A Phase IV, Randomized, Double-Blind, Placebo-Controlled Exploratory Study of Xolair (Omalizumab) for Treatment of Idiopathic Angioedema in Patients Who Remain Symptomatic Despite Current Therapy
Phase: PHASE4
Conditions: Idiopathic Angioedema
Sponsor: University of Wisconsin, Madison

1 
 
 
A Phase IV, Randomized, Double-Blind, Placebo-Controlled 
Exploratory Study of Xolair (Omalizumab) for Treatment of 
Idiopathic Angioedema in Patients Who Remain Symptomatic 
Despite Current Therapy 
 
 
 
 
Authors: 
E. A. Schwantes, MS 
 
Principle or Coordinating 
Investigator: 
R. K. Viswanathan, MD and S.K. Mathur, MD, PhD 
 
Document type: 
Clinical Study Protocol 
 
Version number: 
Release date: 
NCT02966314 
5 
 
5/22/2018

2 
 
Table of contents 
Table of contents ................................................................................................................................. 2 
List of tables ........................................................................................................................................ 3 
List of figures ....................................................................................................................................... 3 
List of abbreviations ............................................................................................................................ 4 
Glossary of terms ............................................................................................................................. 5 
Protocol synopsis ................................................................................................................................ 6 
1 
Background ....................................................................................................................................... 10 
2 
Purpose and rationale ....................................................................................................................... 10 
3 
Objectives .......................................................................................................................................... 11 
3.1 
Primary objectives ................................................................................................................ 11 
3.2 
Secondary objectives ........................................................................................................... 11 
4 
Study design ................................................................................................................................... 11 
5 
Population .......................................................................................................................................... 12 
5.1 
Inclusion criteria ................................................................................................................. 12 
5.2 
Exclusion criteria .................................................................................................................. 13 
6 
Treatment .......................................................................................................................................... 13 
6.1 
Investigational and control drugs ......................................................................................... 13 
6.2 
Treatment arms ................................................................................................................. 13 
6.3 
Treatment assignment ......................................................................................................... 14 
6.4 
Treatment blinding ............................................................................................................... 14 
6.5 
Treating the patient .............................................................................................................. 14 
6.5.1 
Patient numbering .............................................................................................. 14 
6.5.2 
Dispensing the study drug ............................................................................... 14 
6.5.3 
Study drug supply, storage and tracking ........................................................... 13 
6.5.4 
Instructions for prescribing and taking the study drug ..................................... 15 
6.5.5 
Permitted study drug dose adjustments and interruptions ................................ 15 
6.5.6 
Rescue medication .......................................................................................... 14 
6.5.8 
Study drug discontinuation and premature patient withdrawal ........................ 16 
6.5.9 
Emergency unblinding of treatment assignment ............................................... 16 
7 
Visit schedule and assessments .................................................................................................... 16 
7.1 
Information to be collected on screening failures ................................................................ 17 
7.2 
Patient demographics/other baseline characteristics .......................................................... 17 
7.3 
Treatment exposure and compliance ................................................................................ 17 
7.4 
Efficacy .............................................................................................................................. 17 
7.4.1 
Efficacy assessment 1 ..................................................................................... 17 
7.5 
Safety ................................................................................................................................. 18 
7.5.1 
Physical examination ......................................................................................... 18 
7.5.6 
Pregnancy and assessments of fertility ............................................................ 18 
7.6 
Other assessments ............................................................................................................ 17 
7.6.1 
Health-related Quality of Life ........................................................................... 17 
7.6.4 
Other biomarkers .............................................................................................. 18 

3 
 
8 
Safety monitoring ............................................................................................................................ 18 
8.1 
Adverse events .................................................................................................................. 18 
8.2 
Serious adverse event reporting .......................................................................................... 20 
8.3 
Pregnancies ................................................................................................................................ 19 
9 
Data review and database management ........................................................................................ 21 
9.1 
Data collection ................................................................................................................... 21 
9.2 
Database management and quality control ....................................................................... 21 
10 Data analysis ..................................................................................................................................... 21 
10.1 
Populations for analysis ....................................................................................................... 21 
10.2 
Patient demographics/other baseline characteristics .......................................................... 21 
10.3     Treatments (study drug, rescue medication, other concomitant therapies, compliance) ….22 
10.4 
Analysis of the primary objective(s) ................................................................................... 22 
10.4.1 
Variable .............................................................................................................. 22 
10.4.2 
Statistical hypothesis, model, and method of analysis ..................................... 22 
10.4.3 
Handling of missing values/censoring/discontinuations .................................... 22 
10.4.4 
Supportive analyses .......................................................................................... 22 
10.5 
Analysis of secondary objectives ......................................................................................... 22 
10.5.1 
Efficacy (secondary) .......................................................................................... 22 
10.6 
Sample size calculation ..................................................................................................... 23 
10.7 
Power for analysis of critical secondary variables ............................................................... 22 
11 Ethical considerations ........................................................................................................................ 22 
11.1 
Regulatory and ethical compliance .................................................................................... 22 
11.2 
Informed consent procedures ............................................................................................ 22 
11.3 
Responsibilities of the investigator and IRB/IEC/REB ........................................................ 22 
11.4 
Publication of study protocol and results ........................................................................... 23 
12 Protocol adherence ......................................................................................................................... 23 
12.1 
Protocol Amendments........................................................................................................ 23 
13 References ........................................................................................................................................ 23 
 
 
List of tables 
 
Table 7-1 
Assessment schedule ........................................................................................ 16 
 
 
List of figures 
 
Figure 4-1 
Study design .................................................................................................... 12 

4 
 
 
List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
b.i.d. 
twice a day 
CRF 
Case Report/Record Form 
CRD 
Clinical Research and Development 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMS 
Integrated Medical Safety 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
o.d. 
once a day 
p.o. 
oral(ly) 
REB 
Research Ethics Board 
SAE 
serious adverse event 

5 
 
 
Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each medication package in 
studies that dispense medication using an IVR system 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each patient in the study. 
Stage 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points 

6 
 
 
Protocol synopsis 
Title of study: A Phase IV, Randomized, Double-Blind, Placebo-Controlled Exploratory Study of Xolair 
(Omalizumab) for Treatment of Idiopathic Angioedema in Patients Who Remain Symptomatic Despite 
Current Therapy 
Purpose and rationale: The overall hospitalizations for a diagnosis of angioedema doubled from the 
year 2000 to 2009. Although some of the cases represented hereditary angioedema or ace-inhibitor 
induced angioedema, the majority of episodes were idiopathic. Idiopathic Angioedema (IAE) can be life- 
threatening especially when affecting tissues within the respiratory tract. No clear guidelines exist for 
management of this important condition for clinicians. Current therapies typically include avoidance of 
potential triggers and use of medications either for prophylaxis or for acute events, such as 
antihistamines, corticosteroids, and epinephrine. There remains a critical need for therapeutic options to 
provide more effective prophylaxis. 
 
Objectives: 
Primary objective: To estimate the effect of omalizumab in reducing the severity of angioedema 
episodes in patients with IAE. 
Secondary objectives: 
To estimate the effect of omalizumab in improving quality of life in IAE subjects. 
To estimate the effect of omalizumab in reducing frequency, duration of angioedema 
episodes, need for rescue medication/corticosteroids, and need for unscheduled 
clinic/urgent care/ER visits. 
To assess the safety of omalizumab usage in patients with IAE. 
To assess the effect of omalizumab on biomarkers previously implicated in the pathogenesis 
of IAE. 
 
 
Population: Forty adults (age 18 or older) with 2 or more episodes of Idiopathic Angioedema (IAE) in the 
past 6 months, despite current therapy will enter the treatment period. 
 
 
Inclusion/Exclusion criteria: 
Inclusion criteria 
1) Adults or adolescents who are 18 years or older with physician diagnosis of IAE. 
2) Minimum of two episodes of IAE in the past 6 months. 
3) Management with a stable treatment plan for the prior 6 months. 
4) Complement profile (C1 Esterase inhibitor panel) within normal reference values. 
5) If a woman is of child-bearing potential, she must agree to a reliable form of birth control 
including: abstinence, oral contraceptives (birth control pills), Depo-provera, an IUD (intrauterine 
device), or double-barrier contraception (partner using condom and subject using diaphragm, 
contraceptive sponge or cervical cap, and spermicidal). 

7 
 
 
Exclusion criteria 
1) Diagnosis of HAE, Acquired Angioedema, or Ace-inhibitor associated angioedema, which are 
forms of angioedema with known mechanisms and alternate treatment options. 
2) Chronic Urticaria (itching and/or hives) with or without Angioedema which are known mast 
cell mediated processes previously shown to be responsive to the use of omalizumab. 
3) Previous usage of omalizumab in the last 3 months which can affect the patient-related 
outcomes and biomarker assessments if not “washed out” of the system. 
 
4) Patients, who in the judgment of the investigator, have a history or condition that might 
compromise patient safety or compliance, interfere with evaluations, or preclude completion of the 
study. 
 
