Clinical trial NCT01359969
Conditions: Hereditary Angioedema
Keywords: Hereditary Angioedema HAE Angioedema Recombinant C1 Inhibitor rhC1INH Pediatrics
Sponsor: Pharming Technologies B.V.
Start date: 2012-01-17; Completion date: 2017-07-17
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label study is being conducted to confirm the safety, pharmacokinetic profile and efficacy of Ruconest at a dose of 50 U/kg when used for the treatment of acute angioedema attacks in patients, from 2 up to and including 13 years of age.

Detailed description:
This study was an open-label, Phase 2, non-comparative, multinational, multicenter clinical study in pediatric patients from 2 up to and including 13 years of age, with a confirmed diagnosis of HAE. Patients were eligible for treatment with recombinant human C1-inhibitor (rhC1INH) if they presented to the clinic within 5 hours of onset with an acute attack of at least moderate severity without signs of spontaneous regression. Patients received rhC1INH at a dose of 50 U/kg body weight up to a maximum of 4200 U. The reconstituted solution was administered as a slow intravenous (iv) injection over approximately 5 minutes. The patients remained in hospital and were closely monitored in the study center for at least 4 hours after study medication administration.

Arms: arm 1: Patients presented to the clinic within 5 hours of onset received rhC1INH 50 U/kg body weight up to a maximum of 4200 U.
Interventions: intervention 1: rhC1INH
Intervention descriptions: intervention 1: Patients up to 84 kg will receive one i.v. injection of Ruconest at a dose of 50 U/kg. The reconstituted solution should be administered as a slow i.v. injection over approximately 5 minutes. Patients of 84 kg body weight or greater will receive one i.v. injection of Ruconest at the dose of 4200 U (2 vials).

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
COPYRIGHT AND PROPERTY OF PHARMING 
CLINICAL STUDY PROTOCOL 
Open-label, phase II, single arm study to evaluate the 
safety, immunogenicity, pharmacokinetics and efficacy of 
recombinant human C1 inhibitor for the treatment of acute 
attacks in pediatric patients with hereditary angioedema,
from 2 up to and including 13 years of age 
Short title: Safety of Ruconest in 2-13 year old HAE patients 
C1 1209 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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PROTOCOL TITLE: Open-label, phase II, single arm study to evaluate the safety, 
immunogenicity, pharmacokinetics and efficacy of recombinant human C1 inhibitor 
for the treatment of acute attacks in pediatric patients with hereditary angioedema, 
from 2 up to and including 13 years of age 
 
Protocol ID 
C1 1209 
Short title 
Safety of Ruconest in 2-13 year old HAE patients 
Version 
Final incorporating amendment 4 
Date 
10 June 2014 
Sponsor:  
Pharming Technologies B.V. 
Darwinweg 24 
2333 CR Leiden 
The Netherlands 
Project Manager 
: 
 
Phone 
: 
 
Fax 
: 
 
E-Mail 
: 
 
 
Director Clinical Research : 
 
 
Phone 
: 
 
E-Mail 
: 
 
 
Coordinating investigator 
per country 
A list of participating clinical centers and responsible 
investigators will be kept up to date in the Trial Master File 
Clinical Research 
Organization  
PSR Group B.V. 
Crown Business Center Schiphol 
Planetenweg 5 
2132 HN Hoofddorp 
The Netherlands   
Project Manager : 
 
Phone 
: 
 
Fax 
:
 
E-Mail 
: 
  


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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Medical Monitor 
 
Darwinweg 24 
2333 CR Leiden 
The Netherlands 
Phone 
: 
 
E-mail 
: 
 
Safety Reporting 
 
VIGILEX B.V., 
Archimedesweg 17 
2333 CM Leiden 
The Netherlands 
 
Fax 
: 
 
Email 
: 
 
Laboratory organization 
QPS Netherlands B.V. 
Petrus Campersingel 123, 
9713 AG Groningen 
The Netherlands 
Contact 
: 
 
Phone 
: 
 
Fax 
: 
 
E-mail 
: 
 
 




Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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CONFIDENTIAL 
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INVESTIGATOR’S AGREEMENT 
 
 
Open-label, phase II, single arm study to evaluate the safety, immunogenicity, 
pharmacokinetics and efficacy of recombinant human C1 inhibitor for the 
treatment of acute attacks in pediatric patients with hereditary angioedema, 
from 2 up to and including 13 years of age 
 
The information contained in this document is CONFIDENTIAL and, except to the extent 
necessary to obtain informed consent, may not be disclosed unless such disclosure is 
required by government regulation or state/local customs or law. Persons to whom the 
information is disclosed must be informed that the information is CONFIDENTIAL and not be 
further disclosed by them. 
 
By my signature below I agree to conduct this clinical trial in accordance with Good Clinical 
Practice, the Declaration of Helsinki, government regulations and state/local customs or laws, 
including those applying to institutional/ethics review and informed consent. I have read the 
Investigator’s Brochure and protocol. I agree to ensure the confidentiality of my patients; 
however I agree to make available to the CROs, the Sponsor of this clinical trial, and relevant 
regulatory authorities, my patients’ medical records. I am aware of my responsibilities as 
investigator. 
 
 
Name 
Signature 
Date 
Investigator: 
 
 
 
 
 
 
 
 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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1 
TABLE OF CONTENTS 
 
AUTHORIZED SIGNATURE PAGE AND AGREEMENT OF GCP COMPLIANCE 
4 
INVESTIGATOR’S AGREEMENT 
5 
1 
TABLE OF CONTENTS 
6 
2 
LIST OF ABBREVIATIONS 
9 
3 
SYNOPSIS 
11 
4 
INTRODUCTION AND RATIONALE 
14 
4.1 
Introduction 
14 
4.2 
Rationale 
15 
5 
OBJECTIVES 
16 
6 
STUDY DESIGN 
17 
7 
STUDY POPULATION 
18 
7.1 
Population (base) 
18 
7.2 
Inclusion criteria 
19 
7.3 
Exclusion criteria 
19 
7.4 
Differential Diagnosis of Abdominal Pain 
20 
7.5 
Sample size calculation 
20 
8 
TREATMENT OF PATIENTS 
21 
8.1 
Intervention 
21 
8.2 
Co-medication 
21 
8.2.1 
Disallowed Concomitant Medication 
21 
8.2.2 
Rescue medication 
22 
9 
INVESTIGATIONAL MEDICINAL PRODUCT 
23 
9.1 
Name and description of investigational medicinal product 
23 
9.2 
Summary of findings from non-clinical studies 
23 
9.2.1 
Pharmacological characteristics 
23 
9.2.2 
Summary of animal experiments 
23 
9.3 
Summary of findings from clinical studies 
23 
9.4 
Summary of known and potential risks and benefits 
28 
9.4.1 
Expected adverse events during the study 
28 
9.4.2 
Rare adverse events during the study 
28 
9.4.3 
Antidotes 
28 
9.5 
Description and justification of route of administration and dosage 
29 
9.6 
Preparation and labeling of Investigational Medicinal Product 
29 
9.7 
Drug accountability 
30 
10 METHODS 
31 
10.1 Study parameters 
31 
10.1.1 
Main study parameter 
31 
10.1.2 
Secondary study parameters 
31 
10.1.3 
Other study parameters 
31 
10.2 Study procedures 
32 
10.2.1 
Assessment of safety 
32 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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10.2.2 
Blood sampling procedures and parameters 
34 
10.2.3 
Assessment of efficacy 
35 
10.2.4 
Study visit procedures 
36 
10.3 Withdrawal of individual patients 
40 
10.4 Replacement of individual patients after withdrawal 
40 
10.5 Follow-up of patients withdrawn from treatment 
40 
10.6 Subject and Study Stopping Rules 
41 
10.7 Premature termination of the study 
41 
10.8 End of study 
41 
11 SAFETY REPORTING 
42 
11.1 Definition and Handling of Adverse and Serious Adverse Events 
42 
11.1.1 
Adverse Events 
42 
11.1.2 
Adverse Event Intensity 
43 
11.1.3 
Adverse Event Relatedness 
43 
11.1.4 
Serious Adverse Events 
43 
11.1.5 
Reporting Serious Adverse Events 
45 
11.2 Adverse Events of Special Interest 
45 
11.3 Follow-up of Adverse Events 
46 
11.4 Pregnancy 
46 
11.4.1 
Pregnancy Test and Use of Contraception 
46 
11.4.2 
Pregnancy Notification and Follow Up 
46 
11.5 Data Safety Committee 
47 
12 STATISTICAL ANALYSIS 
48 
12.1 Analysis sets 
48 
12.2 Variables 
48 
12.3 Statistical methods 
49 
12.3.1 
General considerations 
49 
12.3.2 
Screening data 
49 
12.3.3 
Safety data 
49 
12.3.4 
Efficacy data 
51 
13 ETHICAL CONSIDERATIONS 
52 
13.1 Regulation statement 
52 
13.2 Recruitment, written consent and assent 
52 
13.3 Benefits and risks assessment 
53 
13.4 Compensation for injury 
53 
13.5 Incentives 
53 
14 ADMINISTRATIVE ASPECTS AND PUBLICATION 
54 
14.1 Access to Source Data and Documents 
54 
14.2 Quality Control and Quality Assurance 
54 
14.2.1 
Study Center Visits and Periodic Monitoring 
54 
14.2.2 
Audit and Inspection 
55 
14.3 Confidentiality of Patients’ Data 
55 
14.4 Data handling and Record Keeping 
55 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
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14.4.1 
Responsibilities 
55 
14.4.2 
Information of Investigators 
55 
14.4.3 
Case Report Forms 
56 
14.4.4 
Changes to Case Report Form Data 
56 
14.4.5 
Investigator Site File 
56 
14.4.6 
Provision of Additional Information 
56 
14.5 Changes in the Conduct of the study 
56 
14.5.1 
Protocol Amendments 
56 
14.6 Annual Reporting 
57 
14.7 Clinical Study Report 
57 
14.8 Publication Policy 
57 
15 SUMMARY OF CHANGES FROM PROTOCOL VERSION 09 NOVEMBER 2012 TO 
PROTOCOL VERSION 10 JUNE 2014 
58 
16 REFERENCES 
59 
17 APPENDICES 
60 
Appendix A: Schedule of Assessments C1 1209 
60 
Appendix B: Visual Analogue Scales 
61 
Appendix C: Treatment Effect Questionnaire 
66 
Appendix D: Investigator Score 
68 
Appendix E: Pharmaceutical instructions 
69 
Appendix F: List of Definitions 
70 
Appendix G: Definitions of Tanner Stages 
73 
 


Pharming Technologies Protocol C1 1209 
 
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2 
LIST OF ABBREVIATIONS  
 
AAE 
Acquired angioedema 
ACE 
Angiotensin converting enzyme 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
AEOSI 
Adverse event of Special Interest 
ALT 
Alanine transaminase 
Anti-HRI 
Antibodies against host related impurities 
Anti-rhC1INH 
Antibodies against recombinant human C1 inhibitor 
AST 
Aspartate transaminase 
BW 
Body weight 
C1INH 
C1 inhibitor 
CA 
Competent authority 
CRF 
Case report form 
CRO 
Clinical research organization 
CT 
Computed tomography 
CV 
Curriculum Vitae 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
EU 
European Union 
EudraCT 
European drug regulatory affairs clinical trials  
FFP 
Fresh frozen plasma 
GCP 
Good clinical practice 
HAE 
Hereditary angioedema 
HRI 
Host related impurities 
i.v. 
Intravenous  
IB 
Investigator’s Brochure 
IC 
Informed consent 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product  
IMPD 
Investigational medicinal product dossier  
IRB 
Investigational review board 
IS 
Investigator score 
ITT 
Intention to treat 
LDH 
Lactate Dehydrogenase 
MASP2 
Mannan-associated serine protease 2 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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MCV 
Mean corpuscular volume 
OPL 
Oro-pharyngeal-laryngeal  
OLE 
Open label extension 
OTC 
Over the counter 
pdC1INH 
Plasma-derived C1 Inhibitor 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-protocol 
QA 
Quality assurance 
RBC 
Red blood cell count 
RCT 
Randomized controlled trial 
rhC1INH 
Recombinant human C1 inhibitor 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
Serpin 
Serine protease inhibitor 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent adverse event 
TEQ 
Treatment Effect Questionnaire 
TTBR 
Time To Beginning of Relief 
TTMS 
Time To Minimal Symptoms 
VAS 
Visual analog scale 
WBC 
White Blood Cell count 
WFI 
Water for injection 
 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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3 
SYNOPSIS 
Rationale:  
The recombinant human C1 inhibitor (rhC1INH) clinical trials have evaluated 424 attack 
treatments in 155 HAE patients. The clinical and laboratory data demonstrate that rhC1INH 
represents an effective and well tolerated therapeutic option for the treatment of acute 
angioedema attacks in HAE patients. 
C1INH deficiency is present at birth, and symptoms usually become apparent in the first or 
second decade of life. Patients typically experience minor swelling in childhood that may go 
unnoticed, with increased severity of symptoms around the time of puberty. 
As a genetic disease, acute attacks of hereditary angioedema have the same pathophysiology in 
children and adults. Also as in adults, treatment with plasma-derived C1INH has been the 
standard of care for acute angioedema attacks in children for several decades. Recently, 
Ruconest was approved in Europe for the treatment of acute angioedema attacks in adults.  
In previous studies, adolescents have been exposed to Ruconest without concerns about either 
efficacy or safety. However, no clinical trial data are available related to Ruconest exposure in 
patients under 14 years of age.  
The main focus of this study is to collect data on safety and to identify eventual potential risks in 
pediatric HAE patients, to whom the product might be administered. 
In this Phase II, open-label study, the aim is to assess the safety and efficacy of Ruconest for the 
treatment of acute HAE attacks in patients, from 2 up to and including 13 years of age.  
Results of this clinical study will help evaluating the clinical benefit of Ruconest in this specific age 
group. 
 
Objectives:  
To assess the clinical safety, immunogenicity, and tolerability of Ruconest in the treatment of 
acute angioedema attacks in 2-13 year old HAE patients.  
To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of Ruconest in the treatment 
of acute angioedema attacks in 2-13 year old HAE patients.  
To assess the efficacy of Ruconest in the treatment of acute angioedema attacks in 2-13 year old 
HAE patients. 
 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
12 of 74 
CONFIDENTIAL 
COPYRIGHT AND PROPERTY OF PHARMING 
Study design:  
An open-label, non-comparative phase II, multinational, multi-center clinical study. 
HAE patients from 2 up to and including 13 years of age will be screened for eligibility and 
enrolled. 
Patients will be eligible for treatment with Ruconest if they present to the clinic within 5 hours of 
onset with an acute attack of at least moderate severity (Investigator Symptoms score (IS) of at 
least 3) without signs of spontaneous regression. 
The patient will remain in hospital and closely monitored in the study center for at least 4 hours 
after study medication administration.  
For safety evaluation, prior to and at Day 28 after study medication administration, a blood 
sample will be drawn for routine laboratory parameters. In addition to monitoring of vital signs 
(prior to and 30 min, 1, 2 and 4 hours after study medication administration), an ECG will be 
recorded prior to and between 30 minutes and 2 hours after study medication administration.  
The evolution of the acute angioedema attack will be monitored by the administration of patient 
questionnaires (Visual Analog Scale (VAS) and Treatment Effect Questionnaire (TEQ)) at 30 min, 
1, 2, 4, 8, and 24 hours, and the Investigator Score (IS) at 30 min, 1, 2 and 4 hours post study 
medication administration.  
For PK/PD evaluation, blood samples will be collected prior to the first treated attack, and at 5 
minutes and between 2 and 4 hours following the first study medication administration.  
Four (4) hours after study medication administration the patient may be discharged from the clinic 
if the investigator judges the patient's condition well enough. The investigator will schedule a 
telephone contact at 24h (± 4 hours) after study medication administration. Follow up visits are 
planned at D28 (±3 days) and D90 (±7 days).  
Multiple attacks can be treated, provided there is a minimum 24 hour interval between 
subsequent treated attacks and with a maximum of 10 attacks in the study, and as long as anti-
rabbit epithelium (dander) IgE testing remains negative. Patients can therefore be treated beyond 
the age of 13. 
 
Study population:  
Patients from 2 up to and including 13 years of age, suffering from hereditary angioedema 
(baseline plasmatic levels of C1INH activity < 50%).  
The criteria for the diagnosis of HAE will consist of a medical history confirmed by laboratory 
investigations.  
 
Intervention:  
One intravenous (i.v.) injection of Ruconest at the dose of 50 U/kg, for patients up to 84 kg; one 
i.v. injection of Ruconest at the dose of 4200U (2 vials) for patients of 84 kg body weight or 
greater.  
The reconstituted solution should be administered as a slow i.v. injection over approximately 5 
minutes. A second dose can be provided, at the investigator’s discretion, in case of insufficient 
therapeutic response. However, not more than two doses should be administered within 24 hours.  


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
13 of 74 
CONFIDENTIAL 
COPYRIGHT AND PROPERTY OF PHARMING 
 
Main study parameters:  
Safety and tolerability by standard criteria (vital signs, ECG, adverse events, routine laboratory 
safety parameters and immunogenicity (anti-host related impurities (HRI) and anti C1INH 
antibodies) 
Efficacy parameters and endpoints (time to beginning of relief, time to minimal symptoms, time to 
complete resolution) 
Pharmacokinetic and pharmacodynamic parameters (C1INH activity and C4 in plasma) during 
treatment for the first attack. 
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
All study-related procedures must be hosted in a familiar environment in facilities selected for 
childcare: the staff must be trained in communicating to and looking after (young) children and 
their legal representatives. All study-related procedures (e.g. blood samplings) will be optimized 
and modeled in order to minimize risk and distress. Age appropriate information will be given to 
the child and his/her representatives prior to any investigations or procedures. Eventual changes 
in the procedures will be announced to them well in advance. 
The level of risk may evolve over time, during the study and with evolving knowledge; as a 
consequence, Pharming Technologies B.V. (the Sponsor) will continuously monitor this aspect. 
By regularly reviewing accumulated outcome data from the pediatric clinical trial program the 
continuing safety of current participants and those yet to be enrolled will be ensured, as well as 
the continuing validity and scientific merit of the study.  
To date, the only significant clinical risk associated with Ruconest is the possibility of allergic 
reaction. To reduce the risk of a drug-induced allergic reaction, all study patients are tested for 
IgE against rabbit epithelium (dander). Only patients who have been shown to have negative 
results for such test should be treated with Ruconest.  


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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CONFIDENTIAL 
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4 
INTRODUCTION AND RATIONALE 
4.1 
Introduction 
HAE is a rare genetic disorder caused by a deficiency in functional endogenous C1INH activity 
with an estimated prevalence of 1 out of 50,000(1). There is no known difference in its prevalence 
across ethnic groups(1, 2) or gender. In most patients, clinical symptoms begin in childhood or 
adolescence; the mean age at onset of the disease is 11.2 years(3). The European Register of 
Hereditary Angioedema, following a survey of 1168 HAE patients from 10 European Union (EU) 
states, reported a median age of symptom onset of 11 years (range 0 to 86 years), and a median 
age of HAE diagnosis of 26 years (range 0 to 90 years)(4). 
Over 150 different mutations of the affected C1INH gene causing HAE have been described, with 
all mutations resulting in reduced C1INH activity(1). All these mutations result in either HAE type I 
or HAE type II. In HAE type I, there are reduced circulating levels of the C1INH protein and 
C1INH activity in patients’ plasma. The median level of C1INH activity in individuals with HAE 
type I is about 20% of normal. In HAE type II, a dysfunctional mutant C1INH protein with no or 
reduced activity is transcribed from the mutated gene. This leads to reduced C1INH activity, with 
C1INH antigenicity levels that are normal or increased. The clinical manifestations of HAE type I 
and II are the same, therefore, in clinical practice, there is no distinction made between HAE 
types I and II. In untreated patients, a diagnosis of HAE is confirmed by the presence of reduced 
C1INH activity levels and low levels of plasma complement component 4 (C4). 
The frequency of acute angioedema attacks varies widely across the HAE population. Patients 
have reported as few as 0 and as many as 50 attacks per year. In one large case series, 31% of 
patients reported <1 attack/year, 23% between 1-5 attacks/year, and 46 % ≥6 attacks/year. The 
frequency of attacks is not associated with the specific genetic mutation causing HAE, or with 
circulating C1INH activity or complement levels. Attacks may be precipitated by physical trauma, 
psychological stress, infection, estrogens or medications, notably ACE (angiotensin converting 
enzyme) inhibitors(5). 
Patients with HAE experience episodic, recurrent acute attacks of angioedema, which are 
characterized by local swelling of soft tissues. Most attacks occur as single attacks, but 10 to 15% 
of attacks occur at multiple anatomical locations at the same time. Acute angioedema attacks 
may occur in the submucosal tissues of the gastrointestinal tract (“abdominal attacks”), vocal 
cords and larynx (“laryngeal attacks”), in the oropharynx (“oropharyngeal attacks”), and in the 
urogenital region (“urogenital attacks”). Attacks may also be localized in the subcutaneous tissues 
of the face (“facial attacks”) or of the arms or legs (“peripheral attacks”). Observed differences 
between locations in time to relief appear to be related to differences in rate of fluid reabsorption, 
and not to any difference in pathophysiology. In the absence of treatment, the swelling due to an 
acute angioedema attacks worsens slowly but relentlessly over the first 24 hours, then gradually 
subsides over the subsequent 48 to 72 hours(1). Acute angioedema attacks in HAE patients impair 
the quality of life, and can be fatal if the angioedema swelling occurs in the larynx and upper 
airways. An untreated attack can persist for up to five days, and may require hospitalization for 
treatment of dehydration and pain management or even intubation(6). 
C1INH is a serine protease inhibitor (serpin), and is the major inhibitor of several complement 
proteases and contact-system proteases. Episodes of acute angioedema in patients with HAE 
result from an insufficient plasma level of functional C1 inhibitor, which allows the plasma 
proteolytic cascades such as complement and contact systems, to become more readily 
activated. This leads to episodic generation of several vasoactive substances such as bradykinin, 
which enhance vasopermeability. The clinical manifestation of this episodic increase in vascular 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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permeability is the occurrence of acute angioedema attacks(1). Administration of a C1INH product 
normalizes C1INH activity and results in the control of complement and contact systems and the 
resolution of symptoms(7). 
A summary of known and potential risks and benefits of the study product is included in section 
9.4. More detailed information is available in the Investigators Brochure (IB). A summary of 
findings from non-clinical and clinical studies can be found below in sections 9.2 and 9.3. 
 
4.2 
Rationale 
Ruconest has been approved in the 27 EU countries plus Norway, Iceland, Liechtenstein and 
Israel for the treatment of acute HAE attacks in adults. Only plasma-derived C1INH products are 
currently labeled for treatment of the pediatric population.  
Results of this clinical study will help evaluate the balance of benefits and risks of Ruconest within 
this specific age group. A description and justification of the route of administration, dosage, 
dosage regimen, and treatment periods of the study medication formation is included in section 
9.5. 
Given the demonstrated efficacy in adults, the disease process being similar in adults and 
children and taking into account that Ruconest is a replacement therapy, the outcome of the 
therapy is likely to be comparable. An analysis of 16 adolescents ranging from 14-17 years of age 
having been treated for a total of 50 HAE attacks in previous studies does not suggest any 
difference in PK, clinical efficacy or safety, including immunosafety between this sub-population of 
adolescents and the overall population studied. Therefore, the current study is considered to be a 
clinical investigation with low risk while presenting the prospect of direct clinical benefit to the 
study participant. 
In this Phase II open-label study, the primary aim is to assess the safety of Ruconest, especially 
when treating acute attacks of HAE, in pediatric patients from 2 up to and including 13 years of 
age. 
 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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5 
OBJECTIVES 
Primary Objective:  
• 
to assess the clinical safety, immunogenicity and tolerability of Ruconest in the treatment of 
acute angioedema attacks in 2-13 year old HAE patients 
Secondary Objectives:  
• 
to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of Ruconest in the 
treatment of acute angioedema attacks in 2-13 year old HAE patients 
• 
to assess the efficacy of Ruconest in the treatment of acute angioedema attacks in 2-13 year 
old HAE patients 
 


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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6 
STUDY DESIGN 
This study is an open-label, Phase II, non-comparative clinical study in pediatric patients from 2 
up to and including 13 years of age, with a confirmed diagnosis of HAE.  
The study will continue until at least 20 patients have been administered with Ruconest for at 
least one acute HAE attack. 
Patients will be eligible for treatment with Ruconest if they present to the clinic within 5 hours of 
onset with an acute attack of at least moderate severity IS of at least 3) without signs of 
spontaneous regression. 
The patient will remain in hospital and closely monitored in the study center for at least 4 hours 
after study medication administration.  
For safety evaluation, prior to and at Day 28 after study medication administration, a blood 
sample will be drawn for routine laboratory parameters. In addition to monitoring of vital signs 
(prior to and 30 min, 1, 2 and 4 hours after study medication administration), an ECG will be 
recorded prior to and between 30 minutes and 2 hours after study medication administration.  
The evolution of the acute angioedema attack will be monitored by the administration of patient 
questionnaires (Visual Analog Scale (VAS) and Treatment Effect Questionnaire (TEQ)) at 30 min, 
1, 2, 4, 8, and 24 hours, and the Investigator Score (IS) at 30 min, 1, 2 and 4 hours post study 
medication administration.  
For PK/PD evaluation, blood samples will be collected prior to the first treated attack, and at 5 
minutes and between 2 and 4 hours following the first study medication administration.  
Four hours after study medication administration the patient may be discharged from the clinic if 
the investigator judges the patient's condition well enough. The investigator will schedule a 
telephone contact at 24h (± 4 hours) after study medication administration. Follow up visits are 
planned at D28 (±3 days) and D90 (±7 days).  
Multiple attacks can be treated, provided there is a minimum 24 hour interval between 
subsequent treated attacks and with a maximum of 10, and as long as anti-rabbit epithelium 
(dander) IgE testing remains negative. Patients can therefore be treated beyond the age of 13. 
A schedule of trial assessments can be found in Appendix A. 
If a new attack is treated before completing the follow-up visits for the previous attack, the D28 or 
D90 visit schedule will be reset based on the most recent treatment. Multiple attacks can be 
treated, provided there is a minimal interval of 24 hours between subsequent treated attacks. 


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7 
STUDY POPULATION 
7.1 
Population (base)  
Male and female patients, from 2 up to and including 13 years of age with a clinically suspected 
and/or confirmed diagnosis of HAE will be recruited for this study. Patients will be identified and 
invited to participate by the investigators at the respective study centers, if possible in close 
collaboration with the existing HAE Associations and/or other patient organizations and/or other 
referring physicians. 
The criteria for the diagnosis of HAE will consist of a medical history supported by central 
laboratory investigations. The medical history of patients may include: 
• 
self-limiting, non-inflammatory subcutaneous angioedema, without urticaria, often 
recurrent and often lasting more than 12h and/or 
• 
recurrent self-remitting abdominal pain without clear organic etiology, often recurrent and 
often lasting more than 6h and/or 
• 
recurrent laryngeal edema 
• 
family members with recurrent angioedema and/or abdominal pain and/or laryngeal 
edema 
A central laboratory will confirm the diagnosis of HAE, defined as: 
• 
<50% of normal levels of C1INH activity 
Secondary laboratory data supporting the diagnosis of HAE are: 
• 
not abnormally low levels of C1q 
• 
absence of C1INH auto antibodies (anti-C1INH IgM and IgG) 
The results of secondary laboratory parameters in plasma collected at screening serves to 
exclude from the study patients with evidence for acquired angioedema (AAE) (by a level of 
C1INH activity <50% of normal, together with a low level of C1q and/or presence of anti-C1INH 
antibodies).  
Patients will be qualified for recruitment in advance and will be instructed to report to the clinical 
centre as quickly as is safely possible at the onset of symptoms of an acute attack. The diagnosis 
of an HAE attack will be made by the investigator based on patient’s and physician’s experience 
and judgment, and the results of physical examination.  
The results of non-invasive diagnostic procedures deemed necessary to exclude other 
pathologies (e.g. cholecystitis, pancreatitis, nephrolithiasis, appendicitis, peritonitis, salpingitis, 
trauma, allergies) and/or the results of study specific safety laboratory investigations should be 
recorded in the CRF. The results of the tests will thus serve to further ensure that a correct 
diagnosis of an HAE attack has been made.  
Patients who present to a study center within 5 hours of onset of an attack of angioedema will be 
evaluated for eligibility by the investigators, based on the clinical presentation of the patient’s 
angioedema symptoms. The investigator will use a scoring tool for each affected anatomical 
location (see form in appendix D), based on a variety of symptoms associated with swelling (such 
as pain and/or respiratory complaints and/or abdominal discomfort and/or urination problems 
depending on the location). An HAE attack in a patient with HAE will be considered eligible if the 
investigator's score at this location at this time of evaluation is at least 3 (moderate symptoms) 


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and there is no evidence of regression of angioedema symptoms prior to treatment. A severity 
score of 4 corresponds to severe symptoms, whereas the highest score of 5 represents a life-
threatening situation. 
If the patient has arrived at the study center within the 5 hour time-frame, but the IS score is less 
than 3 at first evaluation by the investigator, then additional IS scores may be collected within the 
5 hour time-frame from the onset of symptoms. If a significant increase in symptom severity at 
any localization occurs, the time-point within the 5 hour time-frame at which the IS score is at 
least 3 will be further referred to as the Presentation time point. 
 
