routine activity but usually responds to 
medication therapy or other therapy.

Severe:  The AE significantly limits the subject's ability to perform routine 
activities and may not respond to medication therapy or other therapy.  
If the intensity of an AE changes over time, the maximum intensity experienced should be 
recorded.  
9.2
Relationship to Study Drug
The Investigator will determine the relationship between an AE and the study drug using his 
or her clinical judgment and the following definitions.
Associated With the Use of Study Drug
There is a reasonable possibility that the event may have been caused by the study drug, as 
follows:

Definitely Related:  The event follows a reasonable temporal sequence relative to 
the administration of the study drug, and there is no other cause to explain the 
event (or the event reappears after repeat exposure [positive re-challenge]). 

Probably Related:  The event follows a reasonable temporal sequence relative to 
the administration of the study drug, and the event is more likely to be explained 
by the study drug than by another cause. 

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
Possibly Related:  The event follows a reasonable temporal sequence relative to 
the administration of the study drug, but could have been due to another cause 
such as the subject’s clinical state or other drugs/therapies. 
Not Associated With the Use of Study Drug
There is not a reasonable possibility that the event may have been caused by the study drug, 
as follows:

Unlikely to be Related:  The temporal sequence of the event relative to the 
administration of the study drug makes a causal connection improbable, or the 
event could plausibly be explained by another cause such as the subject’s clinical 
state or other drugs/therapies.

Not Related:  Sufficient information exists to indicate that the event is unrelated 
to the study drug.  For example, the event does not follow a reasonable temporal 
sequence relative to the administration of the study drug, a causal relationship is 
considered biologically implausible, or the event is readily explained by another 
cause such as the subject’s clinical state or other drugs/therapies.
9.3
Serious Adverse Events
An SAE is any AE that results in any of the following outcomes:

Death.

A life-threatening event (refers to any AE that places the subject at immediate risk 
of death from the event as it occurred; a life-threatening event does not include an 
event that, had it occurred in a more severe form, might have caused death, but as 
it actually occurred, did not create an immediate risk of death).

Inpatient hospitalization or prolongation of an existing hospitalization 
(hospitalization refers to an overnight admission).  Emergency room (ER) visits 
are not considered serious until any of the other serious outcomes are met.  Any 
elective hospitalization for a pre-existing condition that has not worsened does not 
constitute an SAE.

A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.

A congenital anomaly/birth defect.

Other medically important events that, based upon appropriate medical judgment, 
jeopardize the subject or may require intervention to prevent any of the above 
serious outcomes (e.g., a subject is treated in the ER but is not admitted to the 
hospital).

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Serious adverse events must be reported to Shire VIROPHARMA Drug Safety.  Contact 
information, including telephone and fax numbers, will be provided in the study procedures 
manual.  The Investigator, study coordinator, other designated study personnel, or CRA will 
report SAEs within 24 hours of becoming aware of the event.  Investigators will report all 
SAEs occurring up to 30 days after the last dose of study drug to Shire VIROPHARMA and 
their respective IRA according to local reporting requirements.  If there is any doubt whether 
an AE qualifies as an SAE based on the definitions above, the Investigator should contact the 
Sponsor.  In addition, SAEs with an onset more than 30 days after the last dose of study drug 
should be reported if considered by the Investigator to be related to study drug (i.e., possibly, 
probably, or definitely associated with the use of study drug; see Section 9.2).
If an AE is assessed as serious, all SAE information must be recorded using the SAE form 
(paper or electronic) provided by the Sponsor.  Additional follow-up information (e.g., test 
results, physician narrative, discharge summary, autopsy findings) will be provided to 
supplement the SAE report, with additional follow-up SAE reports submitted as needed.  A 
copy of all initial and follow-up SAE reports, including supplemental documents, will be 
maintained by the Sponsor.  
All suspected unexpected serious adverse reactions (SUSARs) will be reported by the 
Sponsor to the relevant competent authorities in accordance with the European Directive 
2001/20/EC, US FDA regulation 21CFR312.32, and additional relevant regulatory authorities
in accordance with country-specific regulations, as applicable.
9.3.1
Reference Safety Information
For study sites in countries where CINRYZE has received marketing approval for HAE, the 
approved country product label will serve as the Reference Safety Information (RSI). For 
study sites in countries where CINRYZE has not received marketing approval, the company 
core data sheet will serve as the RSI.

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9.4
Other Reportable Events
Certain events that occur in the absence of an AE should be reported to Shire VIROPHARMA
Drug Safety as other reportable events using the Other Reportable Information form (paper or 
electronic) provided by the Sponsor.  These include the following:

Pregnancy exposure (subject becomes pregnant while taking study drug).  Should 
a female subject (or the female partner of a male subject) become pregnant during 
the study, the subject will inform the Investigator.  The subject will be asked to 
follow up with the study site to report the eventual outcome of the pregnancy.  
This information will be tracked by Shire VIROPHARMA Drug Safety.