 
Investigational and reference therapy: 
Treatment 
Arm 
# of 
Patients 
Entered 
Treatment 
Type of Study 
Drug 
Compound 
Min 
Dose 
Max 
Dose 
Frequency 
Admin. Route 
Treatment 
Arm 
20 
Investigational 
Xolair 
(omalizumab) 
300mg 
every 4 weeks 
x 24 weeks 
Subcutaneous 
Placebo 
Arm 
20 
Placebo 
Matching placebo 
every 4 weeks 
x 24 weeks 
Subcutaneous 
 
 
Study design: This study is a randomized, double-blind, placebo-controlled, parallel group trial which will 
study the effects of omalizumab on patients with 2 or more episodes of Idiopathic Angioedema (IAE) in 
the past 6 months, despite current therapy. This study has three periods; screening, treatment, and 
follow-up. Subjects in the screening period will be consented and screened for eligibility criteria. 40 
qualified individuals will enter the treatment period. Individuals will be randomized to either every 4 weeks 
subcutaneous administration of omalizumab 300mg (20 subjects) versus every 4 weeks placebo injection 
(20 subjects) in addition to their previously prescribed management plan for a total of 24 weeks. 
Individuals will then enter a follow-up period of 4 months. Study visits will occur every 4 weeks during the 
treatment period for update of clinical status and administration of omalizumab/placebo injection. After, 
the treatment period individuals will be seen twice for follow-up. The entire study will consist of 10 study 
visits and will last approx. 10 months. 
Efficacy assessments: 
• 
Changes in the patient-related outcome measure of Angioedema Activity Score (AAS7, (Weller 
et al., 2013)) 
Other assessments: 
• 
Changes in the quality of life of idiopathic angioedema patients as determined by the 
Angioedema QoL Questionnaire (AE-QoL, Weller et al., Allergy 2012) 
• 
Changes in the severity of angioedema episodes in the past 4 weeks will be determined using 
changes in the patient-related outcome measure of Angioedema Activity Score (AAS28, 
(Weller et al., 2013)) 
• 
Frequency, duration of IAE episodes (hours), rescue medication or corticosteroid usage, and 
number of unscheduled clinic/urgent care/ER visits will be based on monthly recall with 
questionnaires performed at each study visit. 

8 
 
• 
Visual analog score for IAE severity will be determined at each study visit. 
• 
We will identify any reported AE during the course of the study. 
• 
We will examine changes in basophil flow cytometry (CD63 and CD203 expression), tryptase, 
bradykinin and its degradation products, and platelet activating factor (PAF). 
 
Data analysis: 
The primary analysis will estimate the effect of treatment, compared to placebo, on the change in 
Angioedema Activity Score (AAS7) from baseline to the end of the treatment period using analysis of 
covariance (ANCOVA) with treatment group and baseline AAS7 as covariates. Longitudinal comparisons 
of the repeated (monthly) AAS7 measurements will also be examined using linear mixed effect models in 
a secondary analysis. For the secondary outcomes, a similar strategy will be used, adjusting for the 
baseline value of the outcome where possible, using similar linear models or generalized linear models 
including count regression for frequency outcomes and logistic regression for categorical outcomes. 
Participants will be compared as-randomized using the intention-to-treat principle. Missing data will be 
addressed using multiple imputations. 

9 
 
 
1 
Background 
Angioedema (AE) refers to the rapid swelling of the deep dermis, submucosal and subcutaneous tissue 
while urticaria involves swelling in the upper dermis. It occurs as a result of a transient extravasation of 
fluid into the interstitium due to the release of vasoactive substances. Angioedema can involve various 
tissues and regions of the body including face, lip, tongue, mouth, throat, larynx, extremities, abdomen, 
and genitalia. Angioedema can be life-threatening especially when affecting tissues within the respiratory 
tract. Several different types of AE have been recognized over the years including most notably 
hereditary angioedema (HAE), ACE-inhibitor induced angioedema (ACEI-AE), acquired angioedema 
(AAE), and an idiopathic form (IAE) that could be either histaminergic or nonhistaminergic in etiology. 
IAE is defined as angioedema episodes that occur without any clear identifiable etiology and not 
associated with HAE (hereditary angioedema), ACE-inhibitor induced angioedema, acquired 
angioedema, and angioedema associated with chronic urticaria. 
 
The time course of the angioedema episode is variable lasting anywhere from 1-4 days with the 
nonhistaminergic forms taking longer to resolve. HAE can start to present early in childhood and worsen 
around puberty with symptoms involving the abdominal wall, extremities, face and upper airway and can 
last about 24-48 hours. Recurrent abdominal pain usually prompts its evaluation. ACEI-AE has an 
incidence of approximately 0.1-0.7% with symptoms targeting the face, lips, tongue, larynx and pharynx.   
It is characteristically associated with the usage of an ACE-I. Acquired angioedema is an adult onset   
form often associated with the presence of a lymphoproliferative disorder with symptoms targeting the 
face, upper airways and abdomen. Idiopathic angioedema is poorly characterized and symptoms involve 
the extremities, face, and upper airways with a lower preponderance for the abdomen. While involvement 
of the larynx and pharynx has been reported, it involves the respiratory tract much less frequently. 
 
It is important to establish or exclude an appropriate etiology for AE as the therapeutic algorithms for 
management varies. HAE subtypes (Type I and II) are well characterized forms of AE with known defects 
in the SERPING1 gene resulting in depressed complement profiles (low C4) including abnormal C1 
inhibitor level and/or function. An evaluation of complement profiles and C1 inhibitor level and function 
can help to delineate these entities. A new subtype of HAE (Type III) has been recently described with a 
normal complement profile and C1 inhibitor panel that occurs as a result of mutations in the Factor XII 
gene. It has a more characteristic association to estrogen exposure. Acquired angioedema has a similar 
complement profile to HAE Type I with one distinguishing feature- a low C1q level. No known genetic 
mutations are associated with AAE. ACEI-AE has a normal complement profile and is associated with 
ACE-I usage. Idiopathic angioedema also has a normal complement profile, but some of the 
distinguishing features of the above are lacking. Mechanistically, increased levels of bradykinin and 
degradation products appear to play a role in all forms of angioedema with some forms having a mast-cell 
mediated component that is responsive to antihistamine therapy. 
 
 
2 
Purpose and rationale 
Treatment guidelines are clearly established for the management of HAE I and II for prophylactic and 
abortive purposes, and avoidance of ACE-I is recommended for ACEI-AE. However, no clear guidelines 
exist for the diagnosis or management of IAE. Current therapies typically include avoidance of potential 
triggers and use of medications either for prophylaxis or for acute events, such as antihistamines, 
corticosteroids, and epinephrine. There remains a critical unmet need for therapeutic options to provide 
more effective prophylaxis and possible disease-modification effects for patients with IAE. For example, 
there are some patients using chronic prophylactic antihistamine therapy and for any acute episode of 
IAE, they may take additional on demand medications such as additional doses of antihistamine and/or 
corticosteroid. There are others who may not use any chronic prophylaxis and only use on demand 
antihistamines and/or corticosteroids with acute episodes of IAE. 

10 
 
Omalizumab recently garnered FDA-approval for chronic urticaria with or without angioedema. Evidence 
from trials performed in chronic urticaria suggests that omalizumab is efficacious in controlling both 
urticarial flares and concurrent angioedema episodes. However, omalizumab has not yet been well 
investigated for IAE, though there have been some case reports that suggest efficacy for IAE (Azofra et 
al., 2015; Ozturk and Kocaturk, 2014; Sands et al., 2007; Weller et al., 2013) 
 
With the efficacy observed in urticaria patients, it is clear that omalizumab can suppress mast cell activity, 
although the mechanisms for the benefit remain somewhat unclear. The kinetics of omalizumab effects, 
especially in the context of chronic spontaneous urticaria, suggests that sequestration of IgE molecules is 
not the complete answer. Given the likely role of mast cells in the majority of IAE, we hypothesize that 
omalizumab will have potential disease modifying effects in reducing the severity and frequency of 
IAE. 
 
3 
Objectives 
3.1 
Primary objectives 
To estimate the effect of omalizumab in reducing the severity of angioedema episodes in patients 
with IAE. 
 
3.2 
Secondary objectives 
To estimate the effect of omalizumab in improving quality of life in IAE subjects. 
To estimate the effect of omalizumab in reducing frequency, duration of angioedema episodes, need for 
rescue medication/corticosteroids, and need for unscheduled clinic/urgent care/ER visits. 
To assess the safety of omalizumab usage in patients with IAE. 
To assess the effect of omalizumab on biomarkers previously implicated in the pathogenesis of IAE. 
 
 
4 
Study design 
This study is a randomized, double-blind, placebo-controlled, parallel group trial which will study the 
effects of omalizumab on patients over the age of 18 with 2 or more episodes of Idiopathic Angioedema 
(IAE) in the past 6 months, despite current therapy. This study has three periods; screening, treatment, 
and follow-up. Subjects in the screening period will be consented and screened for eligibility criteria. If 
subjects have not had a complement profile within the normal reference range (C1 Esterase inhibitor 
panel), subjects will be asked to return for a second screening visit to assess their complement profile. 
Subjects in the screening period will also undergo a 24-hour urine collection for mast cell mediators (such 
as n-methyl histamine, 11β- PGF2α, and PGD2 testing) and a blood draw for chronic urticaria index 
testing in addition to the C1 esterase inhibitor panel. If under the subject’s current care guidelines, they are 
taking prednisone or other immunomodulator episodically (on demand usage) we will collect baseline test 
after a 14 day washout period has occurred. If there is no such window or they are taking daily medication, 
we will proceed with the baseline measurements despite the use of an immunomodulatory or prednisone. 
40 qualified individuals will enter the treatment period. Individuals will have a baseline assessment and be 
randomized to either every 4 week subcutaneous administration of omalizumab 300mg (20 subjects) 
versus every 4 week placebo injection (20 subjects) in addition to their previously prescribed management 
plan for a total of 6 months. Individuals will then enter a follow-up period of 4 months. Study visits will occur 
every 4 weeks during the treatment period for update of clinical status and administration of 
omalizumab/placebo injection. After the treatment period individuals will be seen twice for follow-up, 4 
weeks and 12 weeks post treatment. The entire study will consist of 10 study visits and will last approx. 10 
months (see Table 4-1). The blind will be maintained for the full 10 months of the study. 