7.2 
Inclusion criteria 
Screening 
• 
From 2 up to and including 13 years of age  
• 
Clinical and laboratory confirmed diagnosis of HAE (baseline C1INH activity <50% of normal) 
• 
Signed written informed consent (parental permission) signed by the legal guardian(s)  
 
Treatment 
• 
Clinical symptoms of an acute HAE attack 
• 
Onset of eligible symptoms within 5 hours from the moment at which medical evaluation to 
determine eligibility has occurred 
• 
IS score for at least one anatomical location at the time of initial evaluation of at least 3 
(moderate severity or greater) without signs of spontaneous regression 
• 
24h or more have passed since the patient’s last study treatment 
 
7.3 
Exclusion criteria 
Screening 
• 
A diagnosis of acquired C1INH deficiency (AAE) 
• 
A medical history of allergy to rabbits or rabbit-derived products (including rhC1INH, antisera), 
or positive anti-rabbit epithelium (dander) IgE test (cut off>0.35 kU/L in ImmunoCap® assay 
(Phadia, Sweden) or equivalent)  
• 
Treatment with investigational drug in another clinical study in the last 30 days 
• 
Any clinical significant abnormality in the physical examination and/or the routine laboratory 
assessments, that in the opinion of the Investigator makes the patient unsuitable for 
participation in the study 
• 
Patient or legal guardian whose decision to participate might be unduly influenced by 
perceived expectation of gain or harm by participation, such as patient or legal guardian in 
detention due to official or legal order 
• 
Any condition or treatment that in the opinion of the investigator might interfere with the 
evaluation of the study objectives 


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Treatment 
• 
Any changes since screening that would exclude patient based on above exclusion criteria. 
• 
10 HAE attacks were previously treated with study medication. 
• 
Suspicion for an alternate explanation of the symptoms other than an acute HAE attack. 
• 
Use of any disallowed concomitant medication since onset of acute HAE attack (see Section 
8.2.1). 
• 
Positive pregnancy test (urine or serum) 
 
7.4 
Differential Diagnosis of Abdominal Pain  
The investigator will diligently consider the patient’s history, review of systems, physical 
examination, and results of all available laboratory and non-invasive diagnostic tests to establish 
the likelihood that HAE is or is not the cause of the symptoms of the attack with which the patient 
acutely presents. It is recognized that the investigator may, in good faith, consider that HAE is 
responsible for a given attack, and if other criteria for eligibility are met, treat the patient within the 
intended 5 hr window. However, subsequently obtained laboratory test results may suggest that 
symptoms were not due to HAE. If these results are not available, the study medication will be 
administered as scheduled. It is recognized that results of these tests, and/or additional diagnostic 
testing may suggest that the symptoms are not due to HAE. Criteria suggesting alternate 
diagnoses may include: 
1. Total WBC above 20,000 or (segs + bands) above 15,000 
2. Fever (oral temp > 38° C) 
3. Amylase > 2.5 x upper limit of normal for that laboratory 
4. Free air under the diaphragm on KUB X-ray. 
5. Blood in urine or stool in patient in whom these tests were negative at the time of screening 
6. Definitive diagnosis established by any other means, including surgical intervention 
In case the diagnosis of an acute HAE attack is doubted, particularly in the presence of fever, it 
will be important to consider diagnoses other than HAE (e.g. acute abdominal emergencies), and 
perform additional examinations and tests to evaluate other possibilities. Ultrasound and/or other 
imaging procedures may be performed whenever necessary, at the discretion of the investigator, 
but should not be allowed to interfere with initiating treatment within 5 hr of onset. If another 
diagnosis is reached (after a patient has been treated); data for that patient will not be excluded 
from the intention to treat (ITT) analysis or safety and immunogenicity evaluations. 
7.5 
Sample size calculation 
No formal sample size was calculated; it was anticipated that an overall sample of at least 20 
completed patients is a sufficient dataset to meet the objectives of the study; this target number of 
patient is based on feasibility and agreed with the Paediatric Committee of the European 
Medicines Agency. The enrolment of patients will continue until at least 20 different patients are 
treated for at least one acute HAE attack, and the Sponsor determines that sufficient data have 
been collected on repeat treatments. 


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8 
TREATMENT OF PATIENTS 
8.1 
Intervention 
Patients up to 84 kg will receive one i.v. injection of Ruconest at a dose of 50 U/kg. The 
reconstituted solution should be administered as a slow i.v. injection over approximately 5 
minutes. Patients of 84 kg body weight or greater will receive one i.v. injection of Ruconest at the 
dose of 4200 U (2 vials). 
At the discretion of the investigator and depending upon the patient’s clinical response, an 
additional dose may be given to patients following their initial dose as specified above. Not more 
than two doses should be administered within 24 hours.  
 
8.2 
Co-medication 
After recruitment, the patients will in principle continue on the kind and dose of prophylactic 
medication prescribed for HAE that they are currently using. After recruitment, changes in kind 
and dose of maintenance therapy for HAE are only allowed after consultation with the 
investigator. 
The investigator, if possible in collaboration with the Sponsor, will evaluate the impact of any other 
drug treatment deemed necessary for HAE and/or an intercurrent condition after recruitment 
and/or after treatment with study medication.  
All concomitant medications (prescription and/or over-the-counter medications, herbal 
medications, preventative vaccines, vitamins and food supplements) and procedures must be 
recorded in the Case Report Form (CRF). A description of the type of drug or procedure, the 
amount, duration, reason for administration of drug, and the outcome of any procedures must be 
documented. Adverse Events (AEs) related to the administration of a concomitant medication or 
the performance of a procedure must also be documented on the appropriate AE page of the 
CRF.  
8.2.1 Disallowed Concomitant Medication 
Patients presenting with attacks who already have received any medication since the onset of the 
attack likely to interfere with the evaluation of efficacy and safety will not be eligible for treatment 
for this attack. These treatments include: 
• 
Narcotics 
• 
plasma-derived C1 inhibitor 
• 
Fresh frozen plasma 
• 
Bradykinin receptor antagonist 
• 
Analgesics 
• 
Anti-emetics 
• 
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 
As an exception, for the patient’s comfort, paracetamol may be taken, but not within 45 minutes 
before the administration of study medication. Any change in current and optional maintenance 
therapy (androgens and/or anti-fibrinolytics) from the time of the onset of the current attack is not 
allowed. The dosage of androgens and anti-fibrinolytics may not be increased earlier than 24 
hours after the treatment with study medication. 
To minimize impact on the assessment of safety, treatment with other investigational products is 
not allowed from screening until 30 days after the patient’s last follow-up visit has occurred. 


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8.2.2 Rescue medication 
An aim of this open label study is to evaluate the safety and efficacy of Ruconest in symptomatic 
HAE. Therefore, it is recommended to consider administering another dose of Ruconest as a first 
attempt of rescue medication, which is consistent with the SPC instructions. The use of additional 
treatment which might interfere with the evaluation of efficacy and safety is not allowed (exclusion 
criterion) prior to treatment with study medication (see section 8.2.1) and after the administration 
of study medication for as long as possible up to 8 hours. As specified in section 10.1.3, taking 
such additional treatment (other than Ruconest) between the onset of the attack and prior to time 
of initial relief of symptoms, will qualify that attack as "treatment failure". However, appropriate 
and urgent medical need will not be ignored nor withheld: the use of narcotics or other standard 
procedures for the treatment of HAE after treatment with study medication will be allowed at the 
discretion of the investigator.  
Situations in which the investigator may decide to install additional treatment and/or supportive 
measures after the administration of study medication include: 
1. Clear progression of symptom severity, with or without the occurrence of symptoms at new 
angioedema locations. 
2. Unacceptable degree of abdominal pain. 
3. Symptoms indicating life is threatened (respiratory and/or cardiovascular compromise), i.e. 
symptoms requiring immediate additional treatment. Patients developing a life-threatening 
attack (e.g. a laryngeal attack with respiratory and/or cardiovascular compromise) after the 
administration of study medication must also be treated with any treatment procedure 
(including intubation, tracheostomy) deemed necessary.  
4. AEs requiring specific treatment (e.g. in case of anaphylaxis). 
Pain medication, anti-emetics and fluid replacement may be used in case of acute attack(s), if 
needed. In case of therapeutic failure, rescue therapies (such as pdC1INH) or fresh frozen 
plasma may be administered, according to local clinical standards. 
All (escape) medications taken during acute episodes should be recorded on the CRF with 
indication, dose, timing and apparent response.  
All above guidelines are meant to prevent extreme discomfort to the patient during the study and 
to allow adequate and appropriate action to be taken when necessary. Actions unequivocally 
pertinent to patient care should always take priority over study interests. 


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9 
INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
Name and description of investigational medicinal product 
Ruconest 2100 U powder for solution for injection contains the active substance recombinant 
human C1 inhibitor (rhC1INH; conestat alfa) which is purified from the milk of rabbits expressing 
the gene encoding for human C1 inhibitor (C1INH). Each vial contains 2100 units of rhC1INH. 
The amino acid sequence of the recombinant form is identical to that of human C1INH. C1INH is 
a single-chain plasma glycoprotein of molecular mass 73,650 that belongs to the super family of 
serine protease inhibitors in plasma.  
C1INH is the only known inhibitor of activated subcomponents C1s and C1r of complement 
component 1 of the classical pathway of the complement system. In addition, C1INH inhibits the 
Mannan-Associated Serine Protease 2 (MASP2) of the lectin pathway of complement activation. 
Furthermore, it is the major inhibitor of activated factor XII, factor XI and kallikrein of the contact 
system in plasma. 
For further information please refer to the Investigator’s Brochure (IB) (13).  
 
9.2 
Summary of findings from non-clinical studies 
9.2.1 Pharmacological characteristics 
The inhibitory potency of rhC1INH towards the target proteases C1s, kallikrein, factor XIa and 
factor XIIa was found to be comparable with the inhibitory potency of human plasma-derived 
C1INH. In addition, no difference in inhibition of plasmin and thrombin was observed between 
rhC1INH and human plasma-derived C1INH. 
9.2.2 Summary of animal experiments 
Acute and repeated dose toxicology and pharmacology as well as local tolerance studies in rats, 
dogs and rabbits indicate that the preparation may be considered safe. rhC1INH was cleared 
more rapidly from the circulation of the rat and the dog in comparison with plasma-derived 
human C1INH. This faster clearance likely results from the differential and lower degree of 
glycosylation (e.g. less sialylation) in rhC1INH. For further information see the IB (13). 
9.3 
Summary of findings from clinical studies 
The development program of rhC1INH comprises a total of 714 exposures to rhC1INH in 190 
subjects. As can be seen from the table below, it not only concerns symptomatic patients for the 
treatment of acute attacks, but also healthy volunteers and asymptomatic patients. Each of these 
studies is separately discussed in this paragraph. 


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Study 
Study Population 
Number of Subjectsa 
Number of Administrations 
1202/1203 
Symptomatic HAE patients 
14 
21 
1205 RCT 
Symptomatic HAE patients 
25 
25 
1205 OLE 
Symptomatic HAE patients 
62 
168 
1304 RCT 
Symptomatic HAE patients 
16 
16 
1304 OLE 
Symptomatic HAE patients 
57 
194 
Subtotal 
Symptomatic HAE patients 
155 
424 
1101 
Asymptomatic HAE patients 
12 
24 
1106 
Healthy volunteer subjects 
14 
59 
1207 
Asymptomatic HAE patients 
25 
207 
Total all studies 
All populations 
190 
714 
a Because some subjects participated in more than one study, the total number of subjects is smaller than the number reached by 
adding the number of subjects in each of the individual studies. 
 
Study C1 1101-01 
In Study C1 1101-01, administration of escalating doses of rhC1INH (6.25 to 100 U/kg) to 12 
asymptomatic HAE patients resulted in dose-dependent increases of C1INH activity. Doses of 
rhC1INH of 50 U/kg and 100 U/kg were found to restore C1INH activity to normal levels (0.7 -1.3 
U/mL), while doses of 25 U/kg and lower did not. After administration of 50 U/kg rhC1INH, a Cmax 
of 1.36 U/mL is observed. Levels remain above 0.7 U/mL for approximately 2 hours and then 
subside to baseline levels in approximately 4 hours. rhC1INH was shown to be 
pharmacodynamically active in HAE patients through a dose-dependent decrease in the formation 
of C4b/c, the activation cleavage product of plasma complement C4. Doses of 100 U/kg and 50 
U/kg increased mean normalized levels of C4 relative to baseline, and cleavage of C4 resumed 
once C1INH activity levels fell below 0.7 U/mL. Doses of rhC1INH of 25 U/kg or lower only 
resulted in a temporary, minimal elevation of C4 levels relative to baseline. 
 
Studies C1 1202-01 and C1 1203-01 
Exploratory efficacy Studies C1 1202-01 and C1 1203-01 were undertaken in 14 symptomatic 
HAE patients, treated for 21 acute angioedema attacks.  
The treatment appeared safe and well-tolerated. No clinically significant AEs, changes in vital 
signs, safety laboratory parameters or antibody responses to C1INH or rabbit milk protein were 
observed. The PK findings from Study C1 1101-01 were confirmed in HAE patients treated with 
rhC1INH for an acute angioedema attack. Both patients and physicians evaluated treatment with 
rhC1INH as favorable compared to previous untreated attacks. The median time to the beginning 
of relief was 30 and 60 minutes, as reported by physicians and patients, respectively. The median 
time to minimal symptoms was 4 hours. All treated attacks resolved completely and no relapses 
occurred. No difference in response was observed on first and repeated treatments.  


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Study C1 1106-02 
In Study C1 1106-02, fourteen healthy volunteers were enrolled to receive rhC1INH at 100 U/kg 
on five occasions with intervals of approximately 3 weeks between doses. Serial PK sampling 
was performed following the first, third and fifth administrations of rhC1INH. After administration of 
rhC1INH the levels of C1INH activity peaked at median times of about 20-30 minutes and 
thereafter declined to endogenous levels in about 8 to 12 hours. No difference in PK profiles was 
observed following the 1st, 3rd, and 5th administrations of rhC1INH. 
One anaphylactic reaction occurred in an adult female participating in this study on first exposure 
to rhC1INH. This patient had a clinical history of rabbit allergy (not disclosed during the study pre-
consent screening procedure). The patient was also subsequently found to have a clinically 
significant IgE antibody level against rabbit epithelium (dander) allergens.  
No clinically significant changes in hematology, biochemistry, urinalysis, coagulation, vital signs or 
ECG parameters or physical examinations were noted in this study. 
 
Study C1 1207 
In Study C1 1207, an open-label exploratory phase II study, the safety and prophylactic effect of 
weekly administrations of rhC1INH was studied in asymptomatic HAE patients.  Twenty-five 
patients were enrolled and treated with rhC1INH at 8 weekly administrations of 50 U/kg and 
followed up for 42 days after the last administration. 
For the primary endpoint, the incidence of documented HAE attacks during the treatment period 
(breakthrough attacks), a median of 2 attacks over the 8 week period was found corresponding to 
an average of 0.25 attacks per week (range 0 to 1.5). This was lower than the reported history of 
HAE attacks over a two year period prior to entry in the study (0.6 attacks per week (range 0.5 – 
4.5)). 
Immunology testing revealed the presence of confirmed anti-rhC1INH antibodies in 2/25 patients, 
but no neutralizing antibodies. Confirmed antibodies against Host Related Impurities were found 
in 11/25 patients at any time point during the study without associated clinical symptoms. Thirty 
treatment-emergent adverse events were observed during the study in 13 patients, of which two 
were serious adverse events. Four adverse events, all mild in intensity, were considered possibly 
drug-related by the investigator. All other adverse events, including the serious adverse events, 
were assessed as not related to rhC1INH by the investigator. No events led to discontinuation of 
study medication. 
No trends in laboratory values were observed. All out or range and clinical significant laboratory 
parameters were related to adverse events, HAE attacks or concomitant disease. In addition, no 
trends were observed for vital signs, physical examinations or ECG. 
 
Study C1 1304-01 RCT 
In randomized, double blind, saline controlled clinical Study C1 1304-01 RCT, the efficacy and 
safety of rhC1INH 100 U/kg in the treatment of acute angioedema attacks in HAE patients 
compared to saline was evaluated. Thirty-two patients were randomized and treated in the study. 
For the primary endpoint, time to beginning of relief, a statistically significant difference was found 
between 100 U/kg and saline solution groups (62 and 508 minutes, respectively; p=0.003). 
Treatment with rhC1INH was also statistically significant in reducing the time to minimal 
symptoms compared to using saline solution (480 and 1440 minutes, respectively; p=0.005). The 


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analysis of therapeutic failures supported the efficacy of rhC1INH by demonstrating that 
significantly fewer patients in the rhC1INH group had failure compared with patients in the saline 
solution dose group.  
Treatment with rhC1INH did not result in changes in vital signs, ECG, routine clinical laboratory 
safety parameters, and no relevant antibody responses to C1INH or rabbit milk protein impurities 
were observed. No drug-related TEAEs were observed after treatment with rhC1INH. 
 
Study C1 1205-01 RCT 
In randomized, double blind, saline controlled clinical Study C1 1205-01 RCT, the efficacy and 
safety of rhC1INH 100 U/kg and 50 U/kg in the treatment of acute angioedema attacks in HAE 
patients compared to saline was evaluated. Thirty-eight patients were randomized and treated in 
the study. For the primary endpoint, time to beginning of relief, a statistically significant difference 
was found between 100 U/kg and 50 U/kg and saline solution groups (68, 122, and 258 minutes; 
p=0.001 and p < 0.001, respectively). The analysis of therapeutic failures supported the efficacy 
of rhC1INH by demonstrating that significantly fewer patients in the rhC1INH groups had failure 
compared with patients in the saline solution dose group.  
The majority of patients experienced no TEAEs or TEAEs that were mild or moderate in severity 
in all treatment groups. No possibly, probably or definitely related to study treatment SAEs 
occurred during the study. Treatment with rhC1INH did not result in changes in vital signs, routine 
clinical laboratory, safety parameters, and no clinically relevant antibody responses to C1INH or 
rabbit milk protein impurities were observed. 
 
Study C1 1304-01 OLE 
The C1 1304-01 OLE study allowed the open label extension treatment of acute angioedema 
attacks in HAE. In this study, HAE patients could be treated multiple times for subsequent new 
acute angioedema attacks. The initial rhC1INH treatment was a fixed dose of a single 2100 U vial. 
This initial fixed dose could be followed by an additional one or two 2100 U vial(s) at the discretion 
of the investigator and depending on the patient’s clinical response within 4 hours after 
administration of the initial treatment. 
Fifty-seven HAE patients received a total of 194 OLE treatments of acute angioedema attacks.  
Results of the primary endpoint, time to beginning of relief, showed a sustained efficacy of 
rhC1INH in repeated treatments for attacks 1 to 5 of 60, 65, 120, 60 and 61 minutes (Median time 
to beginning of relief using the overall VAS score). The apparent difference of the median time of 
attack 3 (120 min) is likely an artifact of the discrete assessment times, i.e. 60 minutes then 120 
minutes, based on the fact that the 95% confidence intervals for time to beginning of relief for 
attack 3 were similar to the other four attacks analyzed. 
Immunology testing revealed the presence of confirmed anti-rhC1INH antibodies in 4/57 patients 
at any time point during the study, but no neutralizing antibodies. Confirmed antibodies against 
Host Related Impurities were found in 3/57 patients at any time point during the study without 
associated clinical symptoms. 
Twenty-seven patients (47%) reported at least one treatment emergent adverse event, most of 
them mild to moderate in severity. Three adverse events were considered severe, but not related 
to study medication. Four patients experienced possibly related TEAE, as determined by the 
investigator, but none of them required any treatment. There was no increase in the number of 


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TEAEs with repeated treatments. Two SAEs were reported and were both considered as not 
related. None of the TEAEs led to death or study medication discontinuation. Treatment with 
rhC1INH did not result in changes in vital signs, ECG, and routine clinical laboratory safety 
parameters.  
Repeated treatments with rhC1INH appeared generally safe and well tolerated, and did not result 
in a change in adverse event profile or incidence. 
 
Study C1 1205-01 OLE 
The C1 1205-01 OLE study allowed the open label extension treatment of acute angioedema 
attacks in HAE. In this study, HAE patients could be treated multiple times for subsequent new 
acute angioedema attacks. The initial rhC1INH treatment was 50 U/kg with an option for an 
additional 50 U/kg at the discretion of the investigator and depending on the patient’s clinical 
response within 4 hours after administration of the initial treatment. 
Sixty-two HAE patients received a total of 168 OLE treatments of acute angioedema attacks.  
Results of the primary endpoint, time to beginning of relief, showed a sustained efficacy of 
rhC1INH in repeated treatments for attacks 1 to 5 of 63, 61, 37, 51 and 67 minutes (Median time 
to beginning of relief using the overall VAS score). The 95% confidence intervals of the repeated 
attacks are overlapping (30-124 min). 
Immunology testing revealed the presence of confirmed anti-rhC1INH antibodies in 2/62 patients 
at any time point during the study, but no neutralizing antibodies. Confirmed antibodies against 
Host Related Impurities were found in 2/62 patients at any time point during the study without 
associated clinical symptoms. 
Thirty-nine patients (63%) reported at least one treatment emergent adverse event, most of them 
mild to moderate in severity; 8 TEAEs were possibly related to treatment according to the 
investigator's opinion. Seven adverse events were considered severe in intensity, none of them 
assessed by the investigator as treatment related. Twenty-two SAEs were reported in 10 patients. 
Thirteen SAEs were HAE attacks in 7 patients. All SAEs resolved and none was related to 
treatment in the investigator's opinion except for a "hypersensitivity reaction" which was 
considered possibly related to treatment. Laboratory data suggest that the event was not an IgE-
mediated reaction.  
Repeated treatments with rhC1INH showed continued efficacy and appeared generally safe and 
well tolerated. 
 
Adolescent patients treated in the open label extension studies 
In the open label extension studies mentioned above, enrolment of adolescent patients was 
allowed, and this subset of data was separately evaluated. A total of 16 patients have been 
exposed to rhC1INH for a total of 50 treatments of an acute HAE attack, ranging from 14 to 17 
years of age at the time of treatment; 8 patients have been exposed to rhC1INH for at least three 
HAE attacks, 2 patients even up to 7 HAE attacks. 
Due to the different dosing strategies, there was a range in treatment doses, varying from 25 U/kg 
to 100 U/kg. As for the adult population, PK-data in adolescents indicated that a dose of 50 U/kg 
will restore deficient levels of C1INH activity into the normal range (70% to 130%).  


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In the adolescent subpopulation, across studies the medians were 45 minutes for the TTBR. 
These results, irrespective of attack number, are consistent with the overall observed outcomes, 
and do not indicate a need for different dosing strategy in adolescents compared to the adult 
population. 
Six patients (38%) reported at least one TEAE. All Adverse events were mild to moderate in 
severity. None of the recorded adverse events led to premature study discontinuation or death. 
Also, no Serious Adverse Events (SAE) were reported for these patients. No adverse effects were 
observed in vital signs, and none was observed suggesting hypersensitivity reactions or 
thrombogenicity. There were no treatment emergent antibodies. 
This information does not suggest any difference in PK, clinical efficacy or safety, including 
immunosafety between this sub-population of adolescents and the overall population studied.  
For detailed information of safety and effects of rhC1INH in each of the studies mentioned above, 
see the IB (13). 
 
9.4 
Summary of known and potential risks and benefits 
9.4.1 Expected adverse events during the study 
During clinical studies in symptomatic HAE patients, AEs during the study period may relate to the 
multitude of possible symptoms associated with an acute angioedema attack at one or more 
anatomical locations. In some cases it may be difficult to discern symptoms related to an attack 
with certainty from those related to the administration of rhC1INH. 
The safety data analyses from 424 exposures to rhC1INH showed that rhC1INH at doses of 50 
U/kg and 100 U/kg is generally safe and well tolerated (see IB for details). The adverse event 
profile found in the RCT analyses was similar for patients treated in the rhC1INH and saline 
treatment groups. The AE profile was the same across all rhC1INH doses analyzed. There was 
no increase in the incidence of TEAEs with higher rhC1INH dose, administration of additional 
rhC1INH doses for an attack, or with repeat treatment of subsequent attacks.  
To date, the only significant clinical risk associated with rhC1INH is the possibility of allergic 
reaction to host-related impurities (HRI). Only patients who have been shown to have negative 
results for IgE antibodies against rabbit epithelium (dander) should be enrolled in the study. 
It is notable that participation in clinical studies often results in headache, and also that hematoma 
and minor pain may occur as a result of the insertion of intravenous cannulas and venipunctures. 
Risks of these complications are minimized by use of experienced personnel.  
9.4.2 Rare adverse events during the study 
As with any medication, rare side effects cannot be excluded. 
9.4.3 Antidotes 
Specific antidotes against rhC1INH do not exist. For allergic reactions appropriate standard 
treatment regimens indicated by the clinical situation (e.g. epinephrine, antihistamines, 
corticosteroids, etc) will be administered. 
 


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9.5 
Description and justification of route of administration and dosage 
Ruconest has been developed and was approved in the 27 EU countries plus Norway, Iceland , 
Liechtenstein and Israel for the treatment of acute attacks of angioedema in adult patients with 
HAE due to C1 inhibitor activity deficiency. Because C1INH is a plasma glycoprotein, an 
intravenous route of administration has been chosen. 
The efficacy of Ruconest was demonstrated in two independently conducted RCTs in North 
America (Study C1 1205-01 RCT) and in Europe (Study C1 1304-01 RCT). The current study will 
provide further data on the safety and immunogenicity of Ruconest at a dose of 50 U/kg when 
used for the treatment of acute angioedema attacks in 2-13 year old HAE patients.  
Ruconest, at the dose of 50 U/kg body weight (and with a maximum of 4200 U), will be 
administered by slow intravenous injection over a period of approximately 5 minutes. This dose 
and method of administration appeared safe and well tolerated in previously treated patients with 
HAE, including 16 adolescent patients.  
 