Lactation exposure (subject was taking study drug while nursing an infant)

Accidental exposure (someone other than the study subject was exposed to study 
drug)

Overdose (subject received more than the prescribed dose of study drug within a 
given timeframe)

Other medication errors that potentially place subjects at a greater risk of harm 
than was previously known or recognized (e.g., study drug was administered 
intramuscularly instead of intravenously)
9.5
Recording Adverse Events
All AEs must be recorded in the appropriate section of the eCRF.  To improve the quality and 
consistency of AE data, Investigators should observe the following general guidelines:

Standard medical terminology should be used rather than colloquial expressions or 
abbreviations.  

Whenever possible, the AE should be evaluated and reported as a diagnosis rather 
than as individual signs or symptoms.  If a definitive diagnosis is not possible, the 
individual signs and symptoms should be recorded.

If an AE requires a surgical or diagnostic procedure, the illness leading to the 
procedure should be recorded as the AE, not the procedure itself.

Angioedema attacks:  Any angioedema attacks that occur after the first dose of 
study drug will be recorded as an AE or SAE, as appropriate.

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10.0
STUDY MONITORING
The study will be carefully monitored by Shire VIROPHARMA authorized individuals, acting as 
Shire VIROPHARMA agents with respect to current Good Clinical Practice and standard 
operating procedures 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 (e.g., AEs, clinical laboratory tests, vital signs, 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.   
11.0
DATA HANDLING
Site staff will enter data into a 21 CFR Part 11 compliant eCRF built and programmed by 
Shire VIROPHARMA personnel.  Data will be reviewed via programmed edit checks triggered 
by site data entry and manual data validation performed by Shire VIROPHARMA’s Clinical 
Data Management group according to current standard operating procedures (SOPs).  Data 
discrepancies found during data review will be resolved through queries created within the 
eCRF database (automatic or manual) and answered by site staff.  Coding of medical 
terms/conditions and medications will be performed by Shire VIROPHARMA’s Medical Coding 
Group utilizing the versions of the MedDRA and WHO Drug dictionaries currently at use by 
Shire VIROPHARMA at the time of the study.
Only individuals with the appropriate user role and training will be granted access to the 
eCRF.  All training must be documented and tracked via Shire VIROPHARMA’s SOP and 
electronic database training policy.  Database security is maintained by the use of a unique 
username and password combination for each approved user, along with user verification 
checks at set intervals.  All database user administration is performed by Shire 
VIROPHARMA’s eCRF Support Group.  Database hosting services will be performed by the 
eCRF software vendor.  For Study 0624-301, eCRF software and hosting services will be 

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provided by Medidata Solutions, New York.  Validation certificates for software vendors are 
on file at Shire VIROPHARMA.
At database lock, all user roles will be changed to ‘read only’ and no further updates to the 
database will be allowed.  Database close-out documentation will be created by Shire 
VIROPHARMA’s eCRF Support Group and compact discs containing subject data entered into 
the database will be sent to each site’s primary Investigator.  
12.0
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 International 
Conference on Harmonisation (ICH) Tripartite Guideline for Good Clinical Practice and 
applicable regulatory requirements.
13.0
SUBJECT CONFIDENTIALITY
Investigator and his/her staff will be required to manage patient 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, the IRA
approving the study, as well as any applicable regulatory authorities, will be granted access to 
the study patients' 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, subject identity will remain confidential.
14.0
INFORMED CONSENT
The ICH has issued guidelines to provide protection for human subjects in clinical 
investigations.  The ICH Tripartite Guideline for Good Clinical Practice 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.

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A properly executed, written permission statement (i.e., informed consent) shall be obtained 
from each parent/legal guardian and assent shall be obtained from the child (to the extent that 
is compatible with the subject’s understanding) 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 IRA for review and approval prior to 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, FDA regulations, and local IRA 
requirements, as well as state and local law.  
15.0
INDEPENDENT REVIEWING AUTHORITY APPROVAL
The IRA 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 IRA that is 
adequately constituted to provide assurance of that protection will be utilized by each 
investigative site participating in the study.
The IRA will be provided with all appropriate material, including a copy of the informed 
consent/assent for review.  The trial will not be initiated at an investigational site until written 
approval of the research plan and the informed consent/assent document is obtained from the 
appropriate IRA and copies of these documents are received by Shire VIROPHARMA.  

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Appropriate reports on the progress of this study will be made to the IRA in accordance with 
applicable government regulations and in agreement with policy established by the Sponsor.
16.0
PUBLICATION POLICY
Investigator’s right to publish study results is addressed in the clinical trial agreement between 
Investigator and Sponsor.  