11 
 
 
 
Table 4-1 
Study design 
 
 
 
Study Periods 
Screening 
Treatment 
Follow-Up 
Visit Number 
1A 
1B 
2 
3 
4 
5 
6 
7 
8 
9 
Time of Visit 
Screen Screen Baseline Week 
4 
Week 8 Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
36 
Visit window 
-3 to -6 
wks 
-1 to -3 
wks 
 
+7days +7days +7days +7days +7days +7days 
 
Inclusion/Exclusion 
x 
Informed consent 
x 
Physical examination 
x 
 
x 
Dispense AAS28 
 
x (7 
days) 
x 
x 
x 
x 
x 
x 
x (12 
weeks) 
 
Collect AAS28 
 
x (7 
days) 
x 
x 
x 
x 
x 
x 
X (12 
weeks) 
In clinic  
questionnaires (Ae-Qol 
and VAS) 
 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study 
medication 
x 
x 
x 
x 
x 
x 
Laboratory test* 
x 
x 
x 
x 
x 
Urine pregnancy test 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Concomitant Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
* Laboratory testing study grid in Appendix 4 
 
 
5 
Population 
Forty adults (age 18 or older) with 2 or more episodes of Idiopathic Angioedema (IAE) in the past 6 months, 
despite being on recommended therapy for the past 6 months will enter the treatment period at the University of 
Wisconsin-Madison Allergy and Asthma Clinical Research Unit. Once an individual enters the treatment phase 
they will be counted as 1 of the 40 subjects, and they will not be replaced. It is anticipated that we will need to 
screen 60 subjects in order to obtain 40 qualified participants. 
 
Subjects will primarily be recruited by Drs. Mathur and Viswanathan from their clinics. Subjects who are seen in 
their clinics for a diagnosis of idiopathic angioedema will be asked if they are interested in participating in this 
study. If yes, their contact information will be given to the Allergy Research Staff to do a follow up call for a phone 
screen. The following information will be faxed to the allergy research staff: name, phone number, alternate phone 
number, and email address. If no, their information will not be shared with the Allergy Research Staff.  
 
Additionally, we will use UW Health Electronic Medical Record system (HealthLink) to send out recruitment letters. 
Letters will be sent to those individuals (age 18 or older) who have ICD 9/10 code for angioedema with no history 
of drug-induced angioedema, hereditary angioedema, or a history of urticaria. The letters will invite them to 
participate in the study and notify them that they will receive a follow up phone call regarding the study.  
 
Letters will be also be sent out to local allergists notifying them of the study. The letter will include a second letter 
which can be given to their patients they feel would qualify for the study. In addition, advertisements will be placed 

12 
 
around the local hospital and clinics.  
 
This study recruitment and treatment is expected to last 5 years, from the recruitment of the first subject, with 
anticipated end date of 12/2021. Study analysis is expected to last an additional year.  
 
 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
• 
Adults or adolescents who are 18 years or older at the time of screening with physician diagnosis of IAE. 
• 
Minimum of two episodes of IAE in the past 6 months at the time of screening. 
• 
Management of IAE with a stable controller treatment plan for the prior 6 months at the time of 
screening, which will include patients managed using the following approaches: 
-No prophylaxis and only use of on demand medications for episodes of IAE 
-Use of prophylactic medications and additional on demand medications for episodes 
of IAE 
• 
Complement C1 esterase inhibitor panel within normal reference ranges. 
• 
If a woman is of child-bearing potential, she must agree to a reliable form of birth control including: 
abstinence, oral contraceptives (birth control pills), Depo-provera, an IUD (intrauterine device), or 
double-barrier contraception (partner using condom and subject using diaphragm).  
 
5.2 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from study entry: Safety 
Exclusion Criteria 
• 
Unable to give informed written consent, unable to adhere to the outlined visit schedule or unable to 
tolerate the procedures required for participation in this trial. 
• 
Unable, in the judgment of the investigator, to comply with study procedures and/ or directions. 
• 
Treatment with an investigational agent within 30 days of the screening visit. 
• 
Medical examination or laboratory findings that may suggest neoplasms, malignancies, or a history of 
malignancies. 
• 
Nursing mothers, pregnant women, or women of childbearing potential who are planning a pregnancy during 
the course of the study. 
• 
Any history of life-threatening angioedema which affects breathing requiring intubation in the past 2 years 
and prior to angioedema treatment. 
• 
Patients, who in the judgment of the investigator, have a history or condition that might compromise patient 
safety or compliance, interfere with evaluations, or preclude completion of the study. 
 
 
Baseline Exclusion Criteria 
• 
Diagnosis of HAE, Acquired Angioedema, or Ace-inhibitor associated angioedema, which are forms of 
angioedema with known mechanisms and alternate treatment options. 
• 
Chronic Urticaria with or without Angioedema which are known mast cell mediated processes previously 
shown to be responsive to the use of omalizumab. 
• 
Previous use of omalizumab in the last 3 months which can affect the patient-related outcomes and 
biomarker assessments if not “washed out” of the system. 
 

13 
 
 
 
6 
Treatment 
6.1 
Investigational and control drugs 
Omalizumab is a sterile, white, preservative-free, lyophilized powder, contained in a single-use vial that will be 
reconstituted with sterile water for injection (SWFI), USP, and administered as a subcutaneous injection. Each 
omalizumab vial contains 202.5 mg of omalizumab, 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride 
monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial is designed to deliver 150 mg of 
omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP. 
Placebo will be provided by drug supply management 
 
6.2 
Treatment arms 
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1 
• 
Arm 1: 
Omalizumab: 300mg subcutaneous injection every 4 weeks for 24 weeks. Total dose 
will be divided into two 150mg/1.2mL injections. 
• 
Arm 2: 
Placebo Group: two 1.2mL subcutaneous injections every 4 weeks for 24 weeks. 
6.3 
Treatment assignment 
Randomization will be completed by the University of Wisconsin Hospital and Clinics Pharmaceutical Research 
Center using a forced block design. Once a subject has been cleared for initial treatment, the next ascending 
sequential randomization number (and corresponding treatment) will be assigned. 
Subjects will be enrolled and randomized to one of two treatment arms in a 1:1 ratio. 
 
6.4 
Treatment blinding 
All subjects and research staff will be blinded to treatment assignment; study drug will be administered by a single 
unblinded research nurse (who will not be evaluating patients or collecting data). Double blinded treatment will be 
maintained until the conclusion of the study. Randomization and treatment preparation will be handled by the 
unblinded Hospital Pharmacy. Unblinding of the investigators, statisticians and research team will occur at the 
conclusion of data analysis. 
Subjects will remain blinded until analysis of the trial has been completed. At the conclusion of the study analysis, 
participants will be notified through written notification from Drs. Mathur or Viswanathan of their 
treatment 
assignment. 
6.5 
Treating the patient 
 
6.5.1 
Patient numbering 
Patients will be assigned a Subject ID# upon screening; Randomization Number (and treatment) will be assigned 
prior to first treatment, but after subject has been cleared for treatment. 
 
6.5.2 
Dispensing the study drug 
Once randomized to a study treatment, the product will be prepared by unblinded staff in the UW hospital 
pharmacy.  
Omalizumab-assigned subjects 
• 
Reconstitution: 
o 
Using a 1 inch, 18g needle and 3mL syringe, draw up 1.4mL of Sterile Water for Injection (SWFI), 
USP 

14 
 
o 
Slowly add the SWFI to the wet the powder, do not shake 
o 
Gently swirl the upright vial for 5-10 seconds approximately every 5 minutes until dissolved; 
generally, takes 20 minutes to dissolve completely 
o 
Continue to swirl gently until no gel-like particles are visible; do not use if contents are not 
completely dissolved after 40 minutes 
o 
Resulting solution is 150mg/1.2mL 
• 
Drawing up the dose 
o 
Invert the vial for 15 seconds so the solution drains toward the stopper 
o 
Remove all of the solution in the vial by inserting a new 3mL syringe with a 1inch, 18g needle into the 
inverted vial 
o 
Expel any air or bubbles or excess solution to obtain the 1.2mL dose. 
o 
Remove needle and cap with a sterile rubber tip. 
o 
Expiration = 4 hours if stored at room temperature and 8 hours if stored under refrigeration. 
 
Placebo-assigned subjects  
• 
Drawing up the dose 
o 
Draw up 1.2mL placebointo a 3mL syringe. 
o 
Expel any air or bubbles or excess solution to obtain the 1.2mL dose. 
o 
Remove needle and cap with a sterile rubber tip. 
o 
Expiration = 4 hours if stored at room temperature and 8 hours if stored under refrigeration. 
 
6.5.3 
Study drug supply, storage and tracking 
Omalizumab will be provided in 150mg single use vials containing sterile, white, Preservative-Free, lyophilized 
powder. Vials will be stored under refrigeration at 2o to 8o (36o to 46o F). 
Matching placebo will be supplied by Novartis. Vials will be stored at room temperature: 20o to 25o (68o to 77 oF); 
that results in a mean kinetic temperature calculated to be not more than 25o; and that allows for excursions 
between 15o and 30o (59o and 86oF). 
All study provided products must be received at the study site by a designated individual, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated staff have 
access. Storage conditions must be adequately monitored and appropriately documented as source information.  
Investigator or designee must maintain an accurate record of the shipment and dispensing of study drug and all 
supplies are to be used only for subjects on this protocol and not for any other purposes.  Study drug will be 
supplied from Novartis in 3 shipments, 6 months apart. 
 