9.6 
Preparation and labeling of Investigational Medicinal Product 
The Ruconest treatment solutions will be prepared from vials containing 2100 U of lyophilized 
rhC1INH. Each vial will be labeled and packed in a box. Ruconest will be labeled in accordance 
with regulatory requirements as follows: 
 
 
Sample of outer package label: 
 
Recombinant human C1 Inhibitor (rhC1INH) 
Batch Nr.: XXXXX - Expiry date: XX/XXX/XXXX 
Lyophilized powder. For intravenous infusion. 
2100 U/vial - Reconstitute with 14 mL WFI 
 Property of Pharming Technologies B.V. 
Darwinweg 24, NL-2333 CR, Leiden 
The Netherlands - T: 0031 (0) 715247400 
For clinical trial use only  
Protocol Nr.: C1 1209 
To Be Used By Qualified Investigator Only 
Investigator: XXXXXXX 
Store at 2-25 °C 
 


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Sample of vial label: 
 
 
Recombinant human C1 Inhibitor (rhC1INH)  
Protocol Nr.: C1 1209 
Property of Pharming Technologies B.V. - T: 0031 (0) 715247400 
Darwinweg 24, NL-2333 CR, Leiden, The Netherlands 
Batch Nr.: XXXXX - Expiry date XX/XXX/XXXX 
Lyophilized powder. For intravenous infusion. 
2100 U/vial - Reconstitute with 14 mL WFI 
For clinical trial use only  
To Be Used By Qualified Investigator Only 
Investigator; XXXXXXX 
Store at 2-25 °C (35.6-77°F) 
Clinical trial C1 1209 
Pharming Technologies B.V. 
 
Subject initials: 
 
X X X 
 
 
 
Subject number: 
 
X X X X X 
 
Each vial containing the lyophilized material will be reconstituted with 14 mL water for injection 
(WFI) prior to use.  
The preparations will be dispensed at the investigator’s clinical center or by the hospital pharmacy 
of each investigational center with labels containing information similar to the sample label above.  
For detailed pharmaceutical instructions, see Appendix E. 
 
9.7 
Drug accountability 
All study medication will be stored at the responsible investigator’s clinical center and/or the 
Department of Clinical Pharmacy of the various hospitals. Drug accountability will be performed 
and monitored according to ICH-E6(R1) "Guideline for Good Clinical Practice".  
As this study involves i.v. administration of the study medication administered by study personnel, 
patient compliance measures are not necessary. Study medication will be administered under 
direct supervision, according to the center’s standard operating procedures. Two members of the 
center clinical staff (who should include at least one physician) will check the medication label for 
agreement with the study number and the patient’s identity. Information with respect to volume of 
prepared and infused study medication will be documented. 


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10 
METHODS 
10.1 
Study parameters 
10.1.1 Main study parameter 
The primary objective is the assessment of safety and tolerability.  
This will be evaluated by recording of adverse events (spontaneously reported by the patient or 
observed by the investigator.  
Immunogenicity (for all attack treatments) will be evaluated by the following parameters: 
• 
antibodies against host related impurities (anti-HRI)  
• 
antibodies against recombinant human C1INH (IgG and IgM) anti-rhC1INH)  
• 
IgE antibodies against rabbit epithelium (anti rabbit epithelium IgE) 
10.1.2 Secondary study parameters  
At the first attack, pharmacokinetic and pharmacodynamic parameters will be evaluated for: 
• 
C1INH activity and C4.  
The following parameters will be determined: baseline level; Cmax; dose-normalized Cmax; Tmax; 
AUC above baseline; dose-normalized AUC; clearance; volume of distribution; elimination half-life 
(t½); Vmax; Km.  
Efficacy will be evaluated by  
• 
time to beginning of relief assessed by using the overall severity VAS, defined as the first time 
point with a decrease of at least 20 mm with respect to baseline at any eligible location, with 
persistence at the next time point (see section 10.2.3)  
• 
time to minimal symptoms assessed by using the overall severity VAS, defined as the first 
time point at which the overall severity VAS falls below 20 mm for each assessed location  
• 
time to beginning of relief assessed by using the IS-score defined as the first time point with a 
decrease of at least 1 point on the IS-score (investigator assessment) compared to baseline, 
at any eligible location. 
• 
time to minimal symptoms assessed by using the IS-score, defined as the first time point at 
which the IS-score is less than or equal to 1 point for all assessed locations 
All terms are defined in the List of Definitions in Appendix F. See section 10.2.3 for a detailed 
description of these efficacy parameters. 
10.1.3 
Other study parameters 
Safety variables after single and repeat treatment that will be subject to exploratory analysis: 
• 
vital signs 
• 
ECG 
• 
Routine clinical laboratory parameters 
Efficacy variables that will be subject to exploratory analysis: 
• 
time to beginning of relief based on questions 1 and 2 of the TEQ, defined as the first time-
point at which Question 1 is answered as a little better, better or much better and Question 2 


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is answered as yes for the most severe eligible location, with persistence of these responses 
at the next time point. 
• 
time to minimal symptoms on the basis of Question 3 of the TEQ, defined as the first time-
point at which Question 3 is answered as yes for all locations 
• 
time to complete resolution based on the time-point at which all symptoms at all locations 
have resolved 
• 
therapeutic failure: A patient will be assessed as having had a therapeutic failure if any of the 
following occurs:  
o 
time to the beginning of relief of symptoms for the attack based on the overall VAS occurs 
later than 4 hours after baseline 
o 
within 4 hours after beginning of treatment administration and after beginning of relief the 
overall VAS increases again to a value of at least the baseline score 
o 
the patient has occurrence of HAE at a new location within 4 hours after achieving 
beginning of relief of symptoms  
o 
the patient taking any of the medications that may interfere with the assessment of the 
impact of Ruconest on efficacy measures, between the onset of the attack and prior to 
time of initial relief of symptoms including:  
• 
Narcotics 
• 
plasma-derived C1 inhibitor 
• 
Fresh frozen plasma  
• 
Bradykinin receptor antagonist 
• 
Analgesics 
• 
Anti-emetics 
• 
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 
Any change in current and optional maintenance therapy (androgens and/or anti-
fibrinolytics) from the time of the onset of the current attack is not allowed. The dosage of 
androgens and anti-fibrinolytics may not be increased earlier than 24 hours after the 
treatment with study medication. 
For a detailed description and definition of used terms, see Appendix F. 
 
10.2 
Study procedures 
10.2.1 Assessment of safety 
This section describes all safety measurements recorded in this study; procedures for eliciting 
reports of adverse events / inter-current illness are further described in protocol section 11.1. 
10.2.1.1 
General safety measurements 
Vital signs including blood pressure (supine systolic and diastolic), pulse and body temperature), 
and ECG will be considered as general safety parameters.  
10.2.1.2 
Safety laboratory measurements 
Hematology and biochemistry 


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Samples for routine hematology and biochemistry assays will be collected prior to each infusion 
and at Day 28.The routine hematology and biochemistry assays will be performed by the clinical 
centre’s local laboratory.  
The samples will be analyzed for the following hematolgy parameters: ESR, hemoglobin, 
hematocrit, red blood cell count (RBC), MCV, MCH, MCHC, total white blood cell count (WBC), 
platelet count, differential WBC units, neutrophils, lymphocytes, monocytes, eosinophils and 
basophils.  
The samples will be analyzed for the following biochemistry parameters: sodium, potassium, 
chloride, calcium, inorganic phosphate, total protein, albumin, glucose, creatinine, AST, ALT, 
LDH, blood urea nitrogen, bilirubin (total), alkalinephosphatase, Gamma-GT, uric acid, total 
cholesterol, HDL cholesterol, Triglycerides, CRP and amylase. 
Pregnancy testing 
For female patients capable of bearing children (i.e. postmenarcheal girls), a urinary pregnancy 
testing for hCG will be performed prior to each treatment with Ruconest. Alternatively, serum hCG 
may also be performed to test for pregnancy as mandated by the clinical centre and/or Ethics 
Committee or when urine is not produced. 
 
10.2.1.3 
Diagnostic tests, PK/PD and immunological analyses 
Following collection, the samples will be kept and processed at room temperature. The eventual 
plasma aliquots should be immediately stored upright at or below -20 °C until shipment to QPS 
Netherlands BV, where sample analysis will be performed. Investigator manuals will be provided 
to each center detailing the procedures related to central laboratory sample handling and (dry ice) 
shipment. 
Diagnostic assays  
Blood samples for diagnostic assays will be collected at screening. The samples will be analyzed 
for the following parameters: C1INH activity, C1q, C4 and C1INH auto antibodies (IgM, and IgG 
anti-rhC1INH); C4 will also be analyzed at baseline of each attack. 
PK/PD assays 
Blood samples for PK assays will be collected prior to the first treatment, one blood sample 
directly following infusion (named T 5 min, from a vein in the contra-lateral arm) and another 
blood sample between 2-4 hours post-infusion. This sampling time points are considered the most 
useful schedule derived from modelling of adult data. The samples will be analyzed for C1INH 
activity and C4. 
Immunogenicity 
The presence of anti-C1INH IgG and IgM antibodies (tested against immobilized rhC1INH), and of 
antibodies against anti-HRI will be assessed. Cut-off values of each assay were previously 
determined using plasma samples from normal donors and hereditary angioedema patients not 
previously exposed to rhC1INH. Plasma samples found to have an antibody test result above the 
cut-off level of the assay will be tested in confirmatory assay(s): 
• 
Plasma samples above cut-off for anti-C1INH antibody will be tested in an anti-C1INH 
displacement assay, to determine whether or not increased values observed in the ELISAs 


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were due to specific or non-specific responses. Samples that are confirmed positive in the 
displacement assay will then be tested in an assay for neutralizing antibodies. 
• 
Plasma samples that show a response above the cut-off level in the initial anti-HRI ELISA will 
be tested in a displacement assay. 
These tests will be performed on samples obtained at screening, prior to each treatment with 
rhC1INH, and at the Day 28 and Day 90 follow up visits. If the new attack is treated before 
completing the follow-up visits for the previous attack, the D28 or D90 visit schedule will be reset 
based on the most recent treatment.  
These tests and antibody assays mentioned above will be performed by QPS Netherlands B.V. 
• 
C1INH activity will be determined as inhibitory activity against C1 esterase with a 
chromogenic assay.  
• 
C1q assays will be performed by nephelometry. This assay will be performed at screening to 
confirm the diagnosis of HAE and/or to exclude AAE. 
• 
Levels of C4 antigen will be determined by nephelometry. This will be performed at screening 
and at baseline of each attack to support the diagnosis of HAE.  
• 
Anti-rabbit epithelium (dander) and anti-cow milk IgE assays will be performed using a 
validated, commercially available system(8) (ImmunoCAP®, Phadia, Sweden; or equivalent. 
Prior to treatment with Ruconest a negative test for anti-rabbit epithelium (dander) (cut off 
<0.35 kU/L) should be documented. Anti-cow milk IgE will be tested once at screening. Anti-
rabbit epithelium (dander) IgE will be performed at screening, at the Day 28 follow-up visit of 
each attack, every year following screening, and if adverse events are observed indicative of 
hypersensitivity reactions. 
10.2.2 Blood sampling procedures and parameters 
It is recommended, for the sake of patient's comfort, to use butterfly needles and to place a 
catheter during the time of hospitalization for easy blood collection. Also, applying a topical 
anesthetic before catheter placement may be considered. 
For central laboratory testing, the amount of blood taken per patient has been carefully 
considered, to reduce the burden as much as possible. For diagnostic testing, PK/PD analyses, 
and immunology testing, depending on the need, either 1.8, 2.7 or 4.5 mL of venous blood will be 
collected at the designated time points (see below and Appendix A), i.e. by using the smallest 
citrate-tube available. The routine laboratory safety parameters will be assessed in the local 
laboratories, and the required blood volume may vary between laboratories. At the set-up of the 
study, special attention will be given to minimize the required blood volume for this routine safety 
testing. The estimated volumes below are considered the maximally required sample volumes 
based on 5 mL collection tubes. 
The typical amount of blood taken from a patient including a screening visit and following one 
HAE attack during the 90-day follow-up period will be a maximal volume of 30 mL according to 
the schedule below (see also appendix A). If subsequent attacks will be treated with the study 
medication, where PK/PD sampling is no longer scheduled, the volume of blood collection during 
the treatment period is estimated to account for a maximal volume of 25 mL for each additional 
attack. 
If a 2 year old child was followed up for a single HAE attack (assuming an otherwise healthy child 
with a weight of 12 kg, and a whole blood volume of 80 mL/kg BW) the total volume of removed 
blood over a 3 month period would account for 30/960=3.1% of total blood volume. For a 13 year 
old (assuming an average weight 44 kg and a whole blood volume of 75 ml/kg BW) this would be 




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Each of the VAS instruments provides a patient assessment of the intensity of a range of 
symptoms pertinent to a symptomatic anatomical location. The Abdominal VAS instrument 
measures the patient’s perceptions relating to four symptoms (illness, pain, bloatedness, and 
nausea), the OPL VAS instrument measures six symptoms (illness, pain, swelling, breathing, 
speech, and swallowing), the facial VAS instrument measure three symptoms (illness, pain and 
swelling), the Peripheral VAS instrument measures three symptoms (swelling, pain, and use of 
extremity), and the Urogenital VAS instrument measures five symptoms (illness, pain, swelling, 
nausea, and urination). Additionally, the last question for each attack location is an overall 
severity VAS for a global assessment of the intensity of the symptoms at that particular location. 
The wording of the overall severity VAS question is the same for each of the four anatomical 
location VAS instruments. Examples of the forms are attached as Appendix B. 
In addition to completing the VAS forms, patients will answer 3 questions related to the change in 
severity of their symptoms since the initial assessment. This Treatment Effect Questionnaire 
(TEQ) will be administered (following confirmation of eligibility) with the VAS for each symptomatic 
anatomical location. An example of the questionnaire is attached as Appendix C). If needed, 
depending on the patient's level of understanding, parents may assist in completion. 
In case of a new attack location, additional forms (VAS and TEQ) will be provided for the 
patient/legal guardian to complete and the time will be recorded. 
The patient should be observed for 4 hours in the hospital. After each assessment before 
discharge of the patient from clinical observation, the forms will be stored in the patient’s file and 
will not be available for review by the patient or parent/legal guardian or investigator to preserve 
non-biased assessment at each time point by both the patient and study physician. The exception 
to this will be the moment at which the investigator judges the patient's condition well enough for 
discharge from the hospital, enabling the investigator to verify the patient/parent scores.  
The assessment of the angioedema signs by the VAS and TEQ will be performed just before start 
of infusion, and at T30m, T1h, T2h, T4h, T8h and T24h after study medication infusion as shown 
in Appendix A. 
In a diary, dispensed at discharge from the hospital, the patient will be asked to record the 
moment at which all angioedema symptoms at all locations have resolved (complete resolution). If 
needed, depending on the patient's level of understanding, parents may assist in completion. 
The investigator will assess the severity of the patient’s angioedema symptoms using an IS for 
each affected anatomical location (see example in Appendix D). In case of a new attack location, 
additional IS-scores will be recorded. The investigator symptoms score will be assessed at 
presentation of the acute angioedema attack and at 30m, 1h, 2h, and 4h after study medication 
infusion as shown in Appendix A. All results of assessments will be documented in the CRF. 
10.2.4 Study visit procedures 
The sections below list the procedures to be performed for each of the planned time points, as 
shown in the Schedule of Assessment (see Appendix A).  


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10.2.4.1 
Screening Visit 
The following Screening procedures should be performed: 
• 
obtain written informed consent (parental permission) signed by the legal guardian(s)  
• 
record demographics (including gender, race, date of birth) 
• 
general medical history 
• 
perform physical examination (including height and weight), assessment Tanner Stage (see 
Appendix G) 
• 
record vital signs (supine blood pressure, pulse, body temperature) 
• 
obtain past relevant HAE history and HAE Attack history (including maintenance therapy or 
prophylaxis of HAE, total number of treatments with C1INH per year, type of attacks, number 
of attacks per year, impact on Quality of Life and social activities) 
• 
obtain the names of all current prescription and over the counter (OTC) medications, vitamins 
and supplements including start date, dosage, frequency, route, and indication for usage 
• 
obtain blood sample for the following evaluations by the central laboratory: 
o diagnostic confirmation (C1INH activity, C1q, C4 and C1INH auto antibodies (IgM and 
IgG anti-rhC1INH)) 
o anti-HRI antibodies and IgE antibodies against rabbit epithelium (dander) and cow-milk 
• 
verification of inclusion and exclusion criteria upon availability of all relevant (laboratory) data. 
Following the evaluation of a patients' eligibility, the study staff is requested to complete a patient 
screening form, and to send that (by fax or e-mail) to the CRO (PSR-group B.V) in order to keep 
them updated on the progress of patients' recruitment. 
10.2.4.2 
Treatment Visit 
An eligible patient may only be treated if the patient presents with an eligible attack. The patients 
will remain in hospital for 4-5 hours during a treatment visit. The procedures performed at 
subsequent treatment visits will be the same. 
Permitted deviations of actual sampling and assessment time points from those projected in the 
Schedule of Assessments will be within ten percent, calculated from t = 0 (start of study 
medication administration) to the relevant activity. The following procedures will be performed 
over a 4-5 hour period as follows: 
 


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At presentation of the attack: 
• 
assessment of current angioedema signs and evaluation of evolution since onset of 
symptoms, including investigator's symptom score 
• 
perform physical examination (including weight), assessment Tanner Stage (see Appendix G) 
• 
record vital signs (supine blood pressure, pulse, body temperature) 
• 
assess and record changes or additions in current prescription and OTC medications, 
vitamins and supplements including start date, dosage, frequency, route, indication for usage 
since the last study visit  
• 
assess and record if any medications previously reported as taken on an as needed basis 
(PRN) were taken since the onset of symptoms 
• 
record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since the last visit or last 
infusion, if applicable 
• 
evaluate all inclusion and exclusion criteria 
• 
12-lead ECG 
• 
blood sampling for routine laboratory safety parameters, PK/PD (only at first attack) and 
Immunological Analysis (C1INH auto antibodies (IgM and IgG anti-rhC1INH and anti-HRI) and 
C4. 
• 
pregnancy test (only for post-menarcheal female patients) 
• 
assessment of baseline angioedema signs by VAS-scales and TEQ just before infusion. 
 
Infusion (T=0h) 
• 
perform infusion of Ruconest 
 
Directly following infusion (T5 min) 
• 
blood sampling for PK (from a vein in the contra-lateral arm) 
 
30 minutes (± 3 min), and 1 hour (± 6 min), 2 hours (± 12 min) and 4 hours (± 24 min) post-
Infusion 
• 
assessment of current angioedema signs (patient's VAS, TEQ and IS-score)  
• 
record vital signs (supine blood pressure, pulse, body temperature) 
• 
12 lead ECG between 30 min and 2 hours 
• 
blood sampling for PK/PD between 2 and 4 hours post-infusion 
• 
record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since infusion 
• 
record changes in concomitant medication and/or need for rescue medication 
The patient should be observed for 4 hours in the hospital. After 4 hours, the investigator may 
decide to discharge the patient from the hospital if the patient’s condition is judged well enough. 
The investigator may consult the VAS-scores to verify if Time to Beginning of Relief has been 


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achieved. If the patient's condition is not well enough, the patient will remain in the hospital under 
the appropriate medical care.  
At hospital discharge 
• 
perform physical examination 
• 
Dispensation of diary, in which patients will be instructed to record any changes in their 
health 
condition 
and 
concomitant 
treatments 
following 
the 
study 
medication 
administration. Also, the time at which there is complete resolution of the angioedema 
attack symptoms has to be indicated 
• 
Dispensation of additional VAS and TEQ questionnaires. The patients will be instructed to 
continue completing the VAS-score and TEQ at T8h (± 1 hour) and T24h (± 4 hour) (i.e. at 
the time of the phone call). The 8 hour time point may be facilitated by a study 
coordinators phone call.  
The diary and questionnaires (VAS and TEQ) are to be returned on the visit at Day 28. If patients 
report, or if legal guardians notice, deterioration of HAE symptoms, the investigator should be 
contacted immediately. 
 
10.2.4.3 
Follow-up Visits 
 
At 24 hours (± 4h) following treatment administration, a phone call is made to the patient in order 
to: 
• 
assess HAE symptoms (registering localization, severity and time course) in order to 
document the further evolution of the acute attack (resolution, exacerbation, late relapse etc), 
including patient's VAS score and TEQ 
• 
remind about detailed completion of the diary for AEs, concomitant medication  
• 
ask patient if complete resolution of symptoms has occurred, and if so record the exact date 
and time in the CRF 
• 
record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since the last infusion 
• 
record changes in concomitant medication and/or need for rescue medication 
 
On Day 28 (± 3 days) following treatment administration, a center visit is scheduled, at which the 
following procedures are scheduled: 
• 
return of the diary including recording of time of complete resolution of symptoms 
• 
perform routine physical examination 
• 
blood sampling for Immunological Analysis and routine laboratory safety parameters 
• 
assess HAE history during preceding 28 days (e.g. occurrence of intercurrent HAE-episodes 
etc) 
• 
evaluate diary and record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since 
the last infusion 


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• 
evaluate diary and record changes in concomitant medication and/or need for rescue 
medication 
 
On Day 90 (± 7 days) following treatment administration, a center visit is scheduled, at which the 
following procedures are scheduled: 
• 
perform routine physical examination 
• 
record vital signs (supine blood pressure, pulse, body temperature) 
• 
blood sampling for Immunological Analysis 
• 
HAE history since previous treatment (e.g. occurrence of intercurrent HAE-episodes etc). 
• 
record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since the last infusion 
• 
record changes in concomitant medication and/or need for rescue medication 
 
Day 28 and Day 90 visits will occur following an occasion treated with Ruconest. If a new attack is 
treated before completing the follow-up visits for the previous attack, the D28 or D90 visit 
schedule will be reset based on the most recent treatment. In that case, the diary is to be returned 
and evaluated at the time the patient presents in the clinic with the new attack. 
 
Independent of the occurrence of eligible acute HAE attacks, a center visit is scheduled at every 
year (± 1 month) after screening at which the following procedures are scheduled: 
• 
blood sampling for IgE antibodies against rabbit epithelium 
• 
HAE history since previous visit, if applicable (e.g. occurrence of intercurrent HAE-episodes 
etc) 
• 
record and assess new AE/SAE’s or changes to ongoing AE/SAE’s since the last visit, if 
applicable 
• 
record changes in concomitant medication 
10.3 
Withdrawal of individual patients 
Patients can withdraw from the study at any time for any reason without any consequences. The 
responsible investigator can also discontinue study treatment if continuing such treatment is in 
his/her opinion deleterious for the patient’s well-being or for any other reason. 
10.4 
Replacement of individual patients after withdrawal 
There will be no replacement of patients after withdrawal. 
10.5 
Follow-up of patients withdrawn from treatment 
When a patient withdraws from the study a full medical examination (including blood sampling for 
routine safety and immunology analyses) will be performed and follow-up visits Day 28 and Day 
90 will be completed whenever possible. In case of treatment discontinuation because of severe 
or serious adverse events additional blood sampling for hematological, blood chemistry and urine 
laboratory tests or other special examinations may be performed. As described, such patients will 
continue to be followed as specified by the protocol unless they refuse such follow-up. Patients 


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who are withdrawn from treatment due to an AE will be monitored closely until resolution of the 
event or stabilization, at the discretion of the investigator.  
10.6 
Subject and Study Stopping Rules 
Subject stopping rule 
A subject who experiences a treatment-emergent anaphylactic/anaphylactoid reaction or a 
confirmed adverse event of special interest, as specified in section 11.2. will be withdrawn and the 
case will be reviewed, discussed with the treating investigator, and further evaluated as required. 
Study stopping rule 
Further enrollment into the study, and further Ruconest administration in all subjects, will be 
temporarily halted pending a review of the data by the Data Safety Committee if two patients 
experience a treatment-emergent anaphylactic/anaphylactoid reaction or a confirmed adverse 
event of special interest, as specified in section 11.2. Only after review of the relevant data by this 
committee, the study may be reinitiated. 
10.7 
Premature termination of the study 
Both the investigator and the Sponsor reserve the right to terminate the study at any time. Should 
this be necessary, the procedures will be arranged on an individual study center after review and 
consultation by both parties. In terminating the study, the Sponsor and the investigator will ensure 
that adequate consideration is given to the protection of the patients' interests. The pertaining 
Institutional Review Boards and authorities will be informed of any decision to halt, abandon or 
continue the study. 
10.8 
End of study 
The end of the study for a given center is defined as the date at which the last patient follow-up in 
that particular center occurs. The end of study in a given country is defined as the date at which 
the last patient follow-up in that particular country occurs. The global end of the study is defined 
as the date at which the last patient follow-up occurs in the last active center. 
 
 


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11 
SAFETY REPORTING 
11.1 
Definition and Handling of Adverse and Serious Adverse Events 
11.1.1 Adverse Events 
An AE is any undesirable physical, psychological or behavioral effect experienced by a patient 
during participation in an investigational study, in conjunction with the use of the drug or biologic, 
whether or not product-related. This includes any untoward signs or symptoms experienced by 
the patient from the time of signing of the informed consent until completion of the study.  
AEs may include, but are not limited to:  
• 
Subjective or objective symptoms spontaneously offered by the patient  
• 
and/or observed by the Investigator or medical staff  
• 
Findings at physical examinations  
• 
Laboratory abnormalities of clinical significance  
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of 
Ruconest are not considered AEs unless they reoccur after the patient has recovered from the 
preexisting condition or in the opinion of the Investigator they represent a clinically significant 
exacerbation in intensity or frequency.  
Clinical significance is defined as any variation in signs, symptoms, or testing that has medical 
relevance and may result in an alteration in medical care. The Investigator will continue to monitor 
the patient until the assessment returns to baseline or until the Investigator determines that follow-
up is no longer medically necessary. 
The Investigator is responsible for monitoring the safety of patients who have enrolled in the study 
and for accurately documenting and reporting information as described in this section.  
Patients and their legal guardians will be given a diary at discharge from the hospital to record 
any AE following administration of the study medication until follow-up visit Day 28. Also, they will 
be instructed to report to the Investigator any AE that is experienced by the patient.  
Investigators will pose non-leading questions about the occurrence of AEs at each visit. 
Investigators are required to document all AEs occurring during the clinical study, commencing 
with the signing of the ICF through the last follow-up visit (Day 90 after the last treatment).  
All AEs occurring following the signature of the ICF but prior to the first dose of Ruconest will be 
recorded.  
All AEs (including AEs described in the patient’s diary) will be recorded on designated CRF 
pages. Each AE is to be characterized (i.e., verbatim term) and information provided regarding its 
seriousness, start and stop dates, intensity, outcome, and causal relationship with Ruconest.  
It is important that investigators record accurate AE terms on CRFs. Wherever possible, a specific 
disease or syndrome rather than individual associated signs and symptoms will be identified by 
the Investigator and recorded on the CRF. However, if an observed or reported sign or symptom 
is not considered a component of a specific disease or syndrome by the Investigator, or is 
atypical, it should be recorded as a separate AE on the CRF.  
HAE attacks (not treated with study medication) will be recorded in a separate section of the CRF. 


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11.1.2 Adverse Event Intensity 
The Investigator will be required to assess the intensity of the adverse drug/biologic experience 
using the following categories to quantify intensity.  
• 
Mild: events require minimal or no treatment and do not interfere with the patient’s daily 
activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe: events interrupt a patient’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
• 
Life threatening: Potentially life-threatening or disabling. High-risk medical interventions.  
• 
Fatal: patient died 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. Adverse events characterized as intermittent 
require documentation of onset and duration of each episode. 
11.1.3 Adverse Event Relatedness 
The Investigator will make a judgment regarding whether or not, in his/her opinion; the AE was 
related to Ruconest. The Investigator will also evaluate any changes in laboratory values; make a 
determination as to whether the change is clinically important, and whether or not the changes 
were related to study medication. However, even if the Investigator feels there is no relationship 
to the study medication, the AE or clinically significant laboratory abnormality MUST be recorded 
on the CRF.  
Below are guidelines for relationship assessment:  
• 
Unrelated: There was no relationship of the adverse experience to the use of the drug 
or biologic. This may include, but is not limited, to the adverse experience being an 
expected outcome of a previously existing or concurrent disease, concomitant 
medication or procedure the patient experienced during their treatment period.  
• 
Possible: There was no clear relationship of the adverse experience to the use of the 
drug or biologic; however, one cannot definitively conclude that there was no 
relationship.  
• 
Probable: While a clear relationship to the drug or biologic cannot be established, the 
experience is associated with an expected adverse experience or there is no other 
medical condition or intervention which would explain the occurrence of such an 
experience.  
• 
Definite: The relationship of the use of the drug or biologic to the experience is 
considered definitively established.  
If a causal relationship is considered probable, possible, or definite by the Investigator, the AE is 
considered to be “related” for purposes of regulatory reporting.  
11.1.4 Serious Adverse Events 
Serious adverse events (SAEs) will be reportable from the time the patient signs the ICF through 
the last follow-up visit (Day 90 after the last treatment. Adverse events and serious adverse 


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events will not be collected in patients who sign the informed consent but are considered a screen 
failure. Investigators need to complete the Screen Failure CRF which will identify the reason for 
the screen failure. Patients terminated prematurely from the study due to withdrawal of consent 
will continue to be followed as specified by the protocol unless they refuse such follow-up. 
Patients who are withdrawn from treatment due to an adverse event will be monitored closely until 
resolution of the event or stabilization, at the discretion of the investigator. 
An SAE is any AE that results in any of the following outcomes:  
• 
Death  
• 
Life-threatening experience  
• 
Required or prolonged inpatient hospitalization  
• 
Persistent or significant disability/incapacity  
• 
Congenital anomaly  
• 
Important medical events that, based upon appropriate medical judgment, may jeopardize the 
patient and may require medical or surgical intervention to prevent 1 of the outcomes listed 
above.  
 