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17.0
INVESTIGATOR'S STATEMENT (PROTOCOL 0624-301)
A Phase 3, Multicenter, Randomized, Single-blind, Dose-ranging, Crossover Study to 
Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE®
(C1 esterase inhibitor [human]) for the Prevention of Angioedema Attacks in Children 
6 to 11 Years of age With Hereditary Angioedema.
In conducting this clinical trial, I agree to be responsible for:
1. Ensuring that the clinical investigation is conducted according to the signed Form 
FDA 1572 Statement of Investigator (applies to all studies conducted under a US 
IND).
2. Protecting the rights, safety, and welfare of subjects under my care.
3. 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 guidelines and all applicable government regulations.  These guidelines and 
regulations include, but are not limited to:
4. Permission to allow Shire VIROPHARMA (or its designee) and FDA, 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 as 
soon as possible thereafter (no later than 1 week).
5. Submission of the proposed clinical investigation, including the protocol and informed 
consent/assent form, to a duly constituted Independent Reviewing Authority (IRA) for 
approval, and acquisition of written approval for each, prior to the use of the study 
drug.
6. 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 IRA.  
Reference of such will be provided in source documentation.
7. Submission of any proposed protocol amendment to the IRA.  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 IRA 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 IRA approval 
may be obtained by expedited review.
8. Adherence to the study protocol.  For potential inclusion/exclusion criteria protocol 
deviations, submission for approval to Shire VIROPHARMA prior to enrollment of study 

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subjects.  Documentation and explanation of individual post-enrollment protocol 
deviations will be recorded on the appropriate eCRF page or provided in letters to 
Shire VIROPHARMA.
9. Notification to Shire VIROPHARMA of all serious adverse events, regardless of 
relationship to study drug, as specified in the protocol.  Notification to the IRA of 
serious adverse events as specified in the protocol and per additional guidelines as 
provided by the IRA.
10. Notification to IRA of all unanticipated problems within timeframes provided by the 
IRA.  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.
11. 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.
12. Submission of timely progress reports to the IRA and Shire VIROPHARMA at 
appropriate intervals not to exceed 1 year and submission of a final report to the IRA
within 3 months after the completion, termination, or discontinuation of the clinical 
investigation. 
13. 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.
In addition, I agree to provide all the information requested in the eCRF presented to me by 
Shire VIROPHARMA by carefully following the completion guidelines provided as part of the 
eCRF.
If I opt to terminate, the foregoing shall equally apply.
Investigator’s Name (Please Print)
Investigator’s Signature
Date

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18.0
LIST OF REFERENCES
Agostoni and Cicardi, 1992.
Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and 
clinical characteristics in 235 patients. Medicine (Baltimore). 1992; 71(4):206-215.
Agostoni et al., 1980.
Agostoni A, Bergamaschini L, Martignoni G, Cicardi M, Marasini B. Treatment of acute 
attacks of hereditary angioedema with C1-inhibitor concentrate. Ann Allergy. 1980; 
44(5):299-301.
Bergamaschini et al., 1983.
Bergamaschini L, Cicardi M, Tucci A, et al. C1 INH concentrate in the therapy of 
hereditary angioedema. Allergy. 1983; 38(2):81-84. 
Bork et al., 2000.
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W. Asphyxiation by laryngeal edema in 
patients with hereditary angioedema. Mayo Clin Proc. 2000; 75(4):349-354. 
Bork et al., 2006.
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning 
symptoms, affected organs, and course. Am J Med. 2006; 119(3):267-274. 
Caballero, 2012.
Caballero T. Angio-oedema due to hereditary C1 inhibitor deficiency in children.  Allergol 
Immunopathol (Madr).  2012; Mar 12. [Epub ahead of print]
Frank et al., 1976.
Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and 
its management. Ann Intern Med. 1976; 84(5):580-593. 
Farkas et al., 2002.
Farkas H, Harmat G, Füst G, Varga L, Visy B. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol. 2002; 13(3):153-161.
Farkas et al., 2007.
Farkas H, Jakab L, Temesszentandrási G, et al. Hereditary angioedema: a decade of human 
C1-inhibitor concentrate therapy. J Allergy Clin Immunol. 2007; 120(4):941-947.