6.5.4 
Instructions for prescribing and taking the study drug 
Each study drug dose (Omalizumab 300mg or Placebo) will consist of two syringes; each containing 1.2 mL total 
volume. Due to the viscosity of Omalizumab, study drug must be administered by an unblinded Research Nurse. 
Active omalizumab may take a total of 5 to 10 seconds to administer and the placebo significantly less time; as 
such the Research Nurse will slowly administer the placebo at a rate of 0.5 ml per sec. The unblinded Research 
Nurse will continue to maintain the blind for both active and placebo subjects. 
Study drug injections will be repeated every 4 weeks +/- 7 days for a total of 24 weeks under protocol stipulations. 
Administer only under direct medical supervision and observe patient for a minimum of 2 hours following 
administration of any dose given for the first three visits, and then 30 minutes for any subsequent doses. 
 
6.5.5 
Permitted study drug dose adjustments and interruptions 
No dosage modification of study drug will be allowed during this study. 

15 
 
 
If a subject misses a dose of medication by more than a week (7 days), that dose will be skipped. If a subject misses 
more than two subsequent doses in the dosing series the subject will no longer receive study medication, but will 
remain in the study and be labeled SDD (study drug discontinuation). 
 
6.5.6 
Rescue medication 
Study drug must be administered in a location with ready access to emergency medication (epinephrine) and 
supplies in the event of serious hypersensitivity reaction. Study drug administration will occur in the Clinical 
Research Unit North, Allergy Research offices. The allergy research Investigator on-call staff will be available for 
any emergent situations.  Emergency supplies must include those as needed for airway management and 
resuscitation. Subjects must be observed for a minimum of 2 hours before being discharged to home after the first 
three administrations, or 30 min after subsequent doses.  
 
6.5.7 
Study drug discontinuation and premature patient withdrawal 
Study drug must be discontinued if the subject becomes pregnant. 
The investigator has the right to discontinue a patient from study treatment for any medical condition that 
the investigator determines may jeopardize the patient’s safety if he or she continues on study treatment, 
noncompliance (e.g. missed 2 consecutive visits or 3 total visits) or an anaphylactic reaction to study 
drug. Every effort will be made to continue to follow patients who discontinue from study treatment. 
 
 
6.5.8 
Emergency unblinding of treatment assignment 
Subjects will not be unblinded prior to the final analysis of study data. If subjects have an anaphylactic 
reaction to study medication or an idiopathic trigger, they will be treated appropriately and will no 
longer receive study medication. Subjects will be labeled SDD, study drug discontinuation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

16 
 
7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “x” the visits when they are performed. 
 
Table 7-1 
Assessment schedule 
 
Study Periods 
Screening 
Treatment 
Follow-Up 
Visit Number 
1A 
1B 
2 
3 
4 
5 
6 
7 
8* 
9* 
Time of Visit 
Screen Screen Baseline Week 
4 
Week 8 Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
36 
Visit window 
-3 to -6 
wks 
-1 to -3 
wks 
 
+7days +7days +7days +7days +7days +7days 
 
Inclusion/Exclusion 
x 
Informed consent 
x 
Physical examination 
x 
 
x 
Dispense AAS28 
 
x (7 
days) 
x 
x 
x 
x 
x 
x 
X (12 
weeks) 
 
Collect AAS28 
 
x (7 
days) 
x 
x 
x 
x 
x 
x 
X (12 
weeks) 
In clinic  
questionnaires (Ae-Qol 
and VAS) 
 
x 
x 
x 
x 
x 
x 
x 
x 
Administer study 
medication 
x 
x 
x 
x 
x 
x 
Laboratory test* 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Concomitant Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
SDD = Study drug discontinuation 
PPW = Premature patient withdrawal 
*These assessments are still performed after SDD if the subject is willing. 
 
 
7.1 
Information to be collected on screening failures 
At the screening visits the following information will be collected on all subjects: assessment for 
frequency, duration of IAE episodes (hours), rescue medication or corticosteroid usage, complement 
profiles (C1 Esterase inhibitor panel), Chronic Urticaria Index Urine mast cell mediators (such as n-
methyl histamine, 11β- PGF2α, PGD2), AAS7 and 28 and Ae-QOL questionnaire responses, and 
number of unscheduled clinic/urgent care/ER visits in the past year. 
Screen failures may be rescreened at the discretion of the investigator and will keep the same 
screening ID number. 
 
7.2 
Patient demographics/other baseline characteristics 
At the screening visits the following information will be collected on all subjects: assessment for frequency, 
duration of IAE episodes (hours), rescue medication or corticosteroid usage, complement profiles (C1 
Esterase inhibitor panel), Chronic Urticaria Index, Urine mast cell mediators (such as n-methyl histamine, 
11b-PGF2a, PGD2), AAS7, 28 and Ae-QOL questionnaire responses, and number of unscheduled 
clinic/urgent care/ER visits in the past year. 

17 
 
At the baseline visit, we will also examine basophil flow cytometry (CD63 and CD203 expression), 
tryptase, bradykinin and bradykinin degradation products, and platelet activating factor (PAF). 
Complement profiles will be collected for the purposes of study inclusion, C1 Esterase inhibitor panel must be 
within normal reference values. 
 
7.3 
Treatment exposure and compliance 
Questionnaires such as AAS and Ae-QOL will be collected during treatment visits every 4 weeks. 
Additionally, assessment for frequency, duration of IAE episodes (hours), rescue medication or 
corticosteroid usage, visual analog score for IAE severity and number of unscheduled clinic/urgent care/ER 
visits in the previous month will be collected. 
Every 12 weeks, at the treatment visits and at the conclusion of the trial, we will also examine changes in basophil 
flow cytometry (CD63 and CD203 expression), tryptase, bradykinin and its degradation products, and platelet 
activating factor (PAF). 
 
7.4 
Efficacy 
All subjects will be given a paper questionnaire by the research nurses to assess their angioedema disease activity. 
Each patient will be given a quiet room to complete the questionnaire. Patients will report their disease activity on 
an Angioedema Activity Score (AAS, Appendix 1, (Weller et al., 2013)), at baseline and during all study visits. The 
Angioedema Activity Score is a validated disease specific patient- reported outcomes questionnaire. The AAS 
consists of 5 questions plus yes/ no questions for disease presence days. A categorical score between 0 and 3 
has been assigned each answer. The question scores are summed up to an AAS day sum score, 7 AAS day sum 
scores to an AAS week sum score (AAS7) (primary outcome), and 4 ASS week sum scores may be summed up to 
an AAS 4-week sum score (AAS28) per the scoring template. 
Accordingly, the minimum and maximum possible AAS scores are 0-15 (AAS day sum score), 0-105 (AAS7), and 
0-420 (AAS28). 
 
7.4.1 
Efficacy assessment 1 
The Urticaria Activity Score, UAS7, is a widely accepted for its usage in individuals with Urticaria, and has been 
used in previous omalizumab (Xolair) trials, however given the focus of this trial on angioedema, the AAS is more 
relevant. The AAS is a validated, published angioedema tool (Weller et al., 2013). 
 
7.5 
Safety 
All subjects will be assessed for the incidence and severity of adverse events, using an adverse event reporting 
guidelines at each study visit. Data safety monitoring will be completed by the UW Madison ICTR data and safety 
monitoring board (DSMB). We plan to utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study, 
and function as an external DSMB.  Study progress and safety will be reviewed annually (and more frequently if 
needed) by the DMC. The UW ICTR DMC is comprised of experienced members (core plus ad hoc) with expertise 
required to oversee this study. The DMC members will review protocol-specific reports created by statisticians using 
data pulled from the ICTR OnCore clinical research management system. Progress reports, including patient 
recruitment, retention/attrition, and AEs will be provided to the Data Monitoring Committee following each of the 
annual reviews. The DMC members will review protocol-specific reports created by statisticians that serve a non-
voting member role on the DMC using data extracted from the ICTR OnCore-CRM system. These standard reports 
will include an overview of study objectives, a review of actual and projected accrual rates, an evaluation of subject 
demographics, a summary of the number and seriousness of adverse events. An interim analysis of study results 
may be performed and source documents may be reviewed to allow the DMC to independently judge whether the 
overall integrity and conduct of the protocol remain acceptable based on data provided and reported by the Principal 
Investigator. The DMC will make recommendations to the Principal Investigator that could include actions of 
continuation, modification, suspension, or termination. 
 
 

18 
 
7.5.1 
Physical examination 
Participants will be assessed by a trained medical professional for changes in vital signs. 
 
7.5.2 
Pregnancy and assessments of fertility 
 
Pregnancy tests will be administered at the screening visit 1B and all subsequent visits on all pre-menopausal 
female patients by the clinical research staff. Additionally, all pre-menopausal women must agree to maintain a 
reliable form of birth control though out their participation of the study. 
 
7.6 
Other assessments 
 
7.6.1 
Health-related Quality of Life 
Angioedema QoL Questionnaire (AE-QoL, Appendix 2 (Weller et al., 2012)) is a validated symptom specific 
questionnaire. The AE-QoL can be completed at any time during the study visits and subjects will be given a quiet 
room to answer all written questions. Research coordinator will administer and grade the written questionnaires. 
Each questionnaire consists of validated questions pertaining to functioning, fatigue/mood, fears/shame and 
nutrition. The AE-QoL will produce individual’s scores for each assessment as a profile instrument and for a total 
score as an index instrument. The minimum sum for each assessment is 1 point per question and the maximum is 
5 points per question and scores are calculated using the following formula (Σ items - min Σ items) // (max Σ items - 
min Σ items) x 100. Scores are linear in value and reported as a percent, with 0% being the lowest score and 100% 
being the highest. If more than one question is missed, the score is not valid and will not be included in the analysis. 
 