Life-threatening experience. Any adverse experience that places the patient, in the view of the 
reporter, at immediate risk of death from the adverse experience as it occurred, i.e., does not 
include an adverse experience that had it occurred in a more severe form, might have caused 
death.  
Required or prolonged inpatient hospitalization. The adverse experience resulted in an initial 
inpatient hospitalization or prolonged an existing hospitalization of the patient. If a patient is 
hospitalized as part of the clinical use of the product, a period of normal hospitalization will be 
outlined in the protocol or by the judgment of the Investigator. Hospitalizations longer than this 
period will be prolonged hospitalizations.  
Persistent or significant disability/incapacity. An adverse experience that resulted in a 
substantial disruption of a person’s ability to conduct normal life functions.  
Congenital Anomaly. The exposure of the patient to the drug or biologic during pregnancy that is 
judged to have resulted in the congenital anomaly/birth defect.  
Important medical events. Adverse experiences that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, may jeopardize the patient or patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Important medical events or 
interventions may be considered an SAE based upon medical judgment of the Investigator.  


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11.1.5 Reporting Serious Adverse Events 
The necessity and time requirements for reporting of SAEs to Pharming Pharmacovigilance or 
designee and/or regulatory agencies are as follows:  
All SAEs will be reported within 24 hours of the Investigator’s first knowledge of the event, even if 
the experience does not appear to be related to the study medication. The contact details are: 
Address:  
VIGILEX B.V. 
 
Archimedesweg 17 
 
2333 CM Leiden 
 
The Netherlands 
 
Email:  
safety@vigilex.com 
Fax: 
 +31 (0) 71 524 4001 
 
• 
All SAEs will include a detailed description of the event(s). Copies of relevant patient records, 
autopsy reports, and other documents may be requested by and will be sent to Pharming 
Pharmacovigilance Department (contact details as above).  
• 
The Institutional Review Boards (IRB) must be notified in writing of any expedited SAEs. All 
unexpected SAEs associated with the use of the study treatment will be immediately reported 
to appropriate regulatory agencies by Pharming.  
• 
All AEs and SAEs will be noted on the CRF, with a full description including the nature, date 
and time of onset and resolution, determination of seriousness, intensity, causality, corrective 
treatment, and outcome.  
 
11.2 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AEOSI) are AEs that do not meet any criteria for an SAE but 
are nonetheless of particular interest in the context of this study. AEOSIs will be collected for all 
patients during the study period. Although these are non-serious events, the Investigator will be 
asked to provide detailed initial information and follow up to Pharming (see contact details in 
section 11.1.5) by using Pharming’s CRF and SAE Report Form. Pharming Pharmacovigilance 
will periodically review the AE data including all AEOSIs.  
The list of AEOSI with reporting timelines are presented below: 


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Adverse Events of Special Interest 
Reporting timelines to 
Pharming PV 
Type I hypersensitivity reaction due to pre-existing IgE antibodies 
against rabbit antigens 
24 hrs 
Type I hypersensitivity reaction due to cross reaction with IgE 
antibodies against cow milk antigens 
24 hrs 
Type I hypersensitivity reaction due to the formation of IgE 
antibodies against rabbit antigens 
24 hrs 
Type III hypersensitivity reaction due to the formation of 
antibodies against Ruconest  
24 hrs 
Induction of acquired angioedema due to the formation of anti-C1 
inhibitor antibodies 
24 hrs 
Thromboembolic complications 
24 hrs 
 
11.3 
Follow-up of Adverse Events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as indicated, 
and/or referral to the general physician or a medical specialist. 
 
11.4 
Pregnancy 
11.4.1 
Pregnancy Test and Use of Contraception 
No studies of rhC1INH have been conducted in pregnant women. To ensure patient safety, female 
patients capable of bearing children must have a negative pregnancy test prior to study drug 
administration.  
Note that female patients will be considered capable of bearing children if they are postmenarcheal, 
unless they have had a hysterectomy or bilateral oopherectomy.  
Every effort should be made to prevent pregnancy during this study. All patients of reproductive 
potential involved in the study are required to use an effective method of contraception during this 
time. If a patient becomes pregnant, she must not receive any study treatment while pregnant.   
11.4.2 
Pregnancy Notification and Follow Up 
Female patients will be instructed to notify the investigator immediately if they discover they are 
pregnant. The progress of the pregnancy will be followed until its outcome is known (i.e., delivery, 
elective termination, or spontaneous abortion). If the pregnancy results in the birth of a child, 
additional follow-up information may be requested. If the pregnancy results in spontaneous abortion 
or stillbirth, the event should be reported as an SAE.  
Specific instructions regarding documentation of pregnancy are provided in the Safety Plan; however, 
AEs that occur in study patients who become pregnant are reported as described in Section 11.1. 


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11.5 
Data Safety Committee 
No formal (independent) Data Safety Monitoring Board will be installed. However, data will be 
regularly reviewed by an internal committee composed of representatives of Pharmacovigilance, 
medical management and project management, supplemented with qualified experts, one 
international HAE-expert, and one pediatric expert with HAE experience. This committee will discuss 
and analyze safety issues pertaining to the study. Frequency of meetings and responsibilities will be 
described in a separate study specific manual.  
 


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12 
STATISTICAL ANALYSIS 
12.1 
Analysis sets 
The following analysis sets will be considered: 
Screening Set: 
All patients screened for the study, who at screening were eligible 
for treatment. 
Safety Set: 
All patients enrolled in the study, who received at least one study 
treatment. 
Intention to treat (ITT) Set: 
All patients enrolled in the study who received at least one study 
treatment and for whom any efficacy data are available. 
Per protocol (PP) Set: 
All patients of the ITT Set who have at least one attack without any 
major protocol violation. For these patients only the data of attacks 
without major protocol violation are retained. 
The exclusion of patients or data from the analysis sets will be discussed during a pre-analysis 
meeting that will be held before database lock. 
The analysis of key screening data will be performed on the basis of both the Screening Set and 
the ITT Set. The analysis of the safety data will be performed on the basis of the Safety Set. The 
analysis of the efficacy data will be performed on the basis of the ITT Set and the PP Set. 
Exploratory analyses based on Tanner Stage may be performed. 
 
12.2 
Variables 
The following data will be considered in the analysis: 
Safety 
• 
immunogenicity data 
• 
adverse events 
• 
laboratory data (hematology, biochemistry). 
• 
vital signs 
• 
ECG 
Efficacy 
• 
time to beginning of relief on the basis of the overall severity VAS using the first time-point 
with a decrease of at least 20 mm at any eligible location, with persistence at the next time-
point 
• 
time to minimal symptoms assessed by using the overall severity VAS, defined as the first 
time point at which the overall severity VAS fall below 20 mm for all assessed locations 
• 
time to beginning of relief on the basis of the IS using the first time-point with a decrease of at 
least one point at any eligible location 
• 
time to minimal symptoms on the basis of the first time-point at which the IS reaches a value 
of one or less at all locations 
• 
Time to beginning of relief on the basis of Question 1 and 2 of the TEQ, defined as the first 
time-point at which Question 1 is answered as a little better, better or much better and 


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Question 2 is answered as yes for the most severe eligible location, with persistence of these 
responses at the next time point 
• 
Time to minimal symptoms on the basis of Question 3 of the TEQ, defined as the first time-
point at which Question 3 is answered as yes for all locations 
• 
time to complete resolution based on the time-point at which all symptoms at all locations 
have resolved 
• 
therapeutic failure 
 
12.3 
Statistical methods 
12.3.1 General considerations 
A detailed statistical analysis plan (SAP) will be prepared based on the objectives of the protocol. 
Procedures for accounting for missing, unused or spurious data will also be included therein. This 
plan will be finalized as early as possible after creation of the database and at the latest before 
database lock.   
The statistical analysis will consist of: 
• 
Descriptive statistics (mean, median, standard deviation, 95% CI on the mean, minimum, 
maximum, and number of observations) for the quantitative variables, and frequency 
distributions (frequencies and percentages) for the categorical variables (binary and ordinal 
variables). An exact 95% CI will be given for key categorical variables. 
• 
Kaplan-Meier analyses of the time to event variables (time to beginning of relief, time to 
minimal symptoms and time to complete resolution), with estimates of the median and 
quartiles with 95% confidence interval. 
The statistical analysis will be performed using SAS software for WINDOWS, version 9.2 or later. 
12.3.2 Screening data 
A description will be given of the key screening data on the basis of both the Screening Set and 
the ITT Set. 
12.3.3 Safety data 
The analysis of safety will be performed on the basis of the Safety Set. It will be descriptive and 
consist of: 
Immunogenicity data (anti-C1INH antibodies of IgG and IgM, anti-HRI) 
• 
descriptive statistics at each assessment time (attack/day) 
• 
documented list of all immunology data (including the data of the confirmatory assays), for the 
patients for whom any value was observed above the cut-off level 
 
 


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Adverse events 
AEs will be recorded throughout the study. These will be coded using the MedDRA dictionary, 
version 13.1 or later. The analysis will be based on the treatment-emergent adverse events 
(TEAE), which are the AEs with an onset at any time between the start of treatment and 97 days 
after treatment for any treated attack. 
The following documented lists of individual data will be provided for all attacks together: 
• 
documented list of individual data concerning TEAEs 
• 
documented list of baseline adverse events with onset before start of treatment administration 
for the first attack, and for subsequent, AEs with onset between 98 days since the previous 
treated attack and the start of treatment administration  
The analysis of TEAEs will be performed by attack number and all attacks together. It will consist 
of:  
• 
frequency distribution of patients with TEAEs, with serious TEAEs, and with TEAEs causing 
premature discontinuation 
• 
frequency distribution of patients with TEAEs by system organ class 
• 
frequency distribution of patients with TEAEs by system organ class and preferred term 
• 
frequency distribution of patients with related TEAEs by system organ class and preferred 
term 
If relevant: 
• 
frequency distribution of patients with TEAEs by system organ class, preferred term and 
maximal severity 
• 
frequency distribution of patients with TEAEs by system organ class, preferred term and 
strongest relationship 
HAE attacks 
HAE attacks will be separately recorded. The analysis will consist of: 
• 
documented list of individual data concerning HAE attacks 
Laboratory data (hematology, biochemistry) 
• 
Descriptive statistics at each assessment time (attack/day). 
• 
For each attack number descriptive statistics of the difference between the recording before 
treatment and Day 28 (if this visit occurred before the next treatment). 
• 
Frequency distribution of the status (below, within, and above the normal range), at each 
assessment time. 
• 
For each attack number shift table of the status, between the recording before treatment and 
Day 28 (if this visit occurred before the next treatment). 
Vital signs 
• 
descriptive statistics at each assessment time (attack/day) 
 


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ECG 
• 
descriptive statistics at each assessment time (attack/day) 
• For each attack number descriptive statistics of the difference between the recording before 
treatment and after treatment (between 30 min and 2 hours post administration) 
12.3.4  Efficacy data 
The following analyses will be performed on the basis of the ITT Set and the PP Set, separately 
for each attack number.  
• 
Kaplan-Meier analysis for time to beginning of relief on the basis of the overall VAS 
• 
Kaplan-Meier analysis for time to minimal symptoms on the basis of the overall VAS  
• 
Kaplan-Meier analysis for time to beginning of relief on the basis of TEQ questions 1 and 2 
• 
Kaplan-Meier analysis for time to minimal symptoms on the basis of TEQ question 3 
• 
Kaplan-Meier analysis for time to complete resolution 
• 
Kaplan-Meier analysis for time to beginning of relief on the basis of the IS 
• 
Kaplan-Meier analysis for time to minimal symptoms on the basis of the IS. 
• 
frequency distribution for therapeutic failure 
• 
descriptive data for each anatomical location: 
o descriptive statistics of the overall VAS at each assessment time, and of the difference 
between baseline and each assessment after baseline 
o frequency distribution of the IS at each assessment time 
 
The Kaplan-Meier analyses for TTBR and TTMS based on the VAS as well as the frequency 
distribution of the therapeutic failures will be repeated for the first and last attack for the patients 
having been treated for more than one attack. 


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13 
ETHICAL CONSIDERATIONS 
13.1 
Regulation statement 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be submitted 
to the Institutional Review Boards (IRBs) of the respective centers. The IRB may consult with 
experts on pediatric ethical, clinical and psychosocial issues. The study will be conducted in 
compliance with the protocol, GCP regulations and the applicable regulatory requirements. The 
designers of this study have also taken into account guideline ICH-E11 "Clinical Investigation of 
Medicinal Products in the Pediatric Population". 
The regulatory application or submission for regulatory approval will be made by the Sponsor as 
required by national law. 
 
13.2 
Recruitment, written consent and assent 
The investigator will obtain written informed consent (parental permission) for each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study, before applying any study-related procedure to a patient. IRBs 
may require additional written consent using their own locally approved consent form.  
2-13 year old patients are legally unable to provide informed consent. Written consent must be 
obtained from the patient's legal guardian. Age-appropriate material (by using pictures and 
drawings) will be prepared to present to the patients. The investigator and legal guardian have to 
sign and date that document to confirm that the patient has been informed as well as possible. 
Patients who are able to write their first name will be asked to provide their written assent on this 
document. All consent forms, patients' explanatory material and assent forms must be approved 
in advance by the IRB accepted by the investigator’s institution. 
The investigator will explain that the patients are completely free to refuse to enter the study or to 
withdraw from it at any time, without any consequences for their further care and without need for 
justification1. The investigator will complete and sign the informed consent section of the CRF for 
each patient enrolled. 
If a legal guardian is unable to read, an impartial witness should be present during the entire 
informed consent discussion. After the informed consent form and any other written information is 
provided, read, and explained to the patient or their legal guardian, and after oral consent has 
been obtained, if capable of doing so, the patient or their guardian should sign and date the 
informed consent form. The witness should also sign and date the consent form. In addition, the 
patient or their guardian should, if possible, sign an additional form confirming that the materials 
provided have been read and explained to them. The witness should also sign and date this 
additional form. 
Each patient and their legal guardians will be informed that the patient's medical records may be 
reviewed during the course of the clinical study or afterwards, including review by government 
agencies. Each patient and their legal guardians will be informed that the patient's medical data 
will be included in a database and may be reviewed during the course of the clinical study or 
afterwards, including review by government agencies. However, only authorized personnel will 
review these data. Each patient and their legal guardians should be informed that the Investigator 
                                               
1 It is to note that if the patient wishes to withdraw, but the parents and investigator feel that it is in the best interests of the patient to stay in 
the study (e.g. in case of an acute life-threatening attack), then they can overrule the patient. 


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will protect any personal information not related to the study, and that individuals associated with 
the trial are bound by the same confidentiality obligations as other health care professionals with 
regard to patient confidentiality. 
 
13.3 
Benefits and risks assessment 
It is generally acknowledged that pediatric patients should be given medicines which have been 
appropriately evaluated for their use; as a consequence, drugs aimed to have indication for 
children must be formally studied before widespread use. 
Results of this study will help further evaluating the balance of benefits and risks within the 
specific age group. 
Given the demonstrated efficacy in adults, the disease process being similar in adults and 
children and taking into account that Ruconest is a replacement therapy; the outcome of the 
therapy is likely to be comparable. As a consequence, a real and direct benefit is foreseen for the 
participating children. Therefore, the current study is considered as a clinical investigation with 
low risk while presenting the prospect of direct clinical benefit to the study participant. 
To minimize risk, investigators and site personnel should be properly trained and experienced in 
studying the pediatric population, including the evaluation and management of potential pediatric 
adverse events. 
An internal safety monitoring committee will be established that will evaluate the safety aspects of 
the study on an ongoing basis to ensure the safety and welfare of the participating patients.  
 
13.4 
Compensation for injury 
The chance of injury as a result of the study is small. However, the Sponsor has insured this risk 
by taking a liability insurance which is in accordance with the legal requirements in diverse 
countries. This insurance provides cover for damage to research patients through injury or death 
caused by the study. 
The insurance applies to the damage that becomes apparent during the study. A condition is that 
the damage has been communicated in writing to the Sponsor and the insurance company within 
this period. 
 
13.5 
Incentives 
Only costs associated with study participation will be reimbursed, such as transportation costs, 
etc. 


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14 
ADMINISTRATIVE ASPECTS AND PUBLICATION 
14.1 
Access to Source Data and Documents 
The investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), by providing direct access to source data/records. Most of the tests being 
performed are study-related procedures and would not have been regularly performed if the 
patient was not in the study.  
All study data will be handled confidentially. The investigators and responsible CROs will retain 
the originals of all source documents generated at the various study centers, local and Central 
laboratories for a period of 15 years after the report of the study has been finalized, after which all 
study-related documents can be archived and maintained according to GCP regulations. After 15 
years the Sponsor will be notified that the source documents can be retained with the Sponsor or 
destroyed. 
 
14.2 
Quality Control and Quality Assurance 
This study will be conducted according to the Sponsor's and CRO's Standard Operating 
Procedures. Quality assurance will be performed under the responsibility of the Sponsor and 
CRO QA manager. 
14.2.1 Study Center Visits and Periodic Monitoring 
Pre-study visits will be performed to ensure that centers are well equipped to perform the study 
and to evaluate the recruitment potential. At the pre study visit, special attention will be given to 
the following aspects to ensure that the participants’ experiences in the trial are positive and to 
minimize discomfort and distress, according to ICH-E6(R1) "Guideline for Good Clinical Practice" 
and ICH-E11 "Clinical Investigation of Medicinal Products in the Pediatric Population" and 
published guidelines(11). 
• 
personnel knowledgeable and skilled in dealing with the pediatric population and its age-
appropriate needs, including skill in performing pediatric procedures  
• 
a physical setting with furniture, play equipment, activities, and food appropriate for age  
• 
the conduct of studies in a familiar environment such as the hospital or clinic where 
participants normally receive their care  
All above aspects will all be evaluated before it is decided to retain the clinical center or not in the 
study.  
Shortly before the launch of the study, a Site Initiation Visit will be performed, during which all 
protocol modalities will be discussed, including CRF completion. Special attention should be given 
to safety related aspects and the safety reporting procedures put in place (SAEs and AEOSIs). 
Also, options to minimize discomfort of procedures will be discussed, such as:  
• 
topical anesthesia to place IV catheters  
• 
indwelling catheters rather than repeated venipunctures for blood sampling  
The CRO will appoint study Monitor(s) who will contact and visit the investigator(s) regularly. The 
above will be continuously monitored and discussed. The study Monitor will be allowed, on 
request, to inspect the various records of the study. It will be the study Monitor's responsibility to 


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inspect the CRFs at regular intervals throughout the study, to verify the adherence to the protocol 
and the completeness, correctness and accuracy of all CRF entries. The study Monitor should 
have access to laboratory test reports and any other source records and data needed to verify the 
entries on the CRFs. The investigator agrees to cooperate with the study Monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved.  
After source document verification and review by the study Monitor, the original and a copy of the 
CRF will be collected by the study Monitor while 1 copy will remain at the investigational site. The 
original will be sent to the CRO and 1 copy will remain with the study Monitor. 
The Sponsor will only consider CRFs to be complete when each CRF has been reviewed and 
signed by the Investigator, indicating their assurance of the accuracy of all recorded data.  
14.2.2 Audit and Inspection 
This study will be conducted according written SOPs from the Sponsor and CRO, ICH-GCP 
guidelines and local applicable laws. Audits and inspections can be conducted by health 
authorities, the Sponsor, the CRO and/or delegates from these. 
The investigator will make source data and documents for this study available to a medically 
qualified clinical quality assurance auditor after appropriate notification. 
Quality control should be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
 
14.3 
Confidentiality of Patients’ Data 
The responsible investigator will ensure that the patient's anonymity will be preserved. On CRFs 
or any other documents submitted to the Sponsor, the patients will not be identified by their 
names, but by an identification code, consisting of a patient study number. Documents not for 
submission to the Sponsor, i.e. the confidential patient identification code, original consent forms 
and source records will be maintained by the investigator in strict confidence. 
 
14.4 
Data handling and Record Keeping 
14.4.1 Responsibilities 
Monitoring will be done by the CRO, in case this responsibility is delegated in part or totally to a 
third party, the study protocol must be amended. The CRO will be in charge of data management 
and analysis of data. 
QPS Netherlands B.V. will perform the diagnostic and immunosafety assays. 
14.4.2 Information of Investigators 
All participating investigators will be informed about the methods for rating relevant study outcome 
criteria, safety reporting modalities, and how to complete the CRFs. The investigators will be kept 
informed of important information related to the safe use of the IMP as the study proceeds.  


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14.4.3 Case Report Forms 
For each patient enrolled, a CRF will be completed and signed by the investigator or an 
authorized sub-Investigator. All forms will be filled out using an indelible pen, and must be legible. 
The results of the VAS, TEQ and IS will be recorded directly into the CRF without other source 
documents other than the statement that the named forms are completed. Any other information 
in the CRF needs to have source documentation.  
14.4.4 Changes to Case Report Form Data 
Errors occurring in CRFs will be crossed out without obscuring the original entry, the correction 
will be written alongside the initial entry, and the change will be initialed and dated by the 
Investigator or designee. Corrective fluids must not be used. When changes to CRF data are 
necessary following removal of the original CRF from the study center, any such changes will be 
documented on data clarification/resolution forms, which will be signed by the investigator. 
14.4.5 Investigator Site File 
The investigator is responsible for maintaining all records to enable the conduct of the study to be 
fully documented. Copies of the study protocol, study approval letters, all original informed 
consent forms, center copies of all CRFs, study medication dispensing and accountability logs, 
and all correspondence pertaining to the study should be kept by the investigator for the 
maximum period of time required by local regulations; the default time period is 15 years. All such 
records will be kept confidentially, and not shown to persons outside of the study team. 
The investigator is responsible for maintaining a confidential patient identification code, which 
provides the unique link between named source records and anonymous CRF data for the 
Sponsor. The investigator must arrange for the retention of this confidential list for at least fifteen 
years after the completion or discontinuation of the study. 
No study document should be destroyed without prior written agreement between the investigator 
and the Sponsor. Should the investigator elect to assign the study documents to another party, or 
move them to another location, the Sponsor must be notified. 
14.4.6 Provision of Additional Information 
On request, the investigator will supply the Sponsor with additional data relating to the study, or 
copies of relevant source records, which have been made anonymous.  
 
14.5 
Changes in the Conduct of the study 
14.5.1 Protocol Amendments 
Any prospective change to the protocol will be submitted to the approving IRB(s). A ‘substantial 
amendment’ is defined as an amendment to the terms of the EC application, or to the protocol or 
any other supporting documentation, that is likely to affect to a significant degree: 
• 
the safety or physical or mental integrity of the patients of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 


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• 
the quality or safety of any intervention used in the trial 
All substantial amendments will be submitted for approval to the EC and to the Competent 
Authority (CA). 
Non-substantial amendments will be notified to the EC and to the CA and will be recorded and 
filed by the Sponsor. Examples of non-substantial amendments are typing errors and 
administrative changes like changes in names, telephone numbers and other contact details of 
involved persons mentioned in the submitted study documentation. 
 
14.6 
Annual Reporting  
The Sponsor/investigator will submit a summary of the progress of the study to the IRB once a 
year. Information will be provided on the date of inclusion of the first patient, numbers of patients 
included and numbers of patients that have completed the study, SAEs/ SARs, other problems, 
and amendments.  
The Sponsor will submit, once a year throughout the clinical study, a safety report to the EC/IRB 
and CAs of the concerned EU Member States. In addition to the expedited reporting of SUSARs, 
this safety report consists of: 
• 
a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ 
system, per study 
• 
a report concerning the safety of the patients, consisting of a complete safety analysis and an 
evaluation of the balance between the efficacy and the harmfulness of the medicine under 
investigation 
 
14.7 
Clinical Study Report 
The Sponsor will notify the EC/IRB and the CA of the end of the study within a period of 90 days. 
The end of the study is defined as the last patient’s last visit.  
If the end of study is defined otherwise, this new definition should be given. In case the study is 
ended prematurely, the Sponsor will notify the EC/IRB and the CA within 15 days, including the 
reasons for the premature termination. 
Within one year after the end of the study, the Sponsor will submit a final clinical study report with 
the results of the study, including any publications/abstracts of the study, to the IRB and the CA.  
 
14.8 
Publication Policy 
The results of this study will be published in a peer-reviewed journal if applicable and/or if 
considered appropriate. Conditions are subject to (a) separate contract(s) between the 
responsible investigators, the sub investigators and the Sponsor.  
 
 


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15 
SUMMARY OF CHANGES FROM PROTOCOL VERSION 09 NOVEMBER 2012 TO 
PROTOCOL VERSION 10 JUNE 2014 
 
The changes from version 09 November 2012 to version 10 June 2014 are non-substantial.  
The contact details of the Sponsor, Contract Research Organisation and Pharmacovigilance service 
provider have been updated. The time windows for the visits have been added and further detailed 
guidance is provided on collection of PRN used medications. Definitions for relapse and spontaneous 
regression were added.  
. 
 


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16 
REFERENCES 
 
1. 
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-
36. 
2. 
Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. 
Arch Intern Med. 2001 Nov 12;161(20):2417-29. 
3. 
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning 
symptoms, affected organs, and course. Am J Med. 2006 Mar;119(3):267-74. 
4. 
Zingale LC, Zanichelli A, Lambertenghi  Deliliers D, Bellatorre L, Maggioni M, Cicardi M. Use 
of human C1 inhibitor concentrate in 473 Italian patients with C1 inhibitor deficiency: survey of 
1001 infusions.  5th C1 Inhibitor Deficiency Workshop 2007 3 June 2007; Budapest, Hungary; 
2007. p. 76. 
5. 
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al. C1 inhibitor 
deficiency: consensus document. Clin Exp Immunol. 2005 Mar;139(3):379-94. 
6. 
Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical 
characteristics in 235 patients. Medicine (Baltimore). 1992 Jul;71(4):206-15. 
7. 
Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and 
acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor 
deficiency workshop and beyond/ 3rd C1 inhibitor Deficiency Workshop. J Allergy Clin 
Immunol. 2004 Sep;114(3 Suppl):S51-131. 
8. 
Williams PB, Barnes JH, Szeinbach SL, Sullivan TJ. Analytic precision and accuracy of 
commercial immunoassays for specific IgE: establishing a standard. J Allergy Clin Immunol. 
2000 Jun;105(6 Pt 1):1221-30. 
9. 
Zisowsky J, Kause A, Dingemanse J. Drug Development for Pediatric Populations: Regulatory 
Aspects. Pharmaceutics. 2010;2(4):364-88. 
10. 
IRBMED University of Michigan Medical School. Guidance: Blood Draw Guidelines.  2011  
[cited 2011 April 14th]; Available from: http://med.umich.edu/irbmed/guidance/blood draw.htm 
11. 
Shaddy RE, Denne SC. Clinical report--guidelines for the ethical conduct of studies to 
evaluate drugs in pediatric populations. Pediatrics. 2010;125(4):850-60. 
12. 
Bork K, Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in 
four patients with hereditary angioedema. J Am Dent Assoc. 2003 Aug;134(8):1088-94. 
13. 
Investigator’s Brochure. Pharming Group N.V. 2010, feb16. 
14. 
ICH-E6(R1) "Guideline for Good Clinical Practice" 
15. 
ICH-E11 "Clinical Investigation of Medicinal Products in the Pediatric Population" 
 




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Appendix B: Visual Analogue Scales 
 
VISUAL ANALOGUE SCALES (ABDOMINAL) 
 
These VAS-scores were completed by: 
 patient 
 
 parent/legal guardian 
 
Below, you can see some lines.  We would like you to help the doctor to understand how you feel 
right now, by making a mark on each of those lines. Sick people of all ages use this way to show their 
doctors how they feel. If you don't understand any of the words below, please ask your Mom or Dad 
to explain. If you don't want to mark the lines, then your Mom or Dad can mark the lines for you.  
How to mark the lines: you will see that at one end of each line, for example for pain (number 2), it 
says, 'no pain'. At the other end of each line, it says, 'worst pain'. So you can put a mark at one end of 
the line if you feel really good, or at the other end of the line, if you feel as bad as possible. You can 
also put a mark somewhere in the middle, to show the doctor just how you feel. 
 