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Gadek et al., 1980.
Gadek JE, Hosea SW, Gelfand JA, et al. Replacement therapy in hereditary angioedema: 
successful treatment of acute episodes of angioedema with partly purified C1 inhibitor. N 
Engl J Med. 1980; 302(10):542-546.
Gompels et al., 2005.
Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. 
Clin Exp Immunol. 2005; 139:379-394.
Logan and Greaves, 1984.
Logan RA, Greaves MW. Hereditary angio-oedema: treatment with C1 esterase inhibitor 
concentrate. J R Soc Med. 984; 77(12):1046-1048. 
Lumry et al., 2013.
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.
Noyes and Edwards, 2011.
Noyes J, Edwards RT. EQ-5D for the assessment of health-related quality of life and 
resource allocation in children: a systematic methodological review. Value Health. 2011; 
14(8):1117-1129.
Nzeako et al., 2001.
Nzeako UC, Frigas E, Tremaine WJ. Hereditary Angioedema: a broad review for 
clinicians. Arch Intern Med. 2001; 161(20):2417-2429.
Späth et al., 1984.
Späth PJ, Wüthrich B, Bütler R. Quantification of C1-inhibitor functional activities by 
immunodiffusion assay in plasma of patients with hereditary angioedema - evidence of a 
functionally critical level of C1-inhibitor concentration. Complement. 1984; 1(3):147-159.
Wall and Frank, 1990.
Wall RT, Frank M. Reply, Use of purified C1 esterase inhibitor in patients with hereditary 
angioedema. Anesthesiology. 1990; 72(5):957.
Wahn et al., 2012.
Wahn V, Aberer W, Eberl W, et al. Hereditary angioedema (HAE) in children and 
adolescents – a consensus on therapeutic strategies. Eur J Pediatr. 2012; 171(9):1339-
1348.
Waytes et al., 1996.
Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-
heated C1 inhibitor concentrate. N Engl J Med. 1996; 334(25):1630-1634.

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Zuraw, 2003.
Zuraw BL. Diagnosis and management of hereditary angioedema: an American approach.  
Transfus Apher Sci. 2003; 29(3):239-245.
Zuraw, 2008.
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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APPENDIX I:
PROCESSING OF SAMPLES FOR ANALYSES OF 
C1 INH ANTIGEN, C1 INH FUNCTION, 
C4 COMPLEMENT, AND C1 INH ANTIBODIES IN 
HUMAN PLASMA
Plasma samples will be analyzed for C1 INH antigen, functional C1 INH, C4 complement, 
and antibodies to C1 INH according to time points in Schedules 2, 3, 4 and 5.  Details of the 
methods and results will be provided in the clinical study report.  Samples for these analyses 
will be collected as follows:
1. A total of 4 mL of venous blood will be collected via venipuncture or through an 
indwelling venous catheter into pre-chilled K3EDTA-tubes at each sampling time 
point.  

If an indwelling catheter with a heparin lock is used to collect the sample, first 
flush the line, collect 1 mL of blood and properly discard, the next 4 mL of 
blood should be collected in tube containing K3EDTA. 
2. The K3EDTA tubes should be kept cold and centrifuged as soon as possible after 
collection.  Place the tubes on wet ice until the samples can be centrifuged.  Centrifuge 
the samples at 1800 to 2000 times gravity (at 4ºC if possible) for 15 ± 2 minutes.  
Immediately transfer the resulting plasma as follows:

Transfer the plasma equally between the 2 pre-chilled plastic transfer tubes.  
Carefully remove the plasma from the cells, avoiding contamination of plasma 
with white cells or platelets, since these may contribute enzymes that will 
falsely elevate measurements.  Tubes should be appropriately labeled using 
labels supplied by the Sponsor.

The plasma must be stored frozen at −70ºC or colder ideally within 
30 minutes of collection.  If necessary, samples can be stored on slushy ice for 
up to but not exceeding 4 hours.  Samples should never be stored at -20ºC.  In 
addition, thawing and re-freezing can also lead to ex vivo cleavage of 
complement components and spurious production of activation products.  
Therefore, samples cannot be allowed to thaw until analysis.  Samples are to be 
assayed on the first thaw.

All deviations to the collection procedures should be recorded and be included 
in the documentation with the sample shipment to the analytical laboratory. 

All shipping instructions will be provided in a separate laboratory manual. 
CAUTION!  Samples for complement testing are sensitive to cold inactivation.  
Samples must be stored at −70°C or colder.  

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One set of plasma samples for each subject will be shipped frozen on dry ice to the analytical 
laboratory using shipping containers supplied by the Sponsor.  The other set of samples will 
be stored frozen at −70°C or below and shipped to the laboratory following the 
schedule/instructions provided in the laboratory manual.
All samples will be analyzed within the established stability for the samples and will be 
properly 
disposed 
of 
after 
they 
have 
exceeded 
their 
established 
stability. 

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APPENDIX II:
RECOMMENDED PROCEDURES FOR SUSPECTED VENOUS THROMBOEMBOLISM 
OR OTHER THROMBOTIC OR THROMBOEMBOLIC EVENTS