Visual analog scores, Appendix 3 will be collected on all subjects, by a trained research coordinator. At the 
screening visit, the participant will be asked to rate their overall health state at their most recent angioedema event. 
The rating will be done on a scale of 0-100 with 100 increments, with 100 being the best imaginable state, and 0 
being the worst imaginable state. This data will be collected by giving the subject a scale which will be printed on a 
sheet of paper, the subject will then draw a line where they feel best describes their health state at the indicated 
time. The research coordinator will then report the value (as 000) closest to the line drawn. Participants will then 
repeat this value at each subsequent visit if they have had an angioedema event since the previous visit. The 
lowest possible score will be 0 and the highest possible score will be 100. 
 
7.6.2 
Other Biomarkers 
At screening (V1B), venipuncture will be performed for 1-3mL plain red tube and 1-8.5mL serum separator tube. The 
collected tubes will be for analysis of complement C1 Esterase inhibitor panel and Chronic Urticaria Index Instruction 
for urine collection will be sent home with subject (V1A) for 24 hour urine collection, urine will be returned at V1B. 
Urine will be tested for mast cell mediators such as n-methyl histamine, 11βPGF2α, and PGD2. Blood for C1 
Esterase Inhibitor pane and urine will be sent to UWHC central core lab for processing. Blood for CUI will be 
processed by research lab and frozen for batch testing at time of study analysis.  Subjects will be off prednisone for 2 
weeks at V1B, unless prednisone is used as daily therapy. 
At baseline (V2), every 12 weeks (V5, 8) during study treatment, and at 12 weeks post treatment (V9) all subjects 
regardless of study treatment will have a venipuncture. Collection of blood will be performed prior to receiving 
study treatment. Venipuncture will be performed under standard procedures, and 60 ml of blood will be drawn (2-10 
ml Serum Separator Tubes, 1-5 ml red top tube, 2- 10 ml EDTA tubes and 1- 4ml EDTA tube). All samples will be 
processed for serum and plasma by centrifuging at 1500 RPM for 10 min, supernatant will be collected and 
aliquoted in 0.5 ml/ aliquot and immediately frozen at -80 degrees in cryotubes. The additional sample drawn at the 
University of Wisconsin-Madison for basophil flow cytometry method is described below.  
Serum and plasma will be analyzed by commercial ELISA at the conclusion of the study for the following: 
tryptase, bradykinin and it degradation products, and platelet activating factor (PAF). 
Basophil flow cytometry for CD63 and CD203 expression will be performed on 4 ml of EDTA blood. The buffy coat 
will be collected by spinning the samples at 700g for 15 min and collecting the cell population in between the 
erythrocyte layer and the plasma layer. Once the buffy coat (leukocytes) has been collected, the cells will be 
washed in a solution of HEPES-heparin buffered solution (HBE) by centrifugation at 400 g for 10 min. Finally, 

19 
 
pelleted cells with be re-suspended in 5 ml of HBE. Cells with then undergo either no activation, activation by 
FMLP, activation by IgE or activation by calcium ionophore A23187. Cells will   then be stained, and have flow 
cytometry performed using CD63 and CD203 as markers of basophil activation (Chirumbolo et al., 2008).) 
 
 
8 
Safety monitoring 
8.1 
Adverse events 
Definition of an AE: Any untoward medical occurrence in a subject administered a pharmaceutical product temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the use of a medicinal (investigational) product. Anticipated 
day-to-day fluctuations of the disease under study that do not represent a clinically significant exacerbation or 
worsening do not need to be considered an adverse event, unless they: 
1. 
 fulfill the definition of a serious adverse event, or 
2. 
have worsened and are clinically significant requiring medical intervention other than the use of the rescue 
medication, or 
3. 
result in discontinuation of subject from the study. 
  
Investigational Medicinal Product (IMP) includes the drug under evaluation and the comparator drug(s) if specified 
as part of the research objective, given at any time during the study. Medical conditions/ diseases present before 
starting the drug of interest are only considered adverse events if they worsen after starting the drug of interest. 
Beginning at visit 3 and throughout the study, the Investigator and study staff will record all adverse events on an 
adverse event form to be maintained in the subject’s research chart, regardless of the severity or relationship to 
investigational product or procedure. The form will include observation date and resolution date. 
 
All adverse events will be graded by severity using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0, May 28, 2009 listed below: 
Grade 1= Mild adverse event 
Grade 2= Moderate adverse event 
Grade 3= Severe and undesirable adverse event 
Grade 4= Life threatening or disabling adverse event 
Grade 5= Death 
 
Assessment of Causality 
The principal or co-investigator will assess the relationship between investigational product and the occurrence of 
each AE/SAE.  The investigator will use clinical judgment to determine the relationship.  Alternative causes, such 
as natural history of the underlying diseases, concomitant therapy, other risk factors and the temporal relationship 
of the event to the investigational product will be considered and investigated.   
The relationship between as adverse event and the investigational product will be recorded on the study adverse 
event form. The NCI-CTCAE provides the following descriptors and definitions for assigning relationship. This NCI 
nomenclature will be used but causality will be judged by the investigators in the context of asthma. 
 
 
 
 

20 
 
Code 
Descriptor 
Definition 
1 
Unrelated 
The event is clearly not related to the investigational product 
2 
Unlikely 
The adverse event is doubtfully related to the investigational product 
3 
Possible 
The adverse event may be related to the investigational product 
4 
Probable 
The adverse event is likely related to the investigational product  
5 
Definite 
The adverse event is clearly related to the investigational product 
 
Study Related Non-serious and Unexpected or Expected Adverse Event Reporting 
All non-serious and unexpected adverse events will be kept in an adverse event log and reported annually to the 
study DSMC until the completion of the study.  Other adverse events, for any study procedures or use of 
investigational product, that are both not serious and expected will not be reported to the study DSMC. These are 
the expected adverse events listed in the protocol and consent as possible results from a study procedure. The 
investigator will meet all local reporting requirements as dictated by the UW IRB. 
The most common adverse events associated with study drug administration include allergic reaction to the study 
medication, nausea, headache, swelling of the inside of the nose, throat or sinuses, cough, joint pain, and upper 
respiratory infections. 
8.2 
Serious adverse event reporting 
A serious adverse event (SAE) or reaction is defined (21 CFR 312.32 (a) ) as any adverse event occurring at any 
dose that suggests a significant hazard, contraindication, side effect or precaution. This includes, but may not be 
limited to any of the following events: 
 
Death: A death occurring during the study or which comes to the attention of the Investigator during the 
protocol-defined follow-up after the completion of therapy, whether or not considered treatment-related, 
must be reported. 
 
Life-threatening: Any adverse therapy experience that places the participant or participant, in the view 
of the Investigator, at immediate risk of death from the reaction as it occurred. 
 
Hospitalization or prolongation of existing hospitalization. 
 
Persistent or significant disability/incapacity. 
 
Congenital anomaly/birth defect. 
 
An event that required intervention to prevent permanent impairment or damage. 
 
An important medical event that does not meet the criteria listed above may be considered an SAE when, based 
upon appropriate medical judgment, it may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Medical and scientific judgment should be exercised in deciding whether reporting is appropriate in other situations.  
These situations might include an important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. 
Timelines: All serious adverse events (SAEs) from interventional clinical trials must be reported by the sites to 
Novartis and UW Madison DSMB within 24 hours of occurrence of the SAE. The timelines for investigator 
initiated trials reporting to Novartis will be done as per Third Party Study/Investigator Initiated Trial 
Agreement. 
 
 
 
 
 

21 
 
8.2.1 
Adverse Event of Special Interest 
 
Adverse Events of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product. Special interest AEs will be collected and reported to the Sponsor per SAE guidelines.  
The XOLAIR® (omalizumab) Events of Special Interest are: 
•         Anaphylaxis  
•         Drug-induced liver injury 
•         Suspected transmission of an infectious agent by the study drug 
 
8.2.2 
Follow-up reports 
SAEs will be followed until resolution or until it is judged to be permanent, and an assessment will be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the drug of interest, 
the interventions required to treat it, and the outcome. 
The Sponsor shall support Novartis in the following-up of all SAEs so that complete information is available to 
maintain patient safety and also as part of any commitments by Novartis to any Health authority OR specific Health 
authority follow-up requests for the product under investigation. 
 We will use the UW-ICTR for local data monitoring oversight. This plan includes the use of the ICTR OnCore 
clinical research management (OnCore-CRM) system which allows more efficient tracking of protocols and protocol 
subjects. ICTR OnCore-CRM is a secure, web-based, customizable information system that addresses issues 
related to the costs and complexities associated with conducting clinical trials. It provides fully integrated clinical 
data management, study administration, and financial management capabilities for a portfolio of clinical trials. The 
ICTR OnCore-CRM system is specifically designed to improve the efficiency and effectiveness of clinical research 
at large research centers by facilitating core activities such as study setup and activation, accrual, clinical data 
collection and analysis, data and safety monitoring, financial management, and regulatory compliance. 
Safety Review Plan – We plan to utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study. 
Study progress and safety will be reviewed annually (and more frequently if needed) by the DMC. The UW ICTR 
DMC is comprised of experienced members with expertise required to oversee this study. The DMC members will 
review protocol-specific reports created by statisticians using data pulled from the ICTR OnCore clinical research 
management system. Progress reports, including patient recruitment, retention/attrition, and AEs will be provided to 
the Data Monitoring Committee following each of the annual reviews. The DMC members will review protocol-
specific reports created by statisticians that serve a non-voting member role on the DMC using data extracted from 
the ICTR OnCore-CRM system. These standard reports will include an overview of study objectives, a review of 
actual and projected accrual rates, an evaluation of subject demographics, a summary of the number and 
seriousness of adverse events. An interim analysis of study results may be performed and source documents may 
be reviewed to allow the DMC to independently judge whether the overall integrity and conduct of the protocol 
remain acceptable based on data provided and reported by the Principal Investigator. The DMC will make 
recommendations to the Principal Investigator that could include actions of continuation, modification, suspension, 
or termination. 
 