1. How ill do you feel ? 
 
Not at all ill 
Extremely ill 
 
2. Do you have abdominal pain ? 
 
No pain 
Extremely painful 
 
3. Do you feel bloated ? 
 
No, totally empty 
Unbearably full 
 
4. Do you feel nauseous ? 
 
No nausea at all   
Extremely nauseous  
 
5. How severe are the angioedema symptoms now for this location ? 
 
No symptoms 
Extremely disabling 
 


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VISUAL ANALOGUE SCALES (UROGENITAL) 
 
These VAS-scores were completed by: 
 patient 
 
 parent/legal guardian 
 
Below, you can see some lines.  We would like you to help the doctor to understand how you feel 
right now, by making a mark on each of those lines. Sick people of all ages use this way to show their 
doctors how they feel. If you don't understand any of the words below, please ask your Mom or Dad 
to explain. If you don't want to mark the lines, then your Mom or Dad can mark the lines for you.  
How to mark the lines: you will see that at one end of each line, for example for pain (number 2), it 
says, 'no pain'. At the other end of each line, it says, 'worst pain'. So you can put a mark at one end of 
the line if you feel really good, or at the other end of the line, if you feel as bad as possible. You can 
also put a mark somewhere in the middle, to show the doctor just how you feel. 
 
1. How ill do you feel ? 
 
Not at all ill 
Extremely ill 
 
2. Do you have pain in the genital area ? 
 
No pain 
Extremely painful 
 
3. Do you have any swelling in the genital area ? 
 
No swelling 
Extreme swelling 
 
4. Do you feel nauseous ? 
 
No nausea at all 
Extremely nauseous 
 
5. How easily can you urinate ? 
 
Easily         
Cannot urinate at all 
 
6. How severe are the angioedema symptoms now for this location? 
 
No symptoms 
Extremely disabling 
 


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VISUAL ANALOGUE SCALES (ORO-PHARYNGEAL and/or LARYNGEAL) 
 
These VAS-scores were completed by: 
 patient 
 
 parent/legal guardian 
 
Below, you can see some lines.  We would like you to help the doctor to understand how you feel 
right now, by making a mark on each of those lines. Sick people of all ages use this way to show their 
doctors how they feel. If you don't understand any of the words below, please ask your Mom or Dad 
to explain. If you don't want to mark the lines, then your Mom or Dad can mark the lines for you.  
How to mark the lines: you will see that at one end of each line, for example for pain (number 2), it 
says, 'no pain'. At the other end of each line, it says, 'worst pain'. So you can put a mark at one end of 
the line if you feel really good, or at the other end of the line, if you feel as bad as possible. You can 
also put a mark somewhere in the middle, to show the doctor just how you feel. 
 
1. How ill do you feel ? 
 
Not at all ill 
Extremely ill 
 
2. Do you have pain in your mouth or throat ? 
 
No pain  
Extremely painful 
 
3. Do you have any swelling in your mouth or throat ? 
 
No swelling 
Extreme swelling 
 
4. How easy is it to breathe ? 
 
No problems   
Very difficult to breath 
 
5. Is your speech affected ?  
 
Not at all 
Extremely affected/ 
 
 
 
Cannot speak at all 
 
6. Do you have difficulty in swallowing ? 
Not at all       
Great difficulty 
 
7. How severe are the angioedema symptoms now for this location ? 
 
No symptoms       
Extremely disabling 


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VISUAL ANALOGUE SCALES (FACIAL) 
 
These VAS-scores were completed by: 
 patient 
 
 parent/legal guardian 
 
Below, you can see some lines.  We would like you to help the doctor to understand how you feel 
right now, by making a mark on each of those lines. Sick people of all ages use this way to show their 
doctors how they feel. If you don't understand any of the words below, please ask your Mom or Dad 
to explain. If you don't want to mark the lines, then your Mom or Dad can mark the lines for you.  
How to mark the lines: you will see that at one end of each line, for example for pain (number 2), it 
says, 'no pain'. At the other end of each line, it says, 'worst pain'. So you can put a mark at one end of 
the line if you feel really good, or at the other end of the line, if you feel as bad as possible. You can 
also put a mark somewhere in the middle, to show the doctor just how you feel. 
 
1. How ill do you feel ? 
 
Not at all ill 
Extremely ill 
 
2.  Do you have pain in your face?  
 
No pain  
Extremely painful 
 
3.  Do you have any swelling of your face?  
 
No swelling  
Extreme swelling 
 
4.  How severe are the angioedema symptoms now for this location?  
 
No symptoms 
Extreme disabling 
 


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VISUAL ANALOGUE SCALES (PERIPHERAL LOCATIONS) 
 
These VAS-scores were completed by: 
 patient 
 
 parent/legal guardian 
 
Below, you can see some lines.  We would like you to help the doctor to understand how you feel 
right now, by making a mark on each of those lines. Sick people of all ages use this way to show their 
doctors how they feel. If you don't understand any of the words below, please ask your Mom or Dad 
to explain. If you don't want to mark the lines, then your Mom or Dad can mark the lines for you.  
How to mark the lines: you will see that at one end of each line, for example for pain (number 2), it 
says, 'no pain'. At the other end of each line, it says, 'worst pain'. So you can put a mark at one end of 
the line if you feel really good, or at the other end of the line, if you feel as bad as possible. You can 
also put a mark somewhere in the middle, to show the doctor just how you feel. 
 
1. Do you have any swelling ? 
 
No swelling 
Extreme swelling 
 
2. Do you have pain in your extremities ? 
 
No pain  
Extremely painful 
 
3. Do you have difficulty using the swollen extremity ? 
 
No problems 
Extremely difficult 
Can easily move 
 
4. How severe are the angioedema symptoms now for this location? 
 
No symptoms      
Extremely disabling 
 


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Appendix C: Treatment Effect Questionnaire 
 
 
Treatment Effect Questionnaire Pre-dose 
Below, you see 3 questions. We would like you to help the doctor to understand if you feel better or 
worse since you arrived in the hospital. Sick people of all ages use this way to show their doctors how 
they feel. Some sentences and words may be difficult for you to understand. You can ask your Mom 
or Dad to help you.  
 
 
 
Question 1: To what extent has the overall severity of your [abdominal1] HAE attack changed 
since your arrival at the study center?  
Much 
worse 
Worse 
A little 
worse 
Not 
changed 
A little 
better 
Better 
Much 
better 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
 
Question 2: Overall, has the intensity of your [abdominal1] HAE attack symptoms begun to 
decrease noticeably since your arrival at the study center? 
⎕ Yes 
⎕ No 
 
 
 
 
Question 3: At this moment, are your [abdominal1] HAE attack symptoms minimal (barely 
noticeable)? 
⎕ Yes 
⎕ No 
 
 
 
 
1 abdominal is replaced by the relevant attack location 
 
 


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Treatment Effect Questionnaire after Treatment 
Below, you see 3 questions. We would like you to help the doctor to understand if you feel better or 
worse since you got the infusion. Sick people of all ages use this way to show their doctors how they 
feel. Some sentences and words may be difficult for you to understand. You can ask your Mom or 
Dad to help you.  
 
 
 
Question 1: To what extent has the overall severity of your [abdominal1] HAE attack changed 
since you received the infusion?  
Much 
worse 
Worse 
A little 
worse 
Not 
changed 
A little 
better 
Better 
Much 
better 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
⎕ 
 
Question 2: Overall, has the intensity of your [abdominal1] HAE attack symptoms begun to 
decrease noticeably since your received the infusion? 
⎕ Yes 
⎕ No 
 
 
 
 
Question 3: At this moment, are your [abdominal1] HAE attack symptoms minimal (barely 
noticeable)? 
⎕ Yes 
⎕ No 
 
 
1 abdominal is replaced by the relevant attack location 


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Appendix D: Investigator Score 
 
Please use the following severity score for the evaluation of the HAE symptoms: 
Severity 
score 
Evaluation 
 
0 
No symptoms 
1 
Almost no symptoms 
2 
Mild symptoms 
3 
Moderate symptoms 
4 
Severe symptoms 
5 
Life-threatening 
 
 
Abdominal 
 0 
 1 
 2 
 3 
 4 
 5 
Urogenital 
 0 
 1 
 2 
 3 
 4 
 5 
Oro-
Pharyngeal / 
Laryngeal 
 0 
 1 
 2 
 3 
 4 
 5 
Facial 
 0 
 1 
 2 
 3 
 4 
 5 
Peripheral 
 0 
 1 
 2 
 3 
 4 
 5 
If peripheral, please specify the location(s) below:  
Peripheral:  
 


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Appendix E: Pharmaceutical instructions 
 
Background 
Recombinant human C1INH is a powder for solution for injection that must be dissolved with water for 
injections: it is supplied in a 25 ml colorless type I glass vial. The closure consists of a siliconized 
chlorobutyl rubber stopper and a flip-off seal of aluminum and white-colored plastic. 
Each vial of Ruconest is for single use only. 
Aseptic technique should be used for reconstitution, combining and mixing the solutions. 
  
Reconstitution  
Reconstitute each vial of Ruconest (2100 U rhC1INH) with 14 ml water for injections (WFI). Add 
sterile WFI slowly to avoid forceful impact on the powder and mix gently to avoid foaming of the 
solution. The reconstituted solution contains 150 U/ml rhC1INH and appears as a clear colorless 
solution.  
Visually inspect the reconstituted solution in each vial for particulate matter and discoloration. Do not 
use solution exhibiting particulates or discoloration. The product should be used immediately.  
 
Dose calculation 
The recommended dose of Ruconest is 50 U/kg body weight for patients up to 84 kg; and 4200U (2 
vials) for patient from 84 kg or greater.  
Determine the patient’s bodyweight and calculate the total volume of the reconstituted solution 
required to be administered to the patient using the following equation: 
 
Volume to be 
administered (ml)  
= 
body weight (kg) times 50 (U/kg) 
150 (U/ml) 
= 
body weight (kg) 
3 
 
 
Reconstitute each vial with 14 ml WFI. Withdraw the required volume from the vials, making sure 
that the withdrawn volume from the required number of vials is mixed gently. Round up every mL to 
the next integer number. (e.g., if total required volume is 8.33 mL (for a child weighing 25 kg), 
withdraw 9 mL from the reconstituted volume). 
  
Discard the vials containing the reconstituted solution not used during this procedure. 
 


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Appendix F: List of Definitions 
 
Abdominal attack: 
Patients showing symptoms related to swelling of submucosal tissue of the gastrointestinal tract. If 
this diagnosis of an abdominal HAE attack is not obvious or questionable, appropriate diagnostic 
efforts including but not limited to abdominal/pelvic ultrasound, should be undertaken to rule out a 
potential acute abdomen (acute abdominal emergencies).  
 
Angioedema:  
The recurrent swelling (increased amount of interstitial fluid in subcutaneous and/or submucosal 
tissue), occurring in patients with hereditary or acquired angioedema, related to deficiency of 
functional C1INH. 
 
Eligible attack: 
An acute attack of angioedema in the abdomen, facial-oro-pharyngeal region, larynx, urogenital 
region and/or at peripheral localizations, with onset of eligible symptoms within 5 hrs or less from the 
time of determination of eligibility by the study physician, in a patient with HAE, who has a level of 
functional C1INH of less than 50 % of that in pooled normal plasma. An HAE attack in a patient with 
HAE will be considered eligible if the IS score for at least one anatomical location at the time of initial 
evaluation is at least 3. 
 
Eligible site/location: 
Angioedema at site(s) with onset of less than 5 hrs ago and if the IS score at this location at initial 
evaluation is at least 3. 
 
Eligible symptoms: 
Symptoms of angioedema in the abdomen, facial-oro-pharyngeal region, larynx, urogenital region, 
and/or at peripheral localizations (subcutaneous edema; most often at the extremities); including but 
not limited to visible swelling and/or voice change, speech problems, stridor, dyspnea, urine passage 
problems, pain, distress, anxiety, nausea, vomiting, diarrhea, fainting, dehydration, swallowing 
problems/dysphagia, hypotension, hypovolemia, tachycardia, ascites. 
 
Exacerbation: 
Worsening or increase of angioedema, and/or associated symptoms, and/or involvement of additional 
anatomical locations. 
 
Laryngeal edema: 
Clinical signs of laryngeal edema include dysphagia, the sensation of a lump in the throat, a feeling of 
tightness in the throat, voice changes, including hoarseness and roughness, stridor, and dyspnea. 
Additional signs of progressed laryngeal edema may include fear of asphyxiation, and aphonia(12). 
 
New site(s), new manifestation(s), new location(s): 
Acute angioedema attack at a new location will be identified as an IS score greater than 0 at any time 
up to (and including) 24 hours for a location that had an IS score of 0 (or missing IS score) at 
Baseline. 
 
Peripheral edema: 


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Angioedema at peripheral localizations (occurring in subcutaneous rather than submucosal tissue), 
i.e. not localized in the abdomen (gastrointestinal tract) and/or in the facial-oro-pharyngeal region 
and/or in the urogenital region (‘submucosal’ sites), e.g. swelling at extremities, hand, wrist, lower 
arm, upper arm, foot, leg, ear, chest wall, abdominal wall, neck, buttocks. 
 
Early relapse:  
Beginning of relief of symptoms by overall VAS within four hours, followed by an increase of VAS 
score to baseline value or higher, within the first 8 hours after baseline. 
 
Late relapse:  
Beginning of relief of symptoms by overall VAS within four hours, followed by an increase of VAS 
value to baseline value or higher, more than 8 hours after baseline and at most 24 hours after 
baseline. 
 
Spontaneous regression: 
Decrease in symptoms of angioedema scored with investigator score at t = 0 h compared with score 
at the time of initial evaluation by 1 or more at an eligible location.  
 
Submucosal attack: 
Attack with presumed or visible involvement of submucosal tissue at any of the possible eligible sites, 
i.e. localized in the abdomen (gastrointestinal tract), facial-oro-pharyngeal region, larynx, and/or 
urogenital region.  
 
Therapeutic failure:  
Time to the beginning of relief based on the VAS later than 4 hrs after study medication 
administration, relapse of the attack within 4 hrs, and/or occurrence of HAE at a new location within 4 
hours after achieving beginning of relief of symptoms. The episode will also be considered a failure if 
the patient recorded taking medications that may have interfered with the assessment of the impact 
of Ruconest on efficacy measures, prior to time of initial relief of symptoms including: narcotics, 
plasma-derived C1 inhibitor, recombinant human C1 inhibitor, fresh frozen plasma (FFP), or anti-
emetics. 
 
Time to beginning of relief: 
Time to the beginning of relief based on patient’s VAS scores; time lapsed from the beginning of the 
infusion of study medication to the beginning of an effect. This variable will be based on the overall 
VAS for each eligible location. Time to beginning of relief is defined as the first time point at which the 
"overall severity VAS" decreases by at least 20 mm with persistence of the decrease at the next 
assessment time so that for the next value at the location a decrease of at least 20 mm with respect 
to baseline is also observed. Time to beginning of relief will also be calculated based on the IS and 
Questions 1 and 2 of the TEQ. 
 
Time to minimal symptoms: 
Time to minimal symptoms based on patient’s VAS scores; time from the start of the infusion of study 
medication to the first assessment time at which the overall severity VAS reaches a value of less than 
20 mm for all locations. Time to minimal symptoms will also be calculated based on the IS and 
Question 3 of the TEQ.  


Pharming Technologies Protocol C1 1209 
 
EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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Time to complete resolution: 
Time to complete resolution based on the time, as indicated by the patient in the diary, at which all 
angioedema symptoms are fully resolved at all locations. 


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EudraCT number: 2011-000987-92 
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Appendix G: Definitions of Tanner Stages  
The Tanner sexual development stages range from stage I to stage V. Below, the definition for the 
Tanner stages is depicted as extracted from the online Family Practice Notebook website: 
http://www.fpnotebook.com/Endo/Exam/MlTnrStg.htm 
 
Male Tanner stages  
Female Tanner stages 
1. Tanner Stage 1 (Prepubertal)  
1. Height increases at basal rate: 5-6 cm/y  
2. Testes  
 
Smaller than 4 ml or long axis <2.5 cm  
3. Pubic Hair  
 
No coarse, pigmented hair  
4. Penis Stage  
 
No growth  
2. Tanner Stage 2  
1. Height increases at basal rate: 5-6 cm/y  
2. Testes  
1. Size 4 ml or long axis 2.5 to 3.2 cm  
2. Age 11.5 years (age 9.5 to 13.5 years)  
3. Pubic Hair  
1. Minimal coarse, pigmented hair at base of 
penis  
2. Age 12.0 years (age 9.9 to 14.0 years)  
4. Penis Stage  
1. Earliest increased length and width  
2. Age 11.5 years (age 10.5-14.5 years)  
3. Tanner Stage 3 
1. Height increases at accelerated rate: 7-8 cm/y 
2. Testes  
1. Size 12 ml or long axis 3.6 cm 
2. Age 14.0 years (11.5-16.5 years) 
3. Pubic Hair 
1. Coarse, dark curly hair spread over the 
pubis 
2. Age 13.1 years (11.2-15.0 years) 
4. Penis Stage 
1. Increased length and width 
2. Age 12.4 years (10.1-14.6 years) 
5. Other Changes 
1. Gynecomastia may occur (age 13.2 
years) 
2. Voice breaks (age 13.5 years) 
3. Muscle mass increases 
 
1. Tanner Stage 1 (Prepubertal)  
1. Height increases at basal rate: 5-6 cm/y  
2. Breast  
1. Papilla elevation only  
3. Pubic Hair  
1. Villus hair only  
2. No coarse, pigmented hair  
2. Tanner Stage 2  
1. Height increases at accelerated rate: 7-8 cm/y  
2. Breast  
1. Breast buds palpable and areolae enlarge  
2. Age 10.9 years (8.9-12.9 years)  
3. Pubic Hair  
1. Minimal coarse, pigmented hair mainly on 
labia  
2. Age 11.2 years (9.0-13.4 years)  
4. Modifications based on increasingly earlier 
Puberty 
1. White: Stage 2 changes may appear one 
year earlier  
2. Black: Stage 2 changes may appear two 
years earlier  
3. Tanner Stage 3 
1. Height increases at peak rate: 8 cm/y (age 
12.5) 
2. Breast 
1. Elevation of breast contour; areolae 
enlarge 
2. Age 11.9 years (9.9-13.9 years) 
3. Pubic Hair 
1. Dark, coarse, curly hair spreads over 
mons pubis 
2. Age 11.9 years (9.6-14.1 years) 
4. Other changes 
1. Axillary hair develops (13.1 years) 
2. Acne Vulgaris develops (13.2 years) 
 
 


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EudraCT number: 2011-000987-92 
Safety of Ruconest in 2-13 year old HAE patients 
Protocol Version final 4 – 10 June 14 
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Male Tanner stages (cont.) 
Female Tanner stages (cont.) 
4. Tanner Stage 4 
1. Height increases at peak rate: 10 cm/y (age 
13.8) 
2. Pubic Hair 
1. Hair of adult quality 
2. Not spread to junction of medial thigh with 
perineum 
3. Age 13.9 years (12.0-15.8 years) 
3. Penis  
1. Continued growth in length and width 
2. Age 13.2 years (11.2-15.3 years) 
4. Testes  
1. Length 4.1 to 4.5 cm 
5. Other Changes 
1. Axillary hair (age 14.0 years) 
2. Voice changes (age 14.1 years) 
3. Acne Vulgaris (age 14.3 years) 
5. Tanner Stage 5 
1. No further height increases after age 17 years 
2. Pubic Hair 
1. Adult pubic hair distribution (15.3 years) 
2. Pubic hair spreads to medial thigh 
3. No hair spread to linea alba 
3. Penis  
1. Mature genital size by 16.5 years 
4. Testes  
1. Length >4.5 cm 
5. Secondary sexual characteristics 
1. Facial hair present on sides 
2. Mature male physique 
3. Gynecomastia disappears 
 
4. Tanner Stage 4 
1. Height increases at 7 cm/y 
2. Breast 
1. Areolae forms secondary mound on the 
breast 
2. Age: 12.9 years (10.5-15.3 years) 
3. Pubic Hair 
1. Hair of adult quality 
2. No spread to junction of medial thigh with 
perineum 
3. Age: 12.6 years (10.4-14.8 years) 
5. Tanner Stage 5 
1. No further height increases after age 16 years 
2. Breast 
1. Adult breast contour 
2. Areola recesses to general contour of 
breast 
3. Pubic hair 
1. Adult distribution of hair 
2. Pubic hair spreads to medial thigh 
3. Pubic hair does not extend up linea alba 
 
 
Reference  
Marshall WA, Tanner JM Variations in the 
pattern of pubertal changes in boys. .Arch Dis 
Child. 1970;45(239):13-23 
References  
Marshall WA, Tanner JM.  Variations in pattern 
of pubertal changes in girls. Arch. Dis. Child. 
1969; 44 (235): 291–303 
 
 

SAP_001.pdf: 
 
 
 
 
Confidential 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
Protocol Number: C1 1209 
 
 
 
Open-label, phase II, single arm study to evaluate the safety, 
immunogenicity, pharmacokinetics and efficacy of 
recombinant human C1 inhibitor for the treatment of acute 
attacks in pediatric patients with hereditary angioedema, from 
2 up to and including 13 years of age 
 
 
 Short title: Safety of Ruconest in 2-13 year old HAE patients 
 
 
 
Customer: Pharming Technologies B.V., The Netherlands 
Compound: Ruconest  
Study Phase: Phase II 
 
 
 
 
 
 
 
Version: 
3.1.0 
Date: 
17 October 2017 
Authors: 
 
 
 


 
Statistical Analysis Plan 
 
Pharming Technologies 
Protocol Number:  C1 1209 
 
Document: S:\Q_003\Q_02119\Paediatric_Study\Prog_Stat\Documentation\SAP\Statistical 
Analysis Plan V3.1.0.doc 
Authors: 
 
Version and Date: Version 3.1.0, 17th October 2017 
Page 2 of 45 
 
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Table of Contents 
STATISTICAL ANALYSIS PLAN ..............................................................................................1 
PROTOCOL NUMBER: C1 1209 ...............................................................................................1 
CUSTOMER: PHARMING TECHNOLOGIES B.V., THE NETHERLANDS .......................1 
VERSION: 3.1.0 .........................................................................................................................1 
AUTHORS: BOB MURRAY, RACHAEL POOLE, WINITHA LIYANAGE ..........................1 
QUANTICATE LTD. .....................................................................................................................1 
LIST OF ABBREVIATIONS .......................................................................................................5 
1. 
INTRODUCTION........................................................................................................6 
1.1 
Rationale ........................................................................................................................6 
2. 
SUMMARY OF THE PROTOCOL ..........................................................................6 
2.1 
Study Objectives ............................................................................................................6 
2.1.1 
Primary Objective ..........................................................................................................6 
2.1.2 
Secondary Objectives.....................................................................................................6 
2.2 
Study Design ..................................................................................................................6 
2.3 
Sample Size Determination............................................................................................8 
2.4 
Schedule of Events .........................................................................................................9 
3. 
PATIENT ANALYSIS SETS ....................................................................................10 
3.1 
Screening Analysis Set ................................................................................................10 
3.2 
Safety Analysis Set ......................................................................................................10 
3.3 
Intention to Treat Analysis Set (ITT)...........................................................................10 
3.4 
Per Protocol (PP) Analysis Set ....................................................................................10 
3.5 
Pharmacokinetic (PK)/Pharmacodynamic (PD) Concentration Set ............................10 
3.6 
Pharmacokinetic (PK)/Pharmacodynamic (PD) Analysis Set .....................................11 
4. 
STUDY MEASURES .................................................................................................11 
4.1 
Efficacy Measures ........................................................................................................11 
4.1.1 
Definitions....................................................................................................................11 
4.1.2 
Primary Efficacy Measure ...........................................................................................14 
4.1.3 
Secondary Efficacy Measures ......................................................................................14 
4.1.4 
Exploratory Efficacy Measures....................................................................................15 
4.2 
Safety Measures ...........................................................................................................18 
4.2.1 
Exposure to Study Medication .....................................................................................19 
4.2.2 
Adverse Events ............................................................................................................19 
4.2.3 
Clinical Laboratory Evaluations ..................................................................................22 
4.2.4 
Electrocardiogram (ECG) Evaluations ........................................................................23 


 
Statistical Analysis Plan 
 
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Protocol Number:  C1 1209 
 
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4.2.5 
Vital Signs Evaluations ................................................................................................23 
4.2.6 
Physical Examination...................................................................................................24 
4.3 
Other Measures ............................................................................................................24 
4.3.1 
Diagnostic Assays and IgE Testing .............................................................................24 
4.3.2 
PK/PD Assays ..............................................................................................................24 
4.3.3 
Immunogenicity ...........................................................................................................25 
4.3.4 
Patient Disposition .......................................................................................................26 
4.3.5 
Protocol Violations ......................................................................................................26 
4.3.6 
Demographics and Baseline Patient Characteristics ....................................................26 
4.3.7 
Medical History ...........................................................................................................27 
4.3.8 
Concomitant Medications ............................................................................................27 
4.3.9 
Treatment Compliance .................................................................................................28 
4.3.10 
Intercurrent HAE attacks .............................................................................................28 
5. 
STATISTICAL METHODOLOGY.........................................................................28 
5.1 
General Statistical Methods .........................................................................................28 
5.1.1 
General Information .....................................................................................................28 
5.1.2 
Default Descriptive Statistics and Data Rules .............................................................28 
5.2 
Hypotheses and Decision Rules ...................................................................................29 
5.3 
Covariates ....................................................................................................................29 
5.4 
Multi-Centre Data ........................................................................................................29 
5.5 
Handling of Missing Data ............................................................................................29 
5.5.1 
Efficacy Endpoints .......................................................................................................29 
5.5.2 
Safety Endpoints ..........................................................................................................29 
5.6 
Interim Analyses ..........................................................................................................30 
6. 
STATISTICAL ANALYSES ....................................................................................31 
6.1 
Patient Disposition .......................................................................................................31 
6.2 
Protocol Violations ......................................................................................................31 
6.3 
Demographics and Baseline Patient Characteristics ....................................................31 
6.4 
Medical History ...........................................................................................................31 
6.5 
Concomitant Medication ..............................................................................................31 
6.6 
Treatment Compliance .................................................................................................31 
6.7 
Efficacy Analyses ........................................................................................................31 
6.7.1 
VAS..............................................................................................................................32 
6.7.2 
TEQ ..............................................................................................................................32 
6.7.3 
Investigator Symptom Score ........................................................................................32 
6.7.4 
Time to Event Analysis ................................................................................................32 
6.7.5 
Therapeutic Failure ......................................................................................................32 
6.7.6 
Receipt of a Second Dose ............................................................................................32 
6.8 
Safety Analyses ............................................................................................................33 
6.8.1 
Exposure to Study Medication .....................................................................................33 
6.8.2 
Adverse Events ............................................................................................................33 
6.8.3 
Clinical Laboratory Parameters ...................................................................................34 














 
Statistical Analysis Plan 
 
Pharming Technologies 
Protocol Number:  C1 1209 
 
Document: S:\Q_003\Q_02119\Paediatric_Study\Prog_Stat\Documentation\SAP\Statistical 
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3. 
Patient Analysis Sets 
The exclusion of patients from the following protocol defined analysis sets will be decided at a pre-
analysis meeting prior to database lock.  
It is assumed that these pediatric patients have had informed consent provided as appropriate 
before or at screening. However, if there are patients who do not meet this criteria, the SAP will be 
updated prior to database lock to indicate how their data are handled in the analysis. 
3.1 
Screening Analysis Set  
The Screening analysis set is defined as all patients screened for the study, who at screening 
were eligible for treatment. 
The following are reasons for exclusion from the Screening analysis set: 
 
Failing to meet the inclusion/exclusion criteria. 
3.2 
Safety Analysis Set 
The Safety analysis set is defined as the set of patients who received at least one dose of the 
study medication. 
The following are reasons for exclusion from the Safety analysis set: 
 
Patient did not receive at least one dose of the study medication. 
The Safety analysis set will be used for all safety analyses. 
3.3 
Intention to Treat Analysis Set (ITT) 
The ITT is defined as the set of patients who received at least one dose of the study medication, 
and for whom any efficacy data is available. 
The ITT will be the primary analysis set of interest for all efficacy endpoints. 
3.4 
Per Protocol (PP) Analysis Set 
The PP analysis set is defined as all patients in the ITT analysis set that had at least one attack 
without any major protocol violations (see Section 4.3.5). Only data from the attacks without major 
protocol violations will be included for these patients.  
The PP analysis set will be used as the analysis set in the confirmatory efficacy analyses. 
3.5 
Pharmacokinetic (PK)/Pharmacodynamic (PD) 
Concentration Set 
The PK/PD Concentration set is defined as the subset of the Safety analysis set that has at least 
one PK/PD concentration measured. 