8.2.3 
Individual and Overall Study Stopping Rules 
Based upon the definition of Serious Adverse Event as described in 21 CFR 312.32. 
 
Individual Safety Stopping Rules 
Individuals will be stopped from the study if the following events occur: 
a. If anaphylaxis or hypersensitivity AEs occur within 2 hours of administration of study drug. 
b. If anaphylaxis or hypersensitivity AEs occur within 8 hours of study drug on consecutive 
administrations. 
c. If SAE of angioedema or severe allergic reaction, e.g. anaphylaxis, involves hospitalization. 
Anaphylaxis to drug will be distinguished from Angioedema activity primarily by clinical evaluation of symptoms and 
timing of reaction. Anaphylaxis often involves multiple organ systems whereas Angioedema will only be skin without 

22 
 
hives. Anaphylaxis to drug will occur soon after administration (unlikely more than 2 hours later) whereas 
Angioedema can occur at any time. 
Overall Safety Stopping Rules 
The study will be stopped if: 
a. A research related death occurs in any subject. 
b. An event occurs that the investigator feels warrants halting of the study. 
c. If >25% enrolled subjects (after at least 8 subjects enrolled) experience study drug-related AEs.  
d. The same or similar serious and unexpected adverse event associated with the investigational 
product that occurs in at least two subjects. This may include a potentially life-threatening event, 
event requiring hospitalization, or any event that may potentially result in serious harm to other 
research subjects.  
e. For non-serious adverse events, if more than 25% of research subjects meet the 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy in a patient (or a patients’ partner) on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy will be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications. 
 
REPRODUCTIVE RISKS 
Pregnancy Category B 
 
Female who become pregnant during the study or males whose partner becomes pregnant during the study, must 
immediately inform the study doctor. The doctor will discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. The subject’s doctor should monitor until the conclusion of the pregnancy.  
 
 
9 
Data review and database management 
9.1 
Data collection 
 
Data Quality and Management 
1. Description of Plan for Data Quality and Management– The PI, or study staff, will review all data collection forms 
on an ongoing basis for data completeness and accuracy as well as protocol compliance. When possible, data will 
be collected using programs that allow direct transfer to a spreadsheet, in order to avoid human error. When data 
must be manually entered, double-entry will be used to allow accuracy checks. Accuracy checks will be performed 
by a different individual than those involved in data entry. 
2. Frequency of Data Review for these Studies – The frequency of data review for this study will include annual 
review of subject accrual (adherence to protocol regarding demographics, inclusion/exclusion), adverse event rates 
(injuries), and out of range (non-clinically significant) laboratory data. The PI and Data Monitoring Committee will 
review these data annually.  
 
9.2 
Database management and quality control 
Data will be maintained in a REDCap and Oncore database, and it will be the responsibility of the database 
manager to ensure data is entered in a timely manner and to perform routine quality control checks of the 
database.The REDCap server is housed in a state-of-the-art data center managed by the UW SMPH network 
staff. The levels of security for the server are fivefold and include: 1) Physical Security: server is located in a 
secure data center under control of UW School of Medicine and Public Health (SMPH) ITS, which is a dedicated 
computer machine room (passkey access only) containing emergency backup power, an uninterruptible power 
supply (UPS), and an automatic fire detection and suppression system. SMPH ITS does not have access to the 

23 
 
DOM RedCap server; 2) Access controls: Data access is limited to DOM Faculty and staff approved individuals; 3) 
Domain access restrictions: access to DOM computing resources, including the DOM RedCap Server, is restricted 
to individuals with a logon ID for the DOM Domain. Logon IDs are issued only upon approval of the Administrator 
or Data Custodian (PI); 4) Authentication: Password protection is used at the network level for all transactions that 
allow entry and editing of data, provide access to EPHI data, or administrative activities, and; 5) Firewall: located 
behind UW-Madison SMPH firewall. 
 
We will use the UW-ICTR for local data monitoring oversight. This plan includes the use of the ICTR OnCore 
clinical research management (OnCore-CRM) system which allows more efficient tracking of protocols and 
protocol subjects. ICTR OnCore-CRM is a secure, web-based, customizable information system that addresses 
issues related to the costs and complexities associated with conducting clinical trials. It provides fully integrated 
clinical data management, study administration, and financial management capabilities for a portfolio of clinical 
trials. The ICTR OnCore-CRM system is specifically designed to improve the efficiency and effectiveness of 
clinical research at large research centers by facilitating core activities such as study setup and activation, accrual, 
clinical data collection and analysis, data and safety monitoring, financial management, and regulatory 
compliance. 
 
The PI, or study staff, will review all data collection forms on an ongoing basis for data completeness and accuracy 
as well as protocol compliance. When possible, data will be collected using programs that allow direct transfer to a 
spreadsheet, in order to avoid human error. When data must be manually entered, double-entry will be used to 
allow accuracy checks. Accuracy checks will be performed by a different individual than those involved in data 
entry. 
 
The frequency of data review for this study will include annual review of subject accrual (adherence to protocol 
regarding demographics, inclusion/exclusion), adverse event rates (injuries), and out of range (non-clinically 
significant) laboratory data. The PI and Data Monitoring Committee will review these data annually. 
 
10 
Data analysis 
10.1 
Populations for analysis 
Data will be analyzed in the following treatment groups 
1.) An intent-to-treat analysis of all randomized individuals, omalizumab vs. placebo 
2.) A per-protocol analysis of all individuals who received at least 4 study doses, omalizumab vs. placebo 
 
Interim analysis may be conducted at the discretion of the study’s statistician and principal investigators.  
 
10.2 
Patient demographics/other baseline characteristics 
Due to the small sample size, patient demographics will not be used in the data analysis of this study, however for 
the purposes of publication and reporting we will report the distribution per group of the following: gender, age, 
race, and ethnicity. 
The following baseline characteristics will also be assessed for distribution, AAS 7 scores, AeQoL score, visual 
analog scores, and other laboratory data (Urine n-methyl histamine, Urine 11β-PGF2α, Urine PGD2, and 
Chronic urticaria index). Chronic urticaria index will only be deemed usable if the participant has not taken 
prednisone within 14 days of testing. 
 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Due to the small sample size, at this time the data will not be analyzed for individual rescue medications, however 
the usage of rescue medication by individuals will be reported. 
Study drug and compliance will not be analyzed, other than general reporting. 

24 
 
 
10.4 
Analysis of the primary objective(s) 
10.4.1 
Variable 
The primary outcome is the change in the 7-day Angioedema Activity Score (AAS7) from baseline to end of 
treatment period. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will estimate the effect of treatment, compared to placebo, on the change in 
Angioedema Activity Score (AAS7) from baseline to the end of the treatment period using analysis of 
covariance (ANCOVA) with treatment group and baseline AAS7 as covariates. The goal of this analysis is to 
obtain an estimate and 95% confidence interval for the mean treatment effect. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Missing data due to missed visits or early study withdrawal will be addressed using multiple imputation of missing 
data and results from the multiply-imputed data sets combined using the Rubin method. 
Treatment groups will be compared as-randomized using the intention-to-treat principle. 
 
10.4.4 
Supportive analyses 
The mean treatment effect estimate with 95% CI will also be reported from the model without baseline AASS7 
covariate. Departures from a normal distribution will be addressed using data transformations such as the 
logarithm, square root, or other power transformation, and nonparametric regression methods will also be 
considered. Analyses of longitudinal AAS measurements obtained monthly during the treatment period and at the 
9 month follow up visit will be examined using linear mixed effect models. 
 
10.5 
Analysis of secondary objectives 
10.5.1 
Efficacy (secondary) 
The effect of treatment compared to placebo on the change in IAE severity from baseline to the end of the 
treatment period as recorded on a 0-100 visual analog scale will be estimated using ANCOVA with treatment group 
and baseline AAS severity as covariates. The treatment effect on the change in AE-QoL will be estimated using 
similar models with treatment group and baseline AE-QoL as covariates. The change in frequency of IAE episodes 
and their total duration in hours (frequency x duration) will be 
compared using similar baseline-adjusted models. The occurrence (any vs none) and frequency of urgent care visits, 
ER visits, rescue medication and corticosteroid use will be compared using similar baseline- adjusted generalized 
linear models including logistic regression for occurrence and count regression such as Poisson or negative binomial 
regression for frequency variables as appropriate. Laboratory measurements including CD63 and CD203 basophil 
expression, tryptase, bradykinin and its degradation products, and platelet activating factor (PAF) will be compared 
using similar baseline-adjusted models. 
Measurements obtained longitudinally during the treatment period and at the 9 month follow up visit will be 
compared between groups using (generalized) linear mixed effect models. 
 
10.6 
Sample size calculation 
Based on estimated (Weller et al. Allergy 2013) AAS7 standard deviations at baseline and at 6 months of 9.5 and 
a correlation of 0.5 between them, we estimate the standard deviation for the baseline to 6 month change as (2 x 
9.52 x (1-0.5))1/2 =9.5. Under this assumption, enrolling 20 subjects per group will provide an estimate of the size 
of the treatment effect- the difference in the baseline to 6 month change between treatment and placebo groups- 
with a margin of error (half-width of 95% CI) of 6.1. Based on a chart review of patients followed for a diagnosis in 
the UW Health Allergy Clinics, we estimate 100 patients will meet inclusion criteria. Given the additional 988 
patients seen in non-Allergy clinics, we expect the recruitment of 40 subjects is feasible. 

25 
 
10.7 
Power for analysis of critical secondary variables 
Assuming an IAE severity (0-100 visual analog scale) change from baseline standard deviation of 
13.8 (Cicardi, M et al, 2010), we estimate enrolling 20 participants per group will provide an estimate of the 
treatment effect with a margin of error of 8.8. Assuming an AE-QoL change from baseline standard deviation of 
15 (Weller et al Allergy 2012), we estimate enrolling 20 participants per group will provide an estimate of the 
treatment effect with a margin of error of 9.6. 
 
 
11 
Ethical considerations 
11.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonized 
Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and 
with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where required by law or 
regulation), IRB/IEC/REB-approved informed consent, or, if incapable of doing so, after such consent has been 
provided by a legally acceptable representative of the patient. In cases where the patient’s representative gives 
consent, the patient should be informed about the study to the extent possible given his/her understanding. If the 
patient is capable of doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of the procedures 
described in the protocol). The process of obtaining informed consent should be documented in the patient source 
documents. 
Women of child bearing potential should be informed that taking the study medication may involve unknown risks to 
the fetus if pregnancy were to occur during the study and agree that in order to participate in the study they must 
adhere to the contraception requirement for the duration of the study. If there is any question that the patient will 
not reliably comply, they should not be entered in the study. 
 
11.3 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted 
Institutional Review Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) before study 
start. A signed and dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. 
 
11.4 
Publication of study protocol and results 
The University of Wisconsin-Madison study team will be responsible for all study data and its analysis. 
The PIs, Dr. Viswanathan and Dr. Mathur, reserve the right to prepare all manuscripts, and scientific 
presentations of the data at the conclusion of the study. All manuscripts and any form of presentation will 
be sent to Novartis for pre-approval prior to public dissemination. 
This study is required by law to be listed on the clinicaltrials.gov website for the entire trial, and for the 
investigators involved to abide by all of the site rules and regulations for dissemination of results and 
data. 
 
 
 
 
 

26 
 
12 
Protocol adherence 
12.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB. Only amendments that are 
required for patient safety may be implemented prior to IRB approval. Notwithstanding the need for 
approval of formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a deviation 
from the protocol. 
 
13 
References 
1 Azofra, J., Díaz, C., Antépara, I., Jaúregui, I., Soriano, A., Ferrer, M., 2015. Positive response to 
omalizumab in patients with acquired idiopathic nonhistaminergic angioedema. Ann.Allergy 
Asthma Immunol. 114, 418–419.e1. doi:10.1016/j.anai.2015.02.007  
 
2 Chirumbolo, S., Vella, A., Ortolani, R., De Gironcoli, M., Solero, P., Tridente, G., Bellavite, P., 
2008. Differential response of human basophil activation markers: a multi-parameter 
flow cytometry approach. Clin Mol Allergy 6, 12. doi:10.1186/1476-7961-6-12  
 
3 Ozturk, A.B., Kocaturk, E., 2014. Omalizumab in recurring larynx angioedema: a case report. 
Asia Pac Allergy 4, 129–130. doi:10.5415/apallergy.2014.4.2.129 
 
4 Sands, M.F., Blume, J.W., Schwartz, S.A., 2007. Successful treatment of 3 patients with recurrent 
idiopathic angioedema with omalizumab. J. Allergy Clin. Immunol. 120, 979– 981. 
doi:10.1016/j.jaci.2007.07.041 
 
5 Weller, K., Groffik, A., Magerl, M., Tohme, N., Martus, P., Krause, K., Metz, M., Staubach, P., Maurer, 
M., 2013. Development, validation, and initial results of the Angioedema Activity Score. Allergy 
68, 1185–1192. doi:10.1111/all.12209 
 
6 Weller, K., Groffik, A., Magerl, M., Tohme, N., Martus, P., Krause, K., Metz, M., Staubach, P., Maurer, 
M., 2012. Development and construct validation of the angioedema quality of life questionnaire. 
Allergy 67, 1289–1298. doi:10.1111/all.12007 
 
7 Cicardi, M., Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier 
H, Bas M, Greve J, Hoffmann TK, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, 
Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull 
C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anné S, Björkander J, Bouillet L, Cillari E, Hurewitz D, 
Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hébert 
J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Fernández 
Romero DS, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Fan WT  
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.N Engl J Med. 2010 
Aug 5;363(6):532-41. doi: 10.1056/NEJMoa0906393. 
 
8 Kwong, K.Y.C., Jones, C.A. 2006. Improvement of asthma control with omalizumab in 2 obese 
pediatric asthma patients. Ann Allergy Asthma Immunol 97, 288-293. doi: 10.1016/S1081-
1206(10)60791-0 
9 Sposato, B., Scalese, M., Latorre, M., Scichilone, N., Matucci, A., Milanese, M., Masieri, S., Rolla, G., 
Steinhildber, G., Rosati, Y., Vultaggio, A., Folletti, I., Baglioni, S., Bargagli, E., Di Tomassi, M., Pio, R., 
Pio, A., Maccari, U., Maggiorelli, C., Migliorini, M.G., Vignale, L., Pulera, N., Carpagnano, G.E., Foschino 
Barbaro, M.P., Perrella, A., Paggiaro, P.L. 2016. Effects of omalizumab in severe asthmatics across 
ages: A real life Italian experience. Respiratory Medicine 119, 141-149. doi: 
10.1016/j.rmed.2016.09.005

27 
 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1: 
Angioedema Activity Score 

28 
 
AAS 
(Angioedema Activity Score) 
 
Angioedema activity documentation 
 
 
Patient name:   
 
 
Date questionnaire completed (dd mm yyyy):   
    
 
 
 
Week 1: 
 
Instructions: Please document your symptoms retrospectively once a day. Refer to the last 24 hours 
in each case. Please answer all questions as fully as possible 
 
Day 
1 
2 
3 
4 
5 
6 
7 
Have you had a swelling episode in the 
last 24 hours? 
no 
yes 
 
Please answer the questions below about this swelling episode during the last 24 hours. If you did 
not have a swelling episode, leave them blank. 
At what time(s) of day was this swelling 
episode(s) present? 
(please select all applicable times) 
midnight – 8 a.m. 
8 a.m. – 4 p.m. 
4 p.m. - midnight 
How severe is / was the physical 
discomfort caused by this swelling 
episode(s) (e.g., pain, burning, itching?) 
no discomfort 
slight discomfort 
moderate discomfort 
severe discomfort 
Are / were you able to perform 
your daily activities during this 
swelling episode(s)? 
no restriction 
slight restriction 
severe restriction 
no activities possible 
Do / did you feel your appearance is / 
was adversely affected by this swelling 
episode(s)? 
no 
slightly 
moderately 
severely 
How would you rate the overall 
severity of this swelling 
episode? 
negligible 
mild 
moderate 
severe 
 
This document must not be copied or used without the permission of MOXIE GmbH. For scientific or commercial use or in case 
a translation / cross cultural adaptation is intended, please check the terms and conditions on www.moxie-gmbh.de. 
 
 
 
Angioedema Activity Score – American English Version 2012  1 

29 
 
AAS 
(Angioedema Activity Score) 
 
Angioedema activity documentation 
 
 
Week 2: 
 
Instructions: Please document your symptoms retrospectively once a day. Refer to the last 24 hours 
in each case. Please answer all questions as fully as possible 
 
Day 
1 
2 
3 
4 
5 
6 
7 
Have you had a swelling episode in the 
last 24 hours? 
no 
yes 
 
Please answer the questions below about this swelling episode during the last 24 hours. If you did 
not have a swelling episode, leave them blank. 
At what time(s) of day was this swelling 
episode(s) present? 
(please select all applicable times) 
midnight – 8 a.m. 
8 a.m. – 4 p.m. 
4 p.m. - midnight 
How severe is / was the physical 
discomfort caused by this swelling 
episode(s) (e.g., pain, burning, itching?) 
no discomfort 
slight discomfort 
moderate discomfort 
severe discomfort 
Are / were you able to perform 
your daily activities during this 
swelling episode(s)? 
no restriction 
slight restriction 
severe restriction 
no activities possible 
Do / did you feel your appearance is / 
was adversely affected by this swelling 
episode(s)? 
no 
slightly 
moderately 
severely 
How would you rate the overall 
severity of this swelling 
episode? 
negligible 
mild 
moderate 
severe 
 
This document must not be copied or used without the permission of MOXIE GmbH. For scientific or commercial use or in case 
a translation / cross cultural adaptation is intended, please check the terms and conditions on www.moxie-gmbh.de. 
 