 
Statistical Analysis Plan 
 
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Protocol Number:  C1 1209 
 
Document: S:\Q_003\Q_02119\Paediatric_Study\Prog_Stat\Documentation\SAP\Statistical 
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3.6 
Pharmacokinetic (PK)/Pharmacodynamic (PD) Analysis 
Set 
The PK/PD analysis set is defined as the subset of the Safety analysis set that has sufficient 
plasma concentration data.  A patient will be seen as having sufficient plasma concentration data 
if at least the peak plasma concentration (Cmax) can be calculated. 
All PK/PD analyses will be performed on the PK/PD analysis set. 
4. 
Study Measures 
This section describes the measures that were collected and/or derived during the study at the 
time points specified in the Schedule of Events (see Section 2.4). This includes efficacy, safety, 
tolerability and patient characteristics data. 
4.1 
Efficacy Measures 
The efficacy endpoints described in this section will be analyzed according to the analysis 
methods described in Section 6.7. 
Each efficacy measure will be calculated separately for each attack for a patient i.e. if a patient 
has two attacks then time to beginning of relief of symptoms, time to complete resolution of 
symptoms etc. will be calculated separately for each attack. Baseline will be calculated separately 
for each attack too.  
4.1.1 
Definitions 
4.1.1.1 
Treatment Effect Questionnaire (TEQ) 
TEQ responses are recorded repeatedly throughout the study at the following time-points; 
Presentation (Pre-dose) and after treatment at 30 minutes, 1, 2, 4, 8 and 24 hours.  
 
The TEQ responses are measured at up to five different locations (Abdominal, Oro-pharyngeal 
and/or Laryngeal (OPL), Facial, Urogenital or Peripheral), depending on the affected locations.  
 
The TEQ consists of the following questions:  
 
 
Question 1 
o 
Pre-dose – To what extent has the overall severity of your [abdominal1] HAE 
attack changed since your arrival at the study center?  
o 
After treatment – To what extent has the overall severity of your [abdominal1] 
HAE attack changed since you received the infusion?  
o 
Possible responses are ‘Much Worse’, ‘Worse’, ‘A Little Worse’, ‘Not Changed’, ‘A 
Little Better’, ‘Better’ or ‘Much Better’. 
 
 
Question 2 
o 
Pre-dose – Overall, has the intensity of your [abdominal1] HAE attack symptoms 
begun to decrease noticeably since your arrival at the study center? 
o 
After treatment – Overall, has the intensity of your [abdominal1] HAE attack 
symptoms begun to decrease noticeably since you received the infusion? 
o 
Possible responses are ‘Yes’ or ‘No’. 
 
Question 3 


 
Statistical Analysis Plan 
 
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o 
At this moment, are your [abdominal1] HAE attack symptoms minimal (barely 
noticeable)? 
o 
Possible responses are ‘Yes’ or ‘No’. 
 
1 abdominal is replaced by the relevant attack location. 
4.1.1.2 
Visual Analogue Scale (VAS) 
VAS scores on angioedema signs and symptoms are recorded repeatedly throughout the study at 
the following time-points; Presentation, 30 minutes, 1, 2, 4, 8 and 24 hours.  
 
The VAS scores are measured at up to five different locations (Abdominal, Urogenital, OPL, 
Facial, or Peripheral Locations), depending on the affected locations.  
 
A series of location specific VAS assessments are taken with the last VAS question for each 
location indicating the overall severity of angioedema symptoms as felt by the patient for that 
location (0 mm corresponding to ‘No symptoms’ and 100 mm corresponding to ‘Extremely 
disabling’), and is called the Overall VAS score.  
Overall VAS:  The Overall VAS score is Question 4 for attacks at Facial or Peripheral Locations, 
Question 5 for attacks at an Abdominal location, Question 6 for attacks at an 
Urogenital location and Question 7 for attacks at an OPL location.  
 
All VAS tables will be based on the Overall VAS score for a given location, the other VAS scores 
will be listed only.  
 
The Baseline Overall VAS score for each location is defined as the last non-missing measurement 
collected/derived prior to the first study medication administration at Time 0 hours for the attack. 
This would normally be the Presentation Overall VAS assessment. 
 
The change from Baseline Overall VAS score at each post-baseline time-point will be calculated 
as: 
Overall VAS score obtained at the specific post-baseline time-point – Baseline Overall 
VAS score 
4.1.1.3 
Investigator Symptom Scores 
Investigator Symptom (IS) scores are recorded repeatedly throughout the study at the following 
time-points:  
 Presentation, 30 minutes, 1, 2, and 4 hours.  
 
The scores are measured at up to 5 different locations (Abdominal, Urogenital, OPL, Facial, or 
Peripheral). A 6 point ordinal scale is used to indicate the severity of the symptoms.  
Table 4 
Investigator Symptom Scoring System 
 
Score 
Response 
0 
No symptoms 
1 
Almost no symptoms 
2 
Mild symptoms 
3 
Moderate symptoms 
4 
Severe symptoms 
5 
Life-threatening 
 


 
Statistical Analysis Plan 
 
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Protocol Number:  C1 1209 
 
Document: S:\Q_003\Q_02119\Paediatric_Study\Prog_Stat\Documentation\SAP\Statistical 
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The Baseline IS score for each location is defined as the last non-missing measurement 
collected/derived prior to the first study medication administration at Time 0 hours for the attack. 
This would normally be the Presentation IS assessment. 
 
The change from Baseline value at each post-baseline time-point will be calculated as: 
IS score obtained at the specific post-baseline time-point – Baseline value 
4.1.1.4 
Eligible Locations 
An attack can occur at more than one anatomical location (although usually at only either one or 
two). Not all locations are eligible for analysis in this study. An eligible location will therefore be 
defined as a location which fulfills the following criteria: 
 
 
Onset of HAE symptoms at the location was less than 5 hours before start time of 
evaluation; 
 
IS score at the location was at least 3 at Presentation; 
4.1.1.5 
Primary Attack Location 
For patients who present with multiple eligible attack locations the most severe eligible location 
will be the eligible location with the highest IS score at Baseline. If the IS score is equal for two 
locations, the most clinically serious location will be defined as the primary attack location.  
The order of clinical seriousness is OPL, followed by Facial, Abdominal, Urogenital and 
Peripheral. The most severe eligible location will be labeled as “the primary attack location”. 
4.1.1.6 
Disallowed Concomitant Medication 
Patients presenting with attacks who have already received any medication since the onset of the 
attack likely to interfere with the evaluation of efficacy and safety will not be eligible for treatment 
for this attack. These treatments include: 
 
Narcotics 
 
Plasma-derived C1 inhibitor 
 
Fresh frozen plasma 
 
Bradykinin receptor antagonist 
 
Analgesics  
 
Anti-emetics 
 
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 
 
Paracetamol (within 45 minutes before the administration of Ruconest) 
 
As an exception, for the patient’s comfort, paracetamol may be taken, but not within 45 minutes 
before the administration of study medication.  
Any change in current and optional maintenance therapy (androgens and/or anti-fibrinolytics) from 
the time of the onset of the current attack is not allowed. The dosage of androgens and anti-
fibrinolytics may not be increased earlier than 24 hours after the treatment with study medication. 
To minimize impact on the assessment of safety, treatment with other investigational products is 
not allowed from screening until 30 days after the patient’s last follow-up visit has occurred. 


 
Statistical Analysis Plan 
 
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4.1.2 
Primary Efficacy Measure 
4.1.2.1 
Time to beginning of relief based on Overall VAS 
The time to beginning of relief will be assessed using the Overall VAS score, where time of 
beginning of relief will be assessed as the first time point at which the VAS score decreases by at 
least 20mm at any eligible anatomical location compared to Baseline, with persistence of the 
decrease at the next time point.  
 
The time of relief will be the first time point at which the Overall VAS score decreases by at least 
20mm compared to Baseline. For example, if this was achieved at 2 hours with persistence shown 
at 4 hours then the time of beginning of relief of symptoms will be 2 hours.  
 
Patients who do not have beginning of relief during the time that they are followed-up will be 
censored at the last time at which the Overall VAS score is recorded at any eligible anatomical 
location. Note: If a patient was randomized but did not have any post-baseline efficacy data then 
they will be censored at Presentation. Patients who first have a decrease of ≥20mm at the last 
time Overall VAS score was recorded will not have achieved beginning of relief with persistence. 
Therefore, they will be censored at the penultimate time that Overall VAS was recorded. 
 
Time to beginning of relief (minutes) will be calculated as: 
 
Actual date and time of first relief (or date and time of censoring) – Date and time of the 
Baseline Overall VAS assessment 
 
The actual date and time of beginning of relief will be used in the calculation. 
 
The beginning of relief assessed using Overall VAS will be assessed for the first eligible location 
at which time to beginning of relief of symptoms by Overall VAS first occurred. Only locations with 
a  populated start date and time and corresponding Overall VAS will be used for the calculation of 
time to beginning of relief.  
 
For the evaluation of persistence, the decrease of ≥20mm is required at the next assessment time 
for which the Overall VAS score is not missing. For example, if 2 Overall VAS determinations with 
≥20mm decline from Baseline are separated by a missing scheduled assessment then beginning 
of relief with persistence would have still been achieved. 
4.1.3 
Secondary Efficacy Measures 
4.1.3.1 
Time to minimal symptoms based on Overall VAS 
The time of minimal symptoms for an attack assessed using the Overall VAS is defined as the 
time at which the Overall VAS score falls below 20mm for all locations where VAS Scores are 
recorded. 
 
Patients who do not have minimal symptoms during the time that they are followed-up will 
be censored at the last time at which an Overall VAS score is recorded. Note: If a patient 
was randomized but did not have any post-baseline efficacy data then they will be 
censored at Presentation. 
 
A worst-case scenario will be used to impute missing Overall VAS scores for locations. If 
there are 2 non-missing values either side of missing value(s) then last observation 
carried forward (LOCF) or next observation carried backward (NOCB) will be used to 
carry forward or back the largest Overall VAS. If there is only one Overall VAS followed by 
missing values or after missing values it will be carried forward or back. If the Overall VAS 
score for a location is blank at Baseline, but then the location is affected by angioedema 


 
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post-dosing, a score of 0 will be imputed for all post-baseline time-points up until the first 
documented Overall VAS score. The worst-case scenario method will then be applied for 
all subsequent missing Overall VAS scores. 
 
The time to minimal symptoms for patients who receive disallowed concomitant 
medication will be censored at the last time at which the patient had an Overall VAS score 
prior to their receipt of disallowed concomitant medication. If this is Presentation and 
hence prior to study drug administration then the time to minimal symptoms will be 
censored at time 0 minutes. 
 
Time to minimal symptoms (minutes) will be calculated as: 
 
Actual date and time of minimal symptoms (or date and time of censoring) – date and time 
of the Overall VAS assessment at Baseline 
 
Time of the actual date and time of minimal symptoms will be used in the calculation.  
4.1.4 
Exploratory Efficacy Measures 
4.1.4.1 
Time to beginning of relief  based on IS score 
The time to beginning of relief will be assessed using the IS scores, where time of beginning of 
relief will be assessed as the first time point at which the investigator assesses the severity of an 
attack as at least one point less (IS decreased by at least 1 point) compared to Baseline at any 
eligible location.  
 
Patients who do not have beginning of relief during the time that they are followed-up will be 
censored at the last time at which the IS score is recorded for any eligible location. Note: If a 
patient was randomized but did not have any post-baseline efficacy data then they will be 
censored at Presentation. 
 
Time to beginning of relief (minutes) will be calculated as: 
 
Actual date and time of first relief (or date and time of censoring) – Date and time of the 
Baseline IS assessment  
 
The actual date and time of beginning of relief will be used in the calculation. 
4.1.4.2 
Time to minimal symptoms based on IS score 
The time of minimal symptoms for an attack using the assessment by the investigator is defined 
as the time at which the IS at the last location falls to 1 point or below.  
The time to minimal symptoms for an attack assessed using the IS scores will be assessed for all 
locations where IS scores are recorded. 
 
Patients who do not have minimal symptoms during the time that they are followed-up will 
be censored at the last time at which the IS score is recorded. Note: If a patient was 
randomized but did not have any post-baseline efficacy data then they will be censored at 
Presentation. 
 
A worst-case scenario will be used to impute missing IS scores for locations. If there are 2 
non-missing values either side of missing value(s) then LOCF or NOCB will be used to 
carry forward or back the largest IS score. If there is only one IS score followed by 
missing values or after missing values it will be carried forward or back. If the IS score for 
a location is blank at Baseline, but then the location is affected by angioedema post-
dosing, a score of 0 will be imputed for all post-baseline time-points up until the first 


 
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documented IS score. The worst-case scenario method will then be applied for all 
subsequent missing IS scores. 
 
The time to minimal symptoms for patients who receive disallowed concomitant 
medication will be censored at the last time at which the patient had an Overall VAS score 
prior to their receipt of disallowed concomitant medication. If this is Presentation and 
hence prior to study drug administration then the time to minimal symptoms will be 
censored at time 0 minutes. 
 
Time to minimal symptoms (minutes) will be calculated as: 
 
Actual date and time of minimal symptoms (or date and time of censoring) – Date and 
time of the IS assessment at Baseline 
 
The actual date and time of minimal symptoms will be used in the calculation.  
4.1.4.3 
Time to beginning of relief based on TEQ 
Time to beginning of relief of symptoms (TEQ) is assessed using Questions 1 and 2 of the TEQ at 
the most severe eligible location. The time of relief will be the first time point at which the 
response to Question 1 of the TEQ was ‘A Little Better’, ‘Better’ or ‘Much Better’ AND the 
response to Question 2 of the TEQ was ‘Yes’ with persistence of the improvement at the next time 
point AND the response to Question 2 of the TEQ was ‘Yes’). Persistence of the improvement at 
the next time point can be defined to mean that at the next available time point, the response to 
Question 1 of the TEQ was at least as good as the previous response (e.g. if the previous 
response was ‘Better’ then the subsequent response would have to be ‘Better’ or ‘Much Better’, ‘A 
Little Better’ would not be sufficient)  
 
The time of relief of symptoms will be the first time point at which Question 1 of the TEQ was ‘A 
Little Better’, ‘Better’ or ‘Much Better’ AND the response to Question 2 of the TEQ was ‘Yes’. For 
example, if this was achieved at 2 hours with persistence shown at 4 hours then the time of 
beginning of relief of symptoms will be 2 hours.  
 
In addition, any patient who did not have beginning of relief of symptoms during the time that they 
are followed-up will be censored at the last time at which the TEQ is recorded for the primary 
attack location. Note: If a patient was randomized but did not have any post-baseline efficacy data 
then they will be censored at Presentation.  
 
Patients who do not have a response of ‘A Little Better’, ‘Better’ or ‘Much Better’ to Question 1 of 
the TEQ and a response of ‘Yes’ to Question 2 of the TEQ until the last time the TEQ was 
recorded will not have achieved beginning of relief with persistence. Therefore, they will be 
censored at the penultimate time that the TEQ was recorded.  
 
Time to beginning of relief of symptoms (minutes) will be calculated as: 
 
Actual date and time of first relief of symptoms (or date and time of censoring) – Date and 
time of first Study Drug Administration 
 
The actual date and time of beginning of relief of symptoms will be used in the calculation.  
 
To allow for missing data in the calculation of time to beginning of relief of symptoms the following 
rules will be applied. These will ensure that for each patient a conservative approach to estimating 
missing data is used: 


 
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 
If a patient has a response of ‘A Little Better’, ‘Better’ or ‘Much Better’ to Question 1 of the 
TEQ with a missing response to Question 2 of the TEQ then the response to Question 2 
will be imputed as ‘Yes’ if the previous response to Question 2 of the TEQ was ‘Yes’ and 
the next response to Question 2 of the TEQ is ‘Yes’, or else will be imputed as ‘No’ if 
either the previous or subsequent responses are not missing.  
 
If a patient has a response of ‘Yes’ to Question 2 of the TEQ with a missing response to 
Question 1 of the TEQ then the response to Question 1 will be imputed as the worst 
response of the previous and subsequent responses to Question 1.  
4.1.4.4 
Time to minimal symptoms based on TEQ 
Time to minimal symptoms (based on the TEQ) will be defined as the first time at which the 
response to Question 3 of the TEQ is ‘Yes’. 
 
 
Patients who do not have minimal symptoms during the time that they are followed-up will 
be censored at the last time at which the TEQ is recorded. Note: If a patient was 
randomized but did not have any post-baseline efficacy data then they will be censored at 
Presentation.  
 
The time to minimal symptoms for patients who receive disallowed concomitant 
medication will be censored at the last time at which the patient had an Overall VAS score 
prior to their receipt of disallowed concomitant medication. If this is Presentation and 
hence prior to study drug administration then the time to minimal symptoms will be 
censored at time 0 minutes. 
 
Time to minimal symptoms (minutes) will be calculated as: 
 
Actual date and time of minimal symptoms (or date and time of censoring) – Date and 
time of first Study Drug Admin 
 
The actual date and time of minimal symptoms will be used in the calculation.  
4.1.4.5 
Time to complete resolution 
In a diary, dispensed at discharge from the hospital,  the patient will be asked to record the date 
and time at which all angioedema symptoms at all locations have resolved (complete resolution). 
If needed, depending on the patient's level of understanding, parents may assist in completion. 
During the Day 28 follow-up visit, the date and time of complete resolution of symptoms, as 
reported by the patient in the diary, is then recorded in the Day 28 CRF.  
Time to complete resolution of all symptoms at all locations will be assessed using the answer 
recorded on the CRF.  
 
 
Time to complete resolution of symptoms will be defined as ‘Time HAE attack resolved’ on 
the CRF. 
 
Patients who do not have complete resolution of symptoms during the time that they are 
followed-up will be censored at 72 hours if the patient confirms that they did not have 
complete resolution of symptoms during the follow-up time, or at the time of discharge if 
the ‘Date HAE attack resolved’ and ‘Time HAE attack resolved’ on the CRF were not 
completed. 72 hours is chosen as this is the average length of time that swelling would be 
expected to subside without treatment. Note: If a patient was randomized but did not have 
any post-baseline efficacy data then they will be censored at Presentation. 
 
The time to complete resolution of symptoms for patients who receive disallowed 
concomitant medication will be censored at the last time the patient had an Overall VAS 


 
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score prior to their receipt of disallowed concomitant medication. If this is Presentation 
and hence prior to study drug administration then the time to complete resolution of 
symptoms will be censored at time 0 minutes. 
 
Time to complete resolution of symptoms (minutes) will be calculated as: 
 
Actual date and time of complete resolution of symptoms (or date and time of censoring) – 
Date and time of Study Drug Admin 
4.1.4.6 
Therapeutic failure 
A patient will be assessed as having had a therapeutic failure if any of the following occurs:  
 
Time to the beginning of relief of symptoms for the attack based on the Overall VAS 
occurs later than 4 hours after Baseline.  
 
Within 4 hours after beginning of treatment administration and after beginning of relief, the 
Overall VAS increases again to a value of at least the Baseline score.  
 
The patient has occurrence of HAE at a new location within 4 hours after achieving 
beginning of relief of symptoms (Based on an IS score of greater than 0 at a new location 
that had an IS score of 0 at Baseline). Beginning of relief of symptoms here is based on 
the Overall VAS as defined in Section 4.1.2.1. 
 
The patient taking any of the medications that may interfere with the assessment of the 
impact of Ruconest on efficacy measures, between the onset of the attack and prior to 
time of initial relief of symptoms including:  
• 
Narcotics 
• 
Plasma-derived C1 inhibitor 
• 
Fresh frozen plasma 
• 
Bradykinin receptor antagonist 
• 
Analgesics  
• 
Anti-emetics 
• 
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 
• 
Paracetamol (within 45 minutes before the administration of Ruconest) 
 
 
The medical monitor will perform a manual review of the concomitant medications and 
identify those which fall into the above categories. 
4.1.4.7 
Receipt of a second dose 
The number of patients who received two doses of rhC1INH as treatment for a single HAE attack 
will be assessed.  For each HAE attack the following will be presented: 
 
 
The number of patients who received a second dose; 
 
The Baseline Overall VAS score at the primary attack location, split by attacks treated 
with a second dose and those that were treated with a single dose.  
4.2 
Safety Measures 
The primary objective of the study is the assessment of safety and tolerability as evaluated by 
recording of adverse events (AEs) and immunogenicity parameters (anti-HRI, anti-rhC1, anti 
rabbit epithelium IgE).   


 
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4.2.1 
Exposure to Study Medication 
Patients up to 84 kg will receive one i.v. injection of Ruconest at a dose of 50 U/kg. Patients of 
84 kg body weight or greater will receive one i.v. injection of Ruconest at the dose of 4200 U 
(2 vials). At the discretion of the investigator and depending upon the patient’s clinical response, 
an additional dose may be given to patients following their initial dose as specified above. No 
more than two doses should be administered within 24 hours.   
The following variables will be calculated for each attack and dose. They will be presented 
separately for the initial and second dose:  
 
Total volume of medication administered (mL) 
 
Total Dose in U/kg (patients who weighed less than 84 kg) 
 
Total Dose in U/kg (patients who weighed more than or equal to 84 kg)  
 
Duration of Infusion in minutes (only summarized for Attack 1) 
 
Duration of Infusion will be calculated as: 
Stop time of last injection – Start time of first injection (for each attack)  
For patients who received a second injection for the same attack, the duration of exposure will be 
calculated as the sum of the duration of exposure for the first and second doses for the attack. 
 
In addition, the following variables will also be calculated: 
 
 
Was the total volume of medication administered (‘Yes’ or ‘No’) 
 
Did the patient received a second dose (‘Yes’ or ‘No’)  
 
Did the patient receive a second dose for any of their attacks? (Yes/No – summarized 
over all attacks) 
 
Time interval between initial and repeat dose (minutes) 
o 
Date and time of start of repeat dose - Date and time of end of initial dose 
 
The following endpoints will also be calculated: 
 
 
Total number of HAE attacks treated with rhC1INH during the study (categorical and 
continuous summaries) 
 
Total number of rhC1INH doses received during the study (categorical and continuous 
summaries) 
 
Total dose of rhC1INH received in U/kg (continuous summary) 
4.2.2 
Adverse Events 
An adverse event (AE) is any undesirable physical, psychological or behavioral effect experienced 
by a patient during the study, in conjunction with the use of the study medication, whether or not 
product-related. This includes any untoward signs or symptoms experienced by the patient from 
the time of signing of the informed consent until completion of the study. 
AEs may include, but are not limited to: 
 
Subjective or objective symptoms spontaneously offered by the patient and/or observed 
by the Investigator or medical staff.  
 
Findings at physical examinations.  


 
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 
Laboratory abnormalities of clinical significance.  
HAE attacks (not treated with study medication) will be reported separately from other AEs. 
AE data was collected from the time that informed consent was given, for the duration of the trial.   
Missing AE data will be handled according to the rules specified in Section 5.5.2.2. 
4.2.2.1 
Adverse Event Definitions 
A treatment-emergent adverse event (TEAE) is defined as an AE that occurred or increased in 
severity within 97 days of a dose of study medication. If there are partial or missing dates for when 
the AE started then it will be assumed that the AE was treatment emergent unless it can be 
determined from the partial start date or stop date that the AE definitely started before the first 
dose of study medication, or more than 97 days after the patient last received study medication. 
Tables will include only TEAEs, but all AEs will be listed.  
Serious adverse events (SAEs) reported from the time of informed consent until the last follow-up 
visit (Day 90) after the last dose of study medication will be recorded as part of the study.  SAEs 
will be any AE where the question ‘Does the adverse event meet the criteria of serious?’ has been 
answered as ‘Yes’.  
A treatment-emergent serious adverse event (TESAE) is defined in exactly the same manner as a 
TEAE, with the exception that the AE in question must be classified as an SAE. 
Each AE will be assigned to an attack based on the start date. If the AE starts after study 
medication was received for Attack N but prior to study medication being received for Attack N+1 
then the AE will be assigned to Attack N. If it is not possible to ascertain from the partial date 
during which attack the AE occurred then the AE will be assigned to the last possible attack based 
on the partial date. 
 
The time from previous administration of study drug to onset of an AE will be calculated for all 
TEAEs as follows: 
 
Date/Time of onset of AE – Date/Time of the start of previous administration of study 
drug. 
An AE will be classified as related to study medication if the relationship to study medication was 
recorded (on the ‘Study Adverse Events’ CRF page,) as, ‘Possible’, ‘Probable’, ‘Definite’.  An AE 
will be classified as unrelated to study medication if the relationship to study medication was 
recorded as ‘Unrelated’. 
An AE leading to study discontinuation will be defined as an AE where 'Action taken discontinued 
study drug' is selected on the Adverse Events CRF page and/or ‘(Serious) Adverse Event 
experience’ is selected as reason for end of study on the End of Study CRF page. 
An AE leading to death will be any AE where the outcome is marked as “4 (Death)”.  
Adverse Events of Special Interest (AEOSI) are AEs that do not meet any criteria for an SAE but 
are nonetheless of particular interest in the context of this study, as listed below: 
 
Type I hypersensitivity reaction due to pre-existing IgE antibodies against rabbit antigens. 


 
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 
Type I hypersensitivity reaction due to cross reaction with IgE antibodies against cow milk 
antigens. 
 
Type I hypersensitivity reaction due to the formation of IgE antibodies against rabbit 
antigens. 
 
Type III hypersensitivity reaction due to the formation of antibodies against Ruconest.  
 
Induction of acquired angioedema due to the formation of anti-C1 inhibitor antibodies. 
 
Thromboembolic complications.  
4.2.2.2 
Coding of Adverse Event Terms 
The AE term (Investigator term) will be assigned to the lowest level term (LLT), and a preferred 
term (PT) will be classified by a system organ class (SOC) according to the Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus, Version 20. 
Although there can be multiple SOCs for a PT, each PT will be linked with one SOC, namely the 
primary SOC which is automatically assigned by MedDRA. 
The following coding data will be presented: 
 
LLT  
 
PT 
 
SOC 
Coding of AEs will be provided by data management at PSR in a coding spreadsheet alongside 
the coding of CMs and MH. The AE coding data will be merged onto the raw AE data by Subject 
ID and AE number. The final version of this spreadsheet will be provided prior to database lock. 
In the event that no coding information is available for a specific AE, the AE will be presented as 
an ‘Uncodable Event’ in all summary tables. 
AEs will be reported on a per-patient basis. On a per-patient basis this means that even if a 
patient reported the same event repeatedly (i.e., events mapped to the same PT) during the study 
period, the event will be counted only once. In the latter case the event will be assigned the worst 
severity and the strongest relationship to the study medication.  The earliest date will be regarded 
as start date of the event and the latest date/time will be regarded as stop date of the event within 
the assigned study period. 


 
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4.2.3 
Clinical Laboratory Evaluations 
Laboratory evaluations were performed at Presentation of attack and Day 28 in accordance with 
the Schedule of Study Events (Section 2.4). Blood and urine samples were collected and 
analyzed by local laboratory.  
Table 5 presents the quantitative and qualitative laboratory tests that were performed. 
Table 5 
Laboratory Tests 
Laboratory Test (Unit) 
Hematology 
Erythrocyte sedimentation rate (ESR) (mm/hr) 
Hemoglobin (g/L) 
Hematocrit (%) 
Red blood cell count (RBC) (1012/L) 
Mean corpuscular volume (MCV) (fl) 
Mean corpuscular hemoglobin (MCH) (pg) 
Mean corpuscular hemoglobin concentration (MCHC) (g/L) 
Total white blood cell count (WBC) (x109/L) 
Platelet count (x109/L) 
Differential WBC units 
Neutrophils (x109/L) 
Lymphocytes (x109/L) 
Monocytes (x109/L) 
Eosinophils (x109/L) 
Basophils (x109/L) 
 
Biochemistry 
Sodium (mmol/L) 
Potassium (mmol/L) 
Chloride (mmol/L) 
Calcium (mmol/L) 
Inorganic phosphate (mmol/L) 
Total protein (g/L) 
Albumin(mg/L) 
Glucose (mmol/L) 
Creatinine (µmol/L) 
Aspartate aminotransferase (AST)  (U/L) 
Alanine aminotransferase (ALT) (U/L) 
Lactate dehydrogenase (LDH) (µkat/L) 
Blood urea nitrogen (mmol/L) 
Bilirubin (Total) (µmol/L) 
Alkaline phosphatase (U/L) 
Gamma-GT (U/L) 
Uric acid (mg/dL) 
Total cholesterol (mmol/L) 
HDL cholesterol (mmol/L) 
Triglycerides (mmol/L) 
C-Reactive Protein (CRP) (mg/L) 


 
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Amylase (U/L) 
 
Urine Pregnancy Test 
For the quantitative laboratory parameters, if a re-test was performed at any visit, the result from 
the re-test for the specific visit will be used in all analyses.  For the qualitative laboratory 
parameters, if a re-test was performed at any visit, the results of the test performed at the re-test 
will be used. 
For each laboratory test (quantitative and qualitative), the Baseline value is defined as the last 
non-missing measurement collected/derived prior to the first study medication administration at 0 
minutes. 
For the quantitative laboratory test, the change from Baseline value at Day 28 will be calculated 
as the difference between the measurements obtained at Day 28 and the Baseline value.  
Quantitative test results at each visit will be categorized by the laboratory as ‘Normal’ (within the 
reference range) or ‘Abnormal’ (outside the reference range) according to the patients’ individual 
reference ranges provided by the analyzing laboratory (see Appendix 1). Note that Système 
International (SI) standardized units will have to be used alongside the individual reference 
ranges, so the process will be to first convert lab data to SI units and then to compare results to 
the individual reference ranges (also known as “normal ranges”). 
Abnormal results will further classified as being ‘Low’ or ‘High‘ depending on whether the result is 
below or above the reference range limits. For all abnormal values, clinical significance (as 
determined by the Investigator) should be indicated. 
4.2.4 
Electrocardiogram (ECG) Evaluations 
Electrocardiogram (ECG) evaluations were performed at Presentation of attack and between 30 
minutes and 2 hours post infusion with study medication, in accordance with the Schedule of 
Study Events (Section 2.4).   
Only qualitative ECG parameters were collected. 
For the qualitative ECG parameters (morphology), it will be recorded whether the parameter at the 
specific visit was ‘Normal’ or ‘Abnormal’.  For all abnormal values, clinical significance (as 
determined by the Investigator) and any ECG findings should be indicated. 
For each qualitative ECG parameter, the Baseline value is defined as the last non-missing 
measurement collected/derived prior to the first study medication administration at Presentation. 
4.2.5 
Vital Signs Evaluations 
Vital signs evaluations were performed at Screening, Presentation of attack, 30 mins, 1, 2 and 
4 hours post infusion with study medication, and Day 90, in accordance with the Schedule of 
Study Events (Section 2.4). 
 


 
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The following variables were collected: 
 
Height (cm) (Height was collected only at Screening). 
 
Weight (kg) (Weight was collected at Screening and Presentation of attack). 
 
Supine systolic blood pressure (SBP) (mmHg). 
 
Supine diastolic blood pressure (DBP) (mmHg). 
 
Pulse rate (bpm). 
 
Body temperature (°C). 
For each vital signs variable, the Baseline value is defined as the last non-missing measurement 
collected/derived prior to the first study medication administration at Presentation. 
Based on the criteria presented in Appendix 1, clinically significant vital sign measurements will be 
identified at each visit. 
4.2.6 
Physical Examination 
Routine physical examination was performed at Screening, Presentation of attack, Hospital 
discharge, Day 28 and Day 90 in accordance with the Schedule of Study Events (Section 2.4).  
4.3 
Other Measures 
4.3.1 
Diagnostic Assays and IgE Testing 
Blood samples for diagnostic assays will be collected at screening. The samples will be analyzed 
for the following parameters: C1INH activity, C1q, C4 and C1INH auto antibodies (IgM, and IgG 
anti-rhC1INH).  
Assays for IgE antibodies against rabbit epithelium (anti-rabbit epithelium IgE [dander]) will be 
performed at screening, at Day 28 after each attack, every year following screening and if AEs 
indicative of a hypersensitivity reaction are observed. Prior to treatment with Ruconest a negative 
test for anti-rabbit epithelium (dander) (cut off <0.35 kU/L) should be documented.  
Similarly, assays for IgE antibodies against cow milk (anti-cow milk IgE) will be performed once at 
Screening. 
4.3.2 
PK/PD Assays 
Blood samples for PK/PD assays will be collected prior to administration of the study medication 
for the first acute HAE attack (named Presentation), one blood sample directly following infusion 
(at time 5 minutes) and another blood sample between 2-4 hours post-infusion (at time 2-4 hours). 
The samples will be analyzed for C1INH activity (PK) and C4 (PD). C4 is additionally analyzed at 
Presentation of each subsequent acute HAE attack. 
For the first attack, the following PK parameters will be derived, where appropriate, for C1INH 
activity in plasma from the concentration-time data using standard noncompartmental procedures; 
Cmax and AUC0-3.  


 
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4.3.3 
Immunogenicity 
Immunology tests will be performed at Screening and for each attack at Presentation and follow-
up visits Days 28 and 90 in accordance with the schedule of study events.  
 
All patients will be tested using ELISA tests to detect for the presence of antibodies against: 
 
rhC1INH-specific IgG (IgG) [cut-off: >15%] 
 
rhC1INH-specific IgM (IgM) [cut-off: >50%] 
 
HRISPeluate-specific AB (HRI) [cut-off: >100%] 
 
Plasma samples found to be above the respective cut-off level are deemed positive and are 
further analysed in a confirmatory displacement assay (to confirm the initial result and discriminate 
between specific and non-specific responses). 
 
Three assays will be performed during the confirmatory displacement assay: displacement 
rAUCa, displacement rAUCb and displacement, %Difference. The value of “displacement, 
%Difference” is used to determine if a sample is confirmed positive for antibodies (i.e. specific 
antibodies are confirmed).  
 
The following cut-off levels are used for the confirmatory displacement assay (results above cut-
off are deemed positive): 
 
rhC1INH-specific IgG, displacement, %Difference [cut-off: ≥45% i.e. sample contains 
rhC1INH-specific IgG antibodies] 
 
rhC1INH-specific IgM, displacement, %Difference [cut-off: ≥40% i.e. sample contains 
rhC1INH-specific IgM antibodies] 
 
HRISPeluate-specific AB, displacement, %Difference [cut-off: ≥35% i.e. sample contains 
HRISPeluate-specific antibodies] 
 
If specific antibodies are confirmed, a further test with a neutralizing antibody assay is performed. 
In other words, only samples which have been confirmed to have specific anti‐rhC1INH IgG and 
IgM antibodies were then analyzed in the neutralizing C1INH antibody assay.  
 
The following Neutralizing AB cut-off levels are used (results below cut-off are deemed positive): 
 
Neutralizing C1INH-specific AB (%) [cut-off: <64%] 
 
Neutralizing rhC1INH-specific AB (%) [cut-off: <54%] 
 
Note: the original plasma sample and all corresponding confirmatory displacement and 
neutralizing AB assays will have the same requisition number in the QPS data file.  
 
The anti-C1INH antibodies labels that will be used in all outputs are presented in Table 6.  
 
Table 6 
Antibody Labels 
 
Antibodies 
Label 
Antibodies against rhC1INH-specific IgG 
Anti-rhC1INH (IgG) 
Antibodies against rhC1INH-specific IgM 
Anti-rhC1INH (IgM) 
Antibodies against HRISPeluate-specific AB 
Anti-HRI 
Neutralizing antibodies against C1INH-specific AB 
Anti-C1INH NAb 
Neutralizing antibodies against rhC1INH-specific AB 
Anti-rhC1INH NAb 
 
The actual values and whether these are above or below cut-off will be presented in the listings. 
Separate listings will be produced of the results of the screening ELISA and the results from the 


 
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displacement and neutralizing assays. The associated attack number and visit will be clearly 
shown for the results from the displacement and neutralizing assays.  
4.3.4 
Patient Disposition 
The following data will also be presented: 
 
Date of Screening visit. 
 
Date of informed consent. 
 
Date and reason for withdrawal from the study, where applicable. 
The analysis sets and subgroups defined in Section 3 will be analyzed and presented as part of 
the patient disposition data. 
4.3.5 
Protocol Violations 
Protocol violations are defined as violations that might affect the efficacy or treatment of a patient, 
and lead to the exclusion of patients from the analysis sets defined in Section 3.  
Protocol deviations are defined in a separate document produced by Pharming prior to database 
lock. Protocol deviations are determined programmatically by data management, manually during 
data review and identified by the monitors during site visits. All deviations identified will be added 
to an excel spreadsheet which shall be sent to Quanticate. Protocol violations which may lead to 
exclusion from the defined analysis sets will be indentified at the Data Review Meeting prior to 
database lock.  
4.3.6 
Demographics and Baseline Patient Characteristics 
Patient demographic data was collected on the ‘Demographics’ CRF page at Screening visit, 
which comprised of date of birth, gender, Tanner Stage, height, weight and race. 
Age (in years) will be calculated relative to the Screening Visit by means of the following 
algorithm:   
Age (Years) = Visit_Y – Birth_Y – (0 < Visit_M < Birth_M OR (Visit_M = Birth_M AND 0 < 
Visit_D < Birth_D)), with variables as follows: 
 
Birth_Y = Year of birth. 
 
Birth_M = Month of birth. 
 
Birth_D = Day of birth. 
 
Visit_Y = Year of Screening visit. 
 
Visit_M = Month of Screening visit. 
 
Visit_D = Day of Screening visit. 
Missing demography data will be handled according to the rules specified in Section 5.5.2.3. 


 
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4.3.7 
Medical History 
Medical history contains information about conditions that a patient might have suffered from prior 
to the first administration of study medication at Presentation, or conditions that were on-going at 
the time of the first administration of study medication. 
Medical history, relevant HAE history and relevant HAE attack history were collected at 
Screening.  
Each term recorded on the medical history page will be assessed to determine whether the event 
was a past or present condition at Screening. This will be taken directly from the tick box on the 
CRF.  
4.3.7.1 
Coding of Medical History Terms 
The medical history term (Investigator term) is assigned to the LLT, and a PT will be classified by 
a SOC according to the MedDRA thesaurus, Version 18 or higher, depending on the latest version 
available during the study. 
Although there can be multiple SOCs for a PT, each PT will be linked with one SOC, namely the 
primary SOC which is automatically assigned by MedDRA. 
The following coding data will be presented: 
 
LLT 
 
PT 
 
SOC 
Coding of MH will be provided by data management at PSR in a coding spreadsheet alongside 
the coding of AEs and CMs. The MH coding data will be merged onto the raw MH data by Subject 
ID and MH number. The final version of this spreadsheet will be provided prior to database lock. 
Medical history will be reported on a per-patient basis. This means that even if a patient suffered 
the same clinical event repeatedly (i.e., events mapped to the same PT) the event will be counted 
only once and the earliest date will be regarded as start date of the event and the latest date will 
be regarded as stop date of the event. 
4.3.8 
Concomitant Medications 
Concomitant medications include all medications and procedures that a patient used at any stage 
during the study.  Any medication started prior to Presentation with attack and used during the 
study, or medication started at any time after the first study medication administration, thus after 
Presentation, will be included. 
Concomitant medications data was collected throughout the study on the ‘Concomitant 
Medications’ CRF page. 
Missing concomitant medications data will be handled according to the rules specified in 
Section 5.5.2.4. 


 
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4.3.8.1 
Coding of Concomitant Medication Terms 
Concomitant medications are classified according to active drug substance using the World 
Health Organization Anatomical Therapeutic Chemical (WHO ATC) Index 2015 or later. 
The ATC code has 7 characters. The first character gives the anatomical main group (1st level), 
the first 3 characters give the therapeutic main group (2nd level), the first 4 characters give the 
therapeutic subgroup (3rd level), the first 5 characters give a further level therapeutic subgroup (4th 
level), whereas the 7 characters give the subgroup for the chemical substance.  In this study, ATC 
codes are defined to the 4th level. 
Although there can be multiple ATC classes for a drug, each drug will be linked with one ATC 
class which will be assigned manually during the coding process, based on information about the 
indication and route in relation to the study therapeutic area.  This one ATC class will be indicated 
as the ‘primary’ ATC class, and only the primary class will be presented. 
Coding of CMs will be provided by data management at PSR in a coding spread sheet alongside 
the coding of AEs and MH. The CM coding data will be merged onto the raw CM data using the 
variables “Subject ID” and “CM no.”. The final version of this spreadsheet will be provided prior to 
database lock. 
4.3.9 
Treatment Compliance 
As this study involves i.v. administration of the study medication administered by study personnel, 
patient compliance measures will not be reported (as detailed in Section 9.7 of the study protocol). 
4.3.10 
Intercurrent HAE attacks 
Occurrence of intercurrent HAE-episodes will be recorded at Days 28 and 90 after the treated 
attack and at yearly follow up visits from the Screening visit thereafter. 
5. 
Statistical Methodology 
5.1 
General Statistical Methods 
5.1.1 
General Information 
All analysis data sets and output, with the exception of the PK/PD analyses and output, will be 
produced by the Biostatistics Department of Quanticate Ltd using the SAS® system Version 9.3 or 
higher. 
5.1.2 
Default Descriptive Statistics and Data Rules 
Unless otherwise stated, summary statistics including the number of patients, mean, standard 
deviation (SD), median, minimum and maximum, will be presented for all continuous variables.  
Minimum and maximum values will be presented to the same decimal precision as the raw values, 
the mean and median values to one more, and the SD, to two more decimal places than the raw 
values. 


 
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For categorical variables, per category, the absolute counts (n) and percentages (%) of patients 
with data, and if appropriate, the number of patients with missing data, will be presented.  All 
percentages will be presented to one decimal place. 
For AEs reported on a per-patient basis, medical history and concomitant medications, the 
denominator for the percentage calculation will be the number of patients.  A patient will be 
considered at risk if the patient is in the Safety/FAS analysis set. 
5.2 
Hypotheses and Decision Rules 
No formal hypothesis testing will be conducted for this study.  
5.3 
Covariates 
There will be no covariates included in analyses. 
5.4 
Multi-Centre Data 
No analyses by center will be conducted. 
5.5 
Handling of Missing Data 
5.5.1 
Efficacy Endpoints 
For the time to event efficacy endpoints, if there is insufficient data to ascertain whether a patient 
has had an event, it will be assumed that they have not had the event.  
5.5.2 
Safety Endpoints  
5.5.2.1 
Exposure 
If the start of treatment date is missing, the latest possible time of all the pre-dose assessments, 
will be imputed as the start of treatment date. 
5.5.2.2 
Adverse Events 
Missing and/or incomplete dates/times for AEs are imputed in a manner resulting in the earliest 
onset or the longest duration during the treatment period, taking additionally into account that the 
start date/time should not be after the stop date/time.  Stop dates/times will not be imputed if the 
AE is on-going. This will be done as follows: 
For a missing/incomplete start date/time the minimum of the following will be imputed: 
 
The maximum of the earliest possible start date/time and the date/time of first study 
medication administration. 
 
The latest possible start date/time. 
 
The latest possible stop date/time. 
 


 
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For a missing/incomplete stop date/time the maximum of the following will be imputed: 
 
The minimum of the latest possible stop date/time and the date/time of last study 
medication administration. 
 
The earliest possible stop date/time. 
 
The earliest possible start date/time. 
The earliest (latest) possible date is defined as: 
 
The date itself if it is complete. 
 
The date of the first (last) day of the month, if month and year are available but day is 
missing. 
 
The date of the first (last) day of the year, if year is available but day and month are 
missing. 
 
A very early (late) date, e.g., 01JAN1000 00:00hrs (01JAN3000 23:59hrs), if the date is 
completely missing. 
The imputation method will only be used to determine treatment emergence and to determine the 
time of the event relative to the first administration of study medication. 
A worst-case approach will be followed in the event of missing severity or causality data.  If the 
severity is missing, ‘Severe’ will be imputed.  If causality data is missing, ‘Related to study 
medication’ will be imputed. 
In the event that no coding information is available for a specific AE, the AE will be presented as 
an ‘Uncodable Event’ in summary tables. 
5.5.2.3 
Demographics 
For determining age when the date of birth is not known completely, a missing day only will be 
imputed as the 15th, a missing day and month will be imputed as the 2nd of July which is day 183 in 
the year. 
5.5.2.4 
Concomitant Medications 
Missing concomitant medication dates will be handled in a similar fashion as described for AEs in 
Section 5.5.2.2. 
5.6 
Interim Analyses 
No Interim Analyses are planned for this study. 


 
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6. 
Statistical Analyses 
6.1 
Patient Disposition 
Patient Disposition recorded at Screening will be summarized by absolute counts (n) and 
percentages (%).  Percentages will be based on the number of patients with data. This will be 
presented for the Screening Analysis Set and for the ITT Analysis Set. 
6.2 
Protocol Violations 
Protocol Violations will be summarized by absolute counts (n) and percentages (%).  Percentages 
will be based on the number of patients with data. 
6.3 
Demographics and Baseline Patient Characteristics 
Demographics include collected and derived, continuous and categorical variables.  Continuous 
variables will be summarized by the number of patients, mean, SD, median, minimum and 
maximum values.  Categorical variables will be summarized by absolute counts (n) and 
percentages (%).  Percentages will be based on the number of patients with data. This will be 
presented for the Screening Analysis Set, Safety Analysis Set, ITT Analysis Set and PP Analysis 
Set.   
6.4 
Medical History 
Medical History will be summarized by absolute counts (n) and percentages (%).  Percentages will 
be calculated based on the number of patients. This will be presented for the Safety Analysis Set 
Separate summaries will also be presented for Relevant HAE history and Relevant HAE Attack 
History. 
6.5 
Concomitant Medication 
Concomitant Medications will be summarized by absolute counts (n) and percentages (%) for 
each PT within ATC class. Percentages will be calculated based on the number of patients at risk.  
This will be presented for the Safety Analysis Set 
6.6 
Treatment Compliance 
Not applicable as per Section 4.3.9.  
6.7 
Efficacy Analyses 
The efficacy endpoints will include collected and derived continuous and categorical variables.  
Continuous variables will be summarized by the number of patients, mean, SD, median, minimum 
and maximum values.  Categorical variables will be summarized by absolute counts (n) and 
percentages (%).  Percentages will be based on the number of patients with data. 


 
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The ITT Analysis Set will be the primary analysis set of interest in all efficacy analyses, and the 
primary and secondary efficacy analysis will be repeated on the PP Analyses set. Individual 
patient listings will be presented for all efficacy data.  Data will be summarized by attack, e.g. First 
attack, second attack, etc.  
6.7.1 
VAS 
Descriptive statistics for the Overall VAS score and change from Baseline will be presented for 
each time point for the primary attack location first, followed by each anatomical location 
separately.  
6.7.2 
TEQ 
Descriptive statistics for the TEQ responses will be presented for each time point for the primary 
attack location first, followed by each anatomical location separately.  
6.7.3 
Investigator Symptom Score 
Descriptive statistics for the IS score will be presented for each time point for the primary attack 
location first, followed by each anatomical location separately.  
6.7.4 
Time to Event Analysis 
Kaplan-Meier (KM) analyses will be performed for each of the time to event endpoints (time to 
beginning of relief and time to minimal symptoms defined using Overall VAS, IS and TEQ, and 
time to complete resolution).  For patients who have been treated for more than one attack, KM 
analyses for time to beginning of relief and time to minimal symptoms using the Overall VAS score 
will be repeated for first and last attacks.   
Patients who did not have the event of interest will be censored at their last available assessment 
of that endpoint. For VAS endpoints, in most cases the last available assessment will be at 24 
hours post infusion, for IS endpoints it will be 4 hours post infusion.  
Additionally, for each endpoint the number and percentage of patients with the event will be 
presented, along with estimates of the median and quartile time to events with 95% confidence 
intervals.  
6.7.5 
Therapeutic Failure 
The number and percentage of patients who experienced therapeutic failure for each attack will 
be presented alongside a categorical summary of the reasons for failure.  A bar chart will also be 
presented for both first and last attack only.  
6.7.6 
Receipt of a Second Dose 
The number of patients who received a second dose will be summarized using counts and 
percentages. The Baseline Overall VAS score at the primary attack location, split by attacks 
treated with a second dose and those that were treated with a single dose, will be summarized 
using summary statistics.   
 


 
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This will be presented by attack number. In addition, a total column will be presented summarizing 
all attacks. If a patient has more than one attack they will be included multiple times in this 
column.  
 
Finally the summary will present the number of patients who had received two doses of rhC1INH 
for any of their attacks.  
6.8 
Safety Analyses 
Unless otherwise stated, safety data will be presented for the Safety Analysis set. Individual 
patient listings will be presented for all safety data. Where applicable, data will be summarized by 
attack, e.g. First attack, second attack, etc.   
6.8.1 
Exposure to Study Medication 
Exposure to Study Medication will include derived continuous and categorical variables.  
Continuous variables will be summarized by the number of patients, mean, SD, median, minimum 
and maximum values. Categorical variables will be summarized by absolute counts (n) and 
percentages (%). Percentages will be based on the number of patients with data. 
Exposure to rhC1INH will be summarized by attack, for both initial and second doses. The 
following variables will be summarized: 
 
Total volume of medication administered (mL)  
 
Total Dose in U/kg (patients who weighed less than 84 kg) 
 
Total Dose in U/kg (patients who weighed more than or equal to 84 kg)  
 
Duration of Infusion in minutes (only summarized for Attack 1) 
 
In addition, within the same summary, “Time interval between initial and repeat dose (minutes)” 
will be summarized under the subtitle “Overall”. 
Total exposure will also be summarized across the whole study (i.e. not by attack). In particular 
the total number of HAE attacks treated with rhC1INH, the total number of rhC1INH doses 
received and the total dose of rhC1INH will be summarized over all attacks.  
The total number HAE attacks treated with rhC1INH and total number of doses of rhC1INH 
received will be summarized as categorical variables and as continuous variables.  
6.8.2 
Adverse Events 
AEs will be recorded throughout the study. These will be coded using the MedDRA dictionary, 
version 18.0 or later. Tables will only summarize TEAEs; all AEs will be listed. 
TEAEs will be summarized using absolute counts (n) and percentages (%). Summaries will be 
presented by SOC and PT. Results will be sorted by decreasing frequency of the SOC and PT 
within the SOC.  
AE tables will be presented by attack for the Safety Analysis Set. A separate column will be 
included summarizing AEs reported regardless of attack number. For the overall column, 
percentages will be presented out of the total number of patients in the Safety Analysis Set and 
counting will be by patient, so if a patient has the same AE in more than one attack this will only 
be counted once in the overall column.  
 
 


 
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The following tables will be produced: 
 
Overall summary of Adverse Events 
 
 
Incidence of Treatment-Emergent Adverse Events 
 
 
Incidence of Related Treatment-Emergent Adverse Events 
 
 
Incidence of Treatment-Emergent Adverse Events Commencing Within 24 Hours of the 
Completion of the Infusion of Study Drug Administration 
 
Incidence of Treatment-Emergent Adverse Events Commencing Within 28 Days of the 
Completion of the Infusion of Study Drug Administration 
 
Incidence 
of 
Treatment-Emergent 
Adverse 
Events 
by 
Strongest 
Relationship 
(Investigator’s Judgment) 
 
Incidence of Treatment-Emergent Adverse Events by Maximum Severity (Investigator’s 
Judgment) 
 
Incidence of Treatment-Emergent Serious Adverse Events 
 
 
Incidence of Treatment-Emergent Adverse Events Leading to Study Discontinuation  
 
Incidence of Treatment-Emergent Adverse Events of Special Interest  
 
The Summary of Adverse Events table will be presented by attack and will show the following: 
 
Number (%) of Deaths 
 
Number (%) of Treatment-Emergent Deaths 
 
Number (%) of Subjects With At Least One SAE 
 
Number (%) of Subjects With At Least One TESAE 
 
Number (%) of Subjects Who Prematurely Discontinued the Study Due to a TEAE 
 
Number (%) of Subjects With At Least One TEAE 
 
Number (%) of Subjects With At Least One Related TEAE 
 
Number (%) of Subjects Without Any TEAEs 
All AEs will be listed. Listings will include CRF collected data, coded terms (primary SOC and PT) 
and a flag for treatment emergence. The time from last administration of study drug to onset of an 
AE (hours) will be listed for TEAEs. Separate listings will be produced for any SAEs and any AEs 
leading to study discontinuation.  
6.8.3 
Clinical Laboratory Parameters 
Clinical Laboratory Parameters include collected and derived quantitative and qualitative 
parameters.  Parameters will be grouped by category (see Table 5 in Section 4.2.3) Quantitative 
parameters will be summarized by the number of patients, mean, SD, median, minimum and 
maximum values.  Qualitative parameters will be summarized by absolute counts (n) and 
percentages (%).  Percentages will be based on the number of patients with data. 
For each attack, data will be summarized by study visit, and the change from Baseline to Day 28 
(if visit occurred before the next treatment) will be presented. Frequency distributions of the status 
(below, within and above the normal range will be presented by study visit, for each attack. A shift 
table of status at Baseline and Day 28 (if visit occurred before the next treatment) will be 
presented for each attack. 
6.8.4 
Electrocardiogram (ECG) Parameters 
ECG Parameters include collected and derived qualitative parameters.  Qualitative parameters 
will be summarized by absolute counts (n) and percentages (%).  Percentages will be based on 
the number of patients with data. 


 
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6.8.5 
Vital Signs 
Vital Signs include collected and derived continuous and categorical variables.  Continuous 
variables will be summarized by the number of patients, mean, SD, median, minimum and 
maximum values.  Categorical variables will be summarized by absolute counts (n) and 
percentages (%).  Percentages will be based on the number of patients with data. 
6.8.6 
Physical Examination 
Routine physical examination results will be listed for individual patients.  
6.8.7 
HAE attacks 
Individual patient listings will be presented for the date and location of HAE attacks. 
6.8.8 
Immunogenicity 
Descriptive statistics will be presented at each assessment time, by attack. In addition, summaries 
will be presented for anti-rhC1INH IgG, anti-rhC1INH IgM and anti-HRI, by attack, for 
Presentation, Day 28 and Day 90 for the following categories: 
 
Initial assay “below cut-off” 
 
Initial assay “above cut-off” but confirmatory assay missing 
 
Confirmatory assay did not confirm initial result 
 
Confirmatory assay confirmed initial result  
The total number of patients assessed for each antibody will also be summarized by attack and 
timepoint. Confirmatory assays here include displacement assays for anti-rhC1INH IgG, anti-
rhC1INH IgM and anti-HRI and the neutralizing assays for anti-C1INH and anti-rhC1INH. 
Separate listings will be produced for the initial assay results and for the confirmatory assay 
results. Those patients with a confirmed positive result will be highlighted in two further listings 
(again one for initial and one for confirmatory). 
6.9 
Other Analyses 
6.9.1 
Diagnostic Assays and IgE Testing 
Descriptive statistics will be presented for the Safety Analysis Set. In particular, a summary will be 
presented of C1INH, C1q and C4 at Screening and separately of C4 at Presentation.  
A shift table of anti-rabbit epithelium IgE results will be presented to indicate the change from 
Screening to Day 28 of each attack. A negative test for anti-rabbit epithelium has a cut off of <0.35 
kU/L and so the shift table will summarize the categories (“Below or equal to 0.35 kU/L” and 
“Above 0.35 kU/L”). 


 
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All individual patient diagnostic and IgE assay results will also be listed.   
All values below the limit of quantification (BLQ) for C1INH, C1q and C4 will be set to half the 
value of the lower limit of quantification (LLQ) for calculation of summary statistics. Similarly, all 
IgE results BLQ will be set to half the value of LLQ for categorization used in the shift table.  
However, in the listings all BLQ values will be reported as “<LLQ”, where LLQ will be replaced 
with the corresponding value for the LLQ of the parameter. 
6.9.2 
PK and PD Assays 
A series of blood plasma samples will be taken for the analysis of C1INH and C4 activity at the 
following time points relative to a patient’s first attack and dosing: Presentation, 5 minutes and 2-4 
hours (post-dose). Additionally, for the first attack, PK parameters will be calculated and 
presented for C1INH activity.   
6.9.2.1 
PK and PD Concentrations 
To assess the single dose PK and PD profiles, PK and PD concentrations will be listed, 
summarized and plotted for patients in the PK/PD Concentration Set, where missing and BLQ 
values will be handled as detailed in Section 6.9.2.1.1.  
Functional C1INH (PK) concentrations will be in units of % of Normal (i.e. results are expressed 
as a percent based on a pool of plasma collected from healthy volunteers, which was original set 
at 100%) whereas C4 concentrations will be in units of µg/mL. 
The Baseline concentration is defined as the concentration taken at Presentation. 
Summaries and figures will include: 
 
Listing of all PK and PD concentrations sorted by, patient ID and nominal time post-dose. 
The listings of concentrations will include the actual sample collection times, the time of 
dosing and deviations from the nominal time. 
 
A summary of concentrations by nominal time post-dose, where the set of statistics will 
include n, mean, geometric mean, median, SD, coefficient of variation (CV) Geometric 
CV, minimum, maximum and the number of concentrations above the LLQ. 
 
Boxplots of concentrations paneled by nominal time, presented separately on linear and 
logarithmic scales. 
 
Boxplots of concentrations grouped by weight and paneled by nominal time, presented 
separately on linear and logarithmic scales. 
 
The ratio (2-4 hours:Baseline) in C4 versus the ratio (2-4 hours:Baseline) in Functional 
C1INH.  
The subgroups for weight for the boxplots of concentrations will be:  
1) Weight ≤ 30kg  
2) 30kg > Weight ≥ 60kg 


 
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3) 60kg > Weight ≥ 84kg 
4) Weight > 84kg 
Paneling by weight will only be performed if there are a sufficient number of patients in each 
subgroup.  
The range for the x-axes of these plots will be decided on review of the data, and will depend on 
how long the concentration is quantifiable in the matrix. 
For summary statistics and boxplots by sampling time, the nominal PK/PD sampling time will be 
used.  
6.9.2.1.1 
Deviations, missing concentrations and anomalous values 
In all PK and PD summary tables and plots, plasma concentrations will set to missing if one of the 
following cases is true: 
1. A concentration has been collected as not done (ND) or no sample (NS); 
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist. These deviations will be defined at the Data Review 
Meeting. 
Note: summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing. 
All concentrations BLQ will be set to half the value of the LLQ for calculation of concentration 
summary statistics. However, in the listings BLQ values will be reported as “<LLQ”, where LLQ will 
be replaced with the corresponding value for the LLQ. 
6.9.2.2 
PK Parameters  
The following PK parameters will be derived, where appropriate, from the PK and PD Analysis Set 
of plasma concentration-time C1INH data using non-compartmental procedures.  
Table 7 defines the PK parameters which will be calculated in this study. 
Table 7  
PK Parameter Definitions 
Parameter 
Definition 
Cmax 
Peak concentration of C1INH. 
AUC0-3 
Area under the plasma concentration-time curve from Presentation to 3 hours 
post-infusion. 
Table 7 refers to the timepoint 3 hours for AUC0-3. This is identical to the timepoint 2-4 hours in 
Table 2: Study Visits. In all summaries the 2-4 hours label will be used rather than 3 hours. 


 
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Actual PK and PD sampling times will be used in the derivation of PK parameters and will be 
calculated as follows: 
All concentrations BLQ will be set to half the value of the LLQ for calculation of PK parameters. 
AUC(0-3) will be calculated using the linear-up log-down trapezoidal method.  
Cmax will be calculated by taking the maximum C1INH concentration for a patients first attack. It 
will only be calculated if there are three measurements for all three time points. 
If a PK parameter cannot be derived from a patient’s concentration data, the parameter will be 
coded as NC (i.e. not calculated). Note: NC values will not be generated beyond the time that a 
patient discontinues. 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics will 
not be presented if more than 50% of the data are NC.   
If an individual patient has a known biased estimate of a PK parameter (e.g. due to an unexpected 
event), this will be footnoted in the summary tables and will not be included in the calculation of 
summary statistics. Biased estimates will be identified and listed during the Data Review Meeting 
alongside a review of the protocol deviations prior to database lock.  
The summary of PK parameters will include the following statistics: n, mean, geometric mean, 
median, SD, coefficient of variation (CV) Geometric CV, minimum and maximum. 
 
7. 
Changes to the Planned Analyses 
7.1 
Changes to the Analyses Described in the Study 
Protocol and Protocol Amendments 
Due to  an inadequate number of sampling time points; the only PK parameters calculated will be 
AUC0-3 and Cmax. See Section 7.3 for further details. 
7.2 
Changes from the Statistical Analysis Plan Version 1.0.0   
Clarification regarding the review of diary data for completion of the Day 28 CRF was made in 
Section 2.2. Section 6.8.6 was added to describe collection of routine physical examination data.  
Re-numbering of outputs in Attachment 1 was performed to bring tables, listings and figures in line 
with ICH E3 reporting guidelines.  No changes were made to planned analyses.   
7.3 
Changes from the Statistical Analysis Plan Version 2.0.0   
 
The following updates were made to Version 2.0.0. of the SAP: 
 
Section 3.7 concerning analysis of subgroups was removed. 
 
Section 4.1 was updated throughout to give further detail on efficacy measures and 
ensure there are precise instructions for analysis. 
 
Section 4.2.1 had further detail added to clarify how certain exposure measures will be 
calculated. 


 
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 
Section 4.2.2 was updated to better describe definitions of TEAEs and how AEs will be 
coded. Clarification was also given for how AEs should be linked to attacks. 
 
Section 4.2.3 was updated to clarify how lab measurements will be converted to standard 
units. 
 
Section 4.3.1 Was updated to include details of IgE testing. 
 
Section 4.3.2 was updated to highlight that AUC(0-3) and Cmax will be the only PK 
parameters calculated. 
 
Section 4.3.3 was updated with a more detailed description of the immunogenicity study 
procedures. 
 
Section 4.3.5 was updated to better reflect the determination of protocol violations. A list 
of inclusion and exclusion criteria was removed from this section. 
 
Section 4.3.7.1 and 4.3.8.1 were updated to reflect how medical history and concomitant 
medications will be coded. 
 
Section 4.3.10 was added to give details of intercurrent HAE attacks. 
 
Section 6.7.1, 6.7.2 and 6.7.3 were updated to indicate that the relevant summaries will 
be by primary attack first, and then by anatomical location. 
 
Section 6.7.5 was updated to better reflect the output it describes. 
 
Section 6.7.6 was added to give details of a summary of those patients who receive a 
second dose of study medication. 
 
Section 6.8.1 was updated to better reflect the output it originally described and to include 
description of an additional output "Total Exposure to rhC1INH". 
 
Section 6.8.2 was updated to describe in more detail the AE related summaries including 
the addition of three new tables. 
 
Section 6.8.8 was updated to better describe immunogenicity related outputs. 
 
Section 6.9.1 was updated to include description of a new shift table of IgE. 
 
Section 6.9.2 was updated with more detail and to reflect the change in the output 
summaries to be produced. 
 
The following tables were removed from the list of tables, listings and figures: 
o 
Summary of PK/PD Concentrations 
o 
Summary of PK/PD Parameters 
 
The following tables were added to the list of tables, listings and figures: 
o 
Receipt of a Second Dose of rhC1INH 
o 
Functional C1INH (% of Normal) Over Time 
o 
Functional C1INH (% of Normal) Cmax and AUC(0-3) Parameters 
o 
C4 Concentrations Over Time 
o 
Incidence of Related Treatment-Emergent Adverse Events 
o 
Incidence of Treatment-Emergent Adverse Events Commencing Within 24 Hours 
of the Completion of the Infusion of Study Drug Administration 
o 
Incidence of Treatment-Emergent Adverse Events Commencing Within 28 Days 
of the Completion of the Infusion of Study Drug Administration 
o 
Change in Status of Hematology Laboratory Parameters Based on Laboratory 
Reference Ranges from Presentation of Attack to Day 28 
o 
Change in Status of Biochemistry Laboratory Parameters Based on Laboratory 
Reference Ranges from Presentation of Attack to Day 28 
o 
Total exposure to rhC1INH 
o 
Shift Table of IGE 
 
The following listings were removed from the list of tables, listings, and figures: 
o 
Listing of Immunogenicity Data 
 
The following listings were added to the list of tables, listings and figures: 
o 
Initial ELISA Immunology Results 
o 
Neutralizing and Displacement Assay Immunology Results 
o 
Initial ELISA Immunology Results – Patients with a  Confirmed Positive Result 


 
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o 
Neutralizing and Displacement Assay Immunology Results – Patients with a 
Confirmed Positive Result 
 
The following figures were removed from the list of tables, listings and figures: 
o 
Bar Chart of IS Score by Time, Attack Number and Attack Location 
o 
Median PK/PD Concentrations (Linear Scale) 
o 
Median PK/PD Concentrations (Logarithmic Scale) 
o 
PK/PD Concentrations by Patient (Linear Scale) 
o 
PK/PD Concentrations by Patient (Logarithmic Scale) 
 
The following figures were added to the list of tables, listings and figures: 
o 
Boxplot of Functional C1INH (% of Normal) paneled by Time (Linear Scale) 
o 
Boxplot of Functional C1INH (% of Normal) paneled by Time (Logarithmic Scale) 
o 
Boxplot of Functional C1INH (% of Normal) grouped by Weight and paneled by 
Time (Linear Scale) 
o 
Boxplot of Functional C1INH (% of Normal) grouped by Weight and paneled by 
Time (Logarithmic Scale) 
o 
Boxplot of C4 Concentrations paneled by Time (Linear Scale) 
o 
Boxplot of C4 Concentrations paneled by Time (Logarithmic Scale) 
o 
Boxplot of C4 Concentrations grouped by Weight and paneled by Time (Linear 
Scale) 
o 
Boxplot of C4 Concentrations grouped by Weight and paneled by Time 
(Logarithmic Scale) 
o 
Ratio with respect to Baseline in C4 versus Ratio with respect to Baseline in 
Functional C1INH 
7.4 
Changes from the Statistical Analysis Plan Version 3.0.0   
 
The definition of eligible location was updated to be based on the IS score as per protocol 
rather than Overall VAS score.  
 
The definition of Therapeutic Failure was updated to be consistent with that of Disallowed 
Medication in Section 4.1.1.6. 
 
The definition of how to deal with values below the lower limit of quantification for 
diagnostic parameters, IM, PK and PD concentrations was updated. 
 
It was clarified that time to event results censored before exposure to treatment due to 
Disallowed Medication would be censored at 0 minutes. 
7.5 
Changes from the Statistical Analysis Plan Version 4.0.0   
No changes will be made to Version 4.0.0 of the SAP after database lock. Any changes to the 
planned analyses occurring after database lock will be described and justified in the Clinical Study 
Report (CSR).  
 
 


 
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7.6 
Attachments and Appendices 
Appendix 1 Clinical Laboratory Evaluations 
Laboratory Unit Conversion 
All laboratory results will be standardized to Système International (S.I) units at the time of 
analysis.  Laboratory unit conversion factors will be provided by data management at the time of 
data transfer as a separate spreadsheet that will be formatted and imported into SAS. A final 
spreadsheet will be provided prior to database lock.  
Laboratory reference ranges 
Abnormal laboratory results will be classified at the time of analysis as being ‘Low’ or ‘High‘ 
depending on whether the result is below or above the reference range limits.  Individual 
reference ranges are assigned based on the center, age and gender of the patient and will be 
provided by the analyzing laboratory. The individual reference ranges will be provided by data 
management at the time of data transfer as a separate spreadsheet that will be formatted and 
imported into SAS. A final spreadsheet will be provided prior to database lock.   
Database Specifications 
A spreadsheet containing definitions and specification of all collected study parameters has also 
been provided by data management.   


 
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Attachment 1 
List of Tables, Listings and Figures 
Table Number 
Title 
Analysis Set 
Repeat 
Table 14.1.1.1 
Summary of Patient Disposition 
Screening 
Unique 
Table 14.1.1.2 
Summary of Patient Disposition 
ITT 
Repeat 
of 
14.1.1.1 
Table 14.1.2 
Summary of Analysis Sets 
All patients 
Unique 
Table 14.1.3 
Summary of Protocol Violations 
Safety 
Unique 
Table 14.1.4.1 
Summary of Demographics and Baseline Patient 
Characteristics 
Screening 
 
Unique 
Table 14.1.4.2 
Summary of Demographics and Baseline Patient 
Characteristics 
Safety 
Repeat 
of 
14.1.4.1 
Table 14.1.4.3 
Summary of Demographics and Baseline Patient 
Characteristics 
ITT 
Repeat 
of 
14.1.4.1 
Table 14.1.4.4 
Summary of Demographics and Baseline Patient 
Characteristics 
PP 
Repeat 
of 
14.1.4.1 
Table 14.1.5 
Summary of Medical History 
Safety 
Unique 
Table 14.1.6 
Summary of Relevant HAE History 
Safety 
Unique 
Table 14.1.7 
Summary of Relevant HAE Attack History 
Safety 
Unique 
Table 14.1.8 
Summary of Concomitant Medication 
Safety 
Unique 
Table 14.2.1.1.1 
Summary of Overall VAS Score by Time and Attack  
ITT 
Unique 
Table 14.2.1.1.2 
Summary of Overall VAS Score by Time and Attack 
PP 
Repeat 
of 
14.2.1.1.1 
Table 14.2.1.2.1 
Summary of Change in Overall VAS Score from 
Baseline by Time and Attack 
ITT 
Repeat 
of 
14.2.1.1.1 
Table 14.2.1.2.2 
Summary of Change in Overall VAS Score from 
Baseline in VAS by Time and Attack 
PP 
Repeat 
of 
14.2.1.1.1 
Table 14.2.1.3.1 
Summary of TEQ by Time and Attack 
ITT 
Unique 
Table 14.2.1.3.2 
Summary of TEQ by Time and Attack 
PP 
Repeat 
of 
14.2.1.3.1 
Table 14.2.1.4.1 
Summary of Investigator Symptom Score by Time 
and Attack 
ITT 
Unique 
Table 14.2.1.4.2 
Summary of Investigator Symptom Score by Time 
and Attack 
PP 
Repeat 
of 
14.2.1.4.1 
Table 14.2.1.5.1 
Time to Beginning of Relief (VAS, IS and TEQ) 
ITT 
Unique 
Table 14.2.1.5.2 
Time to Beginning of Relief (VAS, IS and TEQ) 
PP 
Repeat 
of 
14.2.1.5.1 
Table 14.2.1.6.1 
Time to Minimal Symptoms (VAS, IS and TEQ) 
ITT 
Repeat 
of 
14.2.1.5.1 
Table 14.2.1.6.2 
Time to Minimal Symptoms (VAS, IS and TEQ) 
PP 
Repeat 
of 
14.2.1.5.1 
Table 14.2.1.7.1 
Time to Complete Resolution (Diary) 
ITT 
Repeat 
of 
14.2.1.5.1 
Table 14.2.1.7.2 
Time to Complete Resolution (Diary) 
PP 
Repeat 
of 
14.2.1.5.1 
Table 14.2.1.8.1 
Summary of Therapeutic Failure 
ITT 
Unique 
Table 14.2.1.8.2 
Summary of Therapeutic Failure 
PP 
Repeat 
of 
14.2.1.8.1 
Table 14.2.1.9 
Receipt of a Second Dose of rhC1INH 
ITT 
Unique 
Table 14.2.2.1.1 
Functional C1INH (% of Normal) Over Time 
PK/PD 
Concentration 
Set 
Unique 
Table 14.2.2.1.2 
Functional C1INH (% of Normal) Cmax and AUC(0-
3) Parameters 
PK/PD 
Analysis Set 
Unique 
Table 14.2.2.2 
C4 Concentrations Over Time 
PK/PD 
Unique 


 
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Table Number 
Title 
Analysis Set 
Repeat 
Concentration 
Set 
Table 14.3.1.1 
Summary of Adverse Events 
Safety 
Unique 
Table 14.3.1.2.1 
Incidence of Treatment-Emergent Adverse Events 
Safety 
Unique 
Table 14.3.1.2.2 
Incidence of Related Treatment-Emergent Adverse 
Events 
Safety 
Repeat 
of 
14.3.1.2.1 
Table 14.3.1.2.3 
Incidence of Treatment-Emergent Adverse Events 
Commencing Within 24 Hours of the Completion of 
the Infusion of Study Drug Administration 
Safety 
Repeat 
of 
14.3.1.2.1 
Table 14.3.1.2.4 
Incidence of Treatment-Emergent Adverse Events 
Commencing Within 28 Days of the Completion of 
the Infusion of Study Drug Administration 
Safety 
Repeat 
of 
14.3.1.2.1 
Table 14.3.1.2.5 
Incidence of Treatment-Emergent Adverse Events 
by Strongest Relationship (Investigator’s Judgment) 
Safety 
Unique 
Table 14.3.1.2.6 
Incidence of Treatment-Emergent Adverse Events 
by Maximum Severity (Investigator’s Judgment) 
Safety 
Unique 
Table 14.3.2.1 
Incidence of Treatment-Emergent Serious Adverse 
Events 
Safety 
Unique 
Table 14.3.2.2 
Incidence of Treatment-Emergent Adverse Events 
Leading to Study Discontinuation 
Safety 
Repeat 
of 
14.3.2.1 
Table 14.3.2.3 
Incidence of Treatment-Emergent Adverse Events 
of Special Interest 
Safety 
Repeat 
of 
14.3.2.1 
Table 14.3.4.1.1 
Summary of Quantitative Laboratory Parameters 
Safety 
Unique 
Table 14.3.4.1.2 
Summary of Change in Quantitative Laboratory 
Parameters from Presentation of Attack to Day 28 
Safety 
Repeat 
of 
14.3.4.1.1 
Table 14.3.4.1.3 
Summary of Quantitative Laboratory Parameter 
Classifications Based on Laboratory Reference 
Ranges 
Safety 
Unique 
Table 14.3.4.1.4 
Change in Status of Hematology Laboratory 
Parameters 
Based 
on 
Laboratory 
Reference 
Ranges from Presentation of Attack to Day 28 
Safety 
Unique 
Table 14.3.4.1.5 
Change in Status of Biochemistry Laboratory 
Parameters 
Based 
on 
Laboratory 
Reference 
Ranges from Presentation of Attack to Day 28 
Safety 
Unique 
Table 14.3.4.1.6 
Incidence of Clinically Significant Quantitative 
Laboratory Parameters 
Safety 
Unique 
Table 14.3.4.1.7 
Change in Status of Quantitative Laboratory 
Parameters According to Clinical Significance from 
Presentation of Attack to Day 28  
Safety 
Unique 
Table 14.3.4.2.1 
Summary of Exposure to Study Medication 
Safety 
Unique 
Table 14.3.4.2.2 
Total exposure to rhC1INH 
Safety 
Unique 
Table 14.3.4.3.1 
Incidence of Clinically Significant ECG Parameters 
Safety 
Unique 
Table 14.3.4.3.2 
Change in Status of ECG Parameters from 
Presentation of Attack to Post-infusion 
Safety 
Unique 
Table 14.3.4.4 
Summary of Vital Signs 
Safety 
Unique 
Table 14.3.4.5.1 
Summary of Anti-C1INH and Anti-HRI Immunology 
Parameters Over Time 
Safety 
Unique 
Table 14.3.4.5.2 
Summary of Anti-C1INH and Anti-HRI Immunology 
Displacement and Neutralizing Antibody Assay 
Results Over Time  
Safety 
Unique 
Table 14.3.4.6.1 
Summary of Diagnostic Parameters at Screening 
Safety 
Unique 
Table 14.3.4.6.2 
Summary of Diagnostic Parameters at Presentation 
of Attack 
Safety 
Unique 
Table 14.3.4.7 
Shift Table of IGE 
Safety 
Unique 
 
 
 
 


 
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Table Number 
Title 
Analysis Set 
Repeat 
Listing 16.2.1 
Listing of Patient Disposition 
All Patients 
Unique 
Listing 16.2.2 
Listing of Protocol Violations 
All Patients 
Unique 
Listing 16.2.3 
Patients Excluded from the Efficacy Analysis 
All Patients 
Unique 
Listing 16.2.4.1 
Listing of Demographics and Baseline Patient 
Characteristics 
All Patients 
Unique 
Listing 16.2.4.2 
Listing of Medical History 
All Patients 
Unique 
Listing 16.2.4.3 
Listing of Relevant HAE history 
All Patients 
Unique 
Listing 16.2.4.4 
Listing of Relevant HAE attack history 
All Patients 
Unique 
Listing 16.2.4.5 
Listing of Concomitant Medications 
All Patients 
Unique 
Listing 16.2.5.1 
Listing of Study Medication Administration 
All Patients 
Unique 
Listing 16.2.6.1.1 
Listing of VAS and change from Baseline in VAS 
All Patients 
Unique 
Listing 16.2.6.1.2 
Listing of TEQ 
All Patients 
Unique 
Listing 16.2.6.1.3 
Listing of Investigator Symptom Score (IS) 
All Patients 
Unique 
Listing 16.2.6.1.4 
Listing of time to event endpoints and therapeutic 
failure 
All Patients 
Unique 
Listing 16.2.6.2.1 
Listing of PK/PD concentrations 
All Patients 
Unique 
Listing 16.2.7.1 
Listing of Adverse Events 
All Patients 
Unique 
Listing 16.2.7.2 
Listing of Serious Adverse Events 
All Patients 
Unique 
Listing 16.2.7.3 
Listing 
of 
Adverse 
Events 
Leading 
to 
Discontinuation from Study 
All Patients 
Unique 
Listing 16.2.8.1 
Listing of Clinical Laboratory Parameters 
All Patients 
Unique 
Listing 16.2.8.2 
Listing of ECG Parameters 
All Patients 
Unique 
Listing 16.2.8.3 
Listing of Vital Signs 
All Patients 
Unique 
Listing 16.2.8.4 
Listing of Physical Examination 
All Patients 
Unique 
Listing 16.2.8.5 
Listing of HAE Attacks 
All Patients 
Unique 
Listing 16.2.8.6.1 
Initial ELISA Immunology Results 
All Patients 
Unique 
Listing 16.2.8.6.2 
Neutralizing and Displacement Assay Immunology 
Results 
All Patients 
Unique 
Listing 16.2.8.6.3 
Initial ELISA Immunology Results – Patients with a  
Confirmed Positive Result 
All Patients 
Unique 
Listing 16.2.8.6.4 
Neutralizing and Displacement Assay Immunology 
Results – Patients with a Confirmed Positive Result 
All Patients 
Unique 
Listing 16.2.8.7 
Listing of Diagnostic Parameters 
All Patients 
Unique 
 
 
 
 
Figure 14.2.1.1.1 
Kaplan Meier Plot of Time to Beginning of Relief for 
First Attack (VAS) 
ITT 
Unique 
Figure 14.2.1.1.2 
Kaplan Meier Plot of Time to Beginning of Relief for 
Last Attack (VAS) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.2.1 
Kaplan Meier Plot of Time to Minimal Symptoms for 
First Attack (VAS) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.2.2 
Kaplan Meier Plot of Time to Minimal Symptoms for 
Last Attack (VAS) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.3 
Kaplan Meier Plot of Time to Beginning of Relief (IS) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.4 
Kaplan Meier Plot of Time to Minimal Symptoms 
(IS) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.5 
Kaplan Meier Plot of Time to Beginning of Relief 
(TEQ) 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.6 
Kaplan Meier Plot of Time to Minimal Symptoms 
ITT 
Repeat 
of 


 
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Table Number 
Title 
Analysis Set 
Repeat 
(TEQ) 
Figure 
14.2.1.1.1 
Figure 14.2.1.7 
Kaplan Meier Plot of Time to Complete Resolution 
ITT 
Repeat 
of 
Figure 
14.2.1.1.1 
Figure 14.2.1.8.1 
Bar Chart of Therapeutic Failure for First Attack 
ITT 
Unique 
Figure 14.2.1.8.2 
Bar Chart of Therapeutic Failure for Last Attack 
ITT 
Repeat 
of 
Figure 
14.2.1.9.1 
Figure 14.2.2.1.1 
Boxplot of Functional C1INH (% of Normal) paneled 
by Time (Linear Scale) 
PK/PD 
Concentration 
Set 
Unique 
Figure 14.2.2.1.2 
Boxplot of Functional C1INH (% of Normal) paneled 
by Time (Logarithmic Scale) 
PK/PD 
Concentration 
Set 
Repeat 
of 
Figure 
14.2.2.1.1 
Figure 14.2.2.1.3 
Boxplot of Functional C1INH (% of Normal) grouped 
by Weight and paneled by Time (Linear Scale) 
PK/PD 
Concentration 
Set 
Unique 
Figure 14.2.2.1.4 
Boxplot of Functional C1INH (% of Normal) grouped 
by Weight and paneled by Time (Logarithmic Scale) 
PK/PD 
Concentration 
Set 
Repeat 
of 
Figure 
14.2.2.1.3 
Figure 14.2.2.2.1 
Boxplot of C4 Concentrations paneled by Time 
(Linear Scale) 
PK/PD 
Concentration 
Set 
Unique 
Figure 14.2.2.2.2 
Boxplot of C4 Concentrations paneled by Time 
(Logarithmic Scale) 
PK/PD 
Concentration 
Set 
Repeat 
of 
Figure 
14.2.2.2.1 
Figure 14.2.2.2.3 
Boxplot of C4 Concentrations grouped by Weight 
and paneled by Time (Linear Scale) 
PK/PD 
Concentration 
Set 
Unique 
Figure 14.2.2.2.4 
Boxplot of C4 Concentrations grouped by Weight 
and paneled by Time (Logarithmic Scale) 
PK/PD 
Concentration 
Set 
Repeat 
of 
Figure 
14.2.2.2.3 
Figure 14.2.3 
Ratio with respect to Baseline in C4 versus Ratio 
with respect to Baseline in Functional C1INH 
PK/PD 
Concentration 
Set 
Unique