 
 
 
 
 
 
 
Angioedema Activity Score – American English Version 2012  2 

30 
 
AAS 
(Angioedema Activity Score) 
 
Angioedema activity documentation 
 
 
 
Week 3: 
 
Instructions: Please document your symptoms retrospectively once a day. Refer to the last 24 hours 
in each case. Please answer all questions as fully as possible 
 
Day 
1 
2 
3 
4 
5 
6 
7 
Have you had a swelling episode in the 
last 24 hours? 
no 
yes 
 
Please answer the questions below about this swelling episode during the last 24 hours. If you did 
not have a swelling episode, leave them blank. 
At what time(s) of day was this swelling 
episode(s) present? 
(please select all applicable times) 
midnight – 8 a.m. 
8 a.m. – 4 p.m. 
4 p.m. - midnight 
How severe is / was the physical 
discomfort caused by this swelling 
episode(s) (e.g., pain, burning, itching?) 
no discomfort 
slight discomfort 
moderate discomfort 
severe discomfort 
Are / were you able to perform 
your daily activities during this 
swelling episode(s)? 
no restriction 
slight restriction 
severe restriction 
no activities possible 
Do / did you feel your appearance is / 
was adversely affected by this swelling 
episode(s)? 
no 
slightly 
moderately 
severely 
How would you rate the overall 
severity of this swelling 
episode? 
negligible 
mild 
moderate 
severe 
 
This document must not be copied or used without the permission of MOXIE GmbH. For scientific or commercial use or in case 
a translation / cross cultural adaptation is intended, please check the terms and conditions on www.moxie-gmbh.de. 
 
 
 
 
 
 
 
Angioedema Activity Score – American English Version 2012  3 

31 
 
AAS 
(Angioedema Activity Score) 
 
Angioedema activity documentation 
 
 
 
 
Week 4: 
 
Instructions: Please document your symptoms retrospectively once a day. Refer to the last 24 hours 
in each case. Please answer all questions as fully as possible 
 
Day 
1 
2 
3 
4 
5 
6 
7 
Have you had a swelling episode in the 
last 24 hours? 
no 
yes 
 
Please answer the questions below about this swelling episode during the last 24 hours. If you did 
not have a swelling episode, leave them blank. 
At what time(s) of day was this swelling 
episode(s) present? 
(please select all applicable times) 
midnight – 8 a.m. 
8 a.m. – 4 p.m. 
4 p.m. - midnight 
How severe is / was the physical 
discomfort caused by this swelling 
episode(s) (e.g., pain, burning, itching?) 
no discomfort 
slight discomfort 
moderate discomfort 
severe discomfort 
Are / were you able to perform 
your daily activities during this 
swelling episode(s)? 
no restriction 
slight restriction 
severe restriction 
no activities possible 
Do / did you feel your appearance is / 
was adversely affected by this swelling 
episode(s)? 
no 
slightly 
moderately 
severely 
How would you rate the overall 
severity of this swelling 
episode? 
negligible 
mild 
moderate 
severe 
 
This document must not be copied or used without the permission of MOXIE GmbH. For scientific or commercial use or in case 
a translation / cross cultural adaptation is intended, please check the terms and conditions on www.moxie-gmbh.de. 
 
 
 
 
 
 
 
Angioedema Activity Score – American English Version 2012  4 

32 
 
AAS 
(Angioedema Activity Score) 
Scoring Template 
 
The AAS consists of 5 questions as well as an opening question. A score between 0 and 3 is assigned 
to every answer field. The question scores are summed up to an AAS day sum score, 7 AAS day sum 
scores to an AAS week sum score (AAS7), and 4 ASS week sum scores may be summed up to an 
AAS 4-week sum score (AAS28). Accordingly, the minimum and maximum possible AAS scores are 
0-15 (AAS day sum score), 0-105 (AAS7), and 0-420 (AAS28). 
The opening question may be used to count the number of angioedema affected days during the AAS 
documentation period but has no score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document must not be copied or used without the permission of MOXIE GmbH (www.moxie-gmbh.de) Angioedema Activity 
Score – Scoring Template - Version 2012 1 
4-Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Days of week 4 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 3 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 2 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 1 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 

33 
 
AAS 
(Angioedema Activity Score) 
 
Scoring Template 
 
 
Example for AAS scoring: 
 
 
 
 
 
 
This document must not be copied or used without the permission of MOXIE GmbH (www.moxie-gmbh.de) 
 
Angioedema Activity Score – Scoring Template - Version 2012 2 
9 10 0  0  0  0  0 
0 10 12 7 0  0  0 
0  0  0   0  0  0  0 
0 13 10 4  0  0  0 
19 
29 
0 
27 
75 

34 
 
AAS 
(Angioedema Activity Score) 
Scoring Template 
The AAS consists of 5 questions as well as an opening question. A score between 0 and 3 is assigned 
to every answer field. The question scores are summed up to an AAS day sum score, 7 AAS day sum 
scores to an AAS week sum score (AAS7), and 4 ASS week sum scores may be summed up to an 
AAS 4-week sum score (AAS28). Accordingly, the minimum and maximum possible AAS scores are 
0-15 (AAS day sum score), 0-105 (AAS7), and 0-420 (AAS28). 
The opening question may be used to count the number of angioedema affected days during the AAS 
documentation period but has no score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document must not be copied or used without the permission of MOXIE GmbH (www.moxie-gmbh.de) 
 
Angioedema Activity Score – Scoring Template - Version 2012 1 
4-Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Day sum scores 
Week sum score 
Days of week 4 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 3 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 2 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
Days of week 1 
1 2 3 4 5 6 7 
n 
n 
n 
n 
n 
n 
n 
y 
y 
y 
y 
y 
y 
y 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 

35 
 
AAS 
(Angioedema Activity Score) 
Scoring Template 
 
 
Example for AAS scoring: 
 
 
 
 
 
 
 
 
 
This document must not be copied or used without the permission of MOXIE GmbH (www.moxie-gmbh.de) 
 
Angioedema Activity Score – Scoring Template - Version 2012 2 
9 10 0  0  0  0  0 
0 10 12 7 0  0  0 
0  0  0   0  0  0  0 
0 13 10 4  0  0  0 
19 
29 
0 
27 
75 

36 
 
Instructions for evaluation of the AAS 
 
 
AAS scoring system: 
 
The Angioedema Activity Score (AAS) consists of only 5 questions. The AAS scoring 
system is very easy. A score between 0 and 3 is assigned to every field that can be 
ticked by the completing patient. The fields ticked by the patient are summed up to a 
total score. Accordingly, the minimum and maximum possible AAS scores are 0 and 
15. The answer to the first question does not get any points and is not included in the 
computation of the AAS score. Please find the score for each field in the template 
below. This template is only meant to be used for the AAS score calculations. The 
patients must not see this template. 
 
 
 
AAS scoring template: 
 
 
Day 
1 
2 
3 
4 
5 
6 
7 
Did you experience a swelling during 
the last 24 hours? 
no 
yes 
 
Please answer the questions below only in case you did experience a swelling 
during the last 24 hours! 
In which period(s) did you have the 
swelling(s)? 
(please choose all applicable periods) 
midnight - 8 a.m. 
1 
1 
1 
1 
1 
1 
1 
8 a.m. – 4 p.m. 
1 
1 
1 
1 
1 
1 
1 
4 p.m. - midnight 
1 
1 
1 
1 
1 
1 
1 
How strong is or was the physical 
discomfort caused by the swellings (e.g. 
pain, burning, itching)? 
none 
0 
0 
0 
0 
0 
0 
0 
mild 
1 
1 
1 
1 
1 
1 
1 
moderate 
2 
2 
2 
2 
2 
2 
2 
severe 
3 
3 
3 
3 
3 
3 
3 
Did you experience any limitations 
regarding your normal daily activities 
because of the current swelling(s)? 
no limitations 
0 
0 
0 
0 
0 
0 
0 
slight limitations 
1 
1 
1 
1 
1 
1 
1 
strong limitations 
2 
2 
2 
2 
2 
2 
2 
daily activities not possbile 
3 
3 
3 
3 
3 
3 
3 
Do or did you feel disfigured because of 
the current swelling(s)? 
no 
0 
0 
0 
0 
0 
0 
0 
mild 
1 
1 
1 
1 
1 
1 
1 
moderate 
2 
2 
2 
2 
2 
2 
2 
severe 
3 
3 
3 
3 
3 
3 
3 
As how strong would you overall rate 
the current swelling(s)? 
negligible 
0 
0 
0 
0 
0 
0 
0 
mild 
1 
1 
1 
1 
1 
1 
1 
moderate 
2 
2 
2 
2 
2 
2 
2 
severe 
3 
3 
3 
3 
3 
3 
3 
 
This document must not be copied or used without the permission of MOXIE GmbH. 

37 
 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2: 
Angioedema Quality of Life   
Scores 

38 
 
AE-QoL 
Quality of Life Questionnaire for Patients with Recurrent Swelling Episodes 
 
Patient name:   
 
 
 
Date questionnaire completed (dd mmm yyyy):   
    
 
 
 
Instructions: This questionnaire asks a number of questions. Please read each question carefully and 
choose from the five answers the one that fits best for you. Please do not think too long about the 
questions; be sure to answer all of the questions and to give only one answer to each question, i.e., to 
check only one box for each question. 
 
 
Indicate how often within the last 4 weeks 
you have been restricted in the areas of 
your daily life listed below because of 
swelling episodes (angioedema). 
(regardless of whether or not you have 
actually experienced swelling episodes 
during that time period) 
Never 
Rarely 
Occasionally 
Often 
Very 
often 
1.   Work 
□ 
□ 
□ 
□ 
□ 
2.   Physical activity 
□ 
□ 
□ 
□ 
□ 
3.   Leisure time 
□ 
□ 
□ 
□ 
□ 
4.   Social relations 
□ 
□ 
□ 
□ 
□ 
5.   Eating and drinking 
□ 
□ 
□ 
□ 
□ 
In the following questions we would like to 
get more details about the difficulties and 
problems that may be associated with your 
recurrent swelling episodes (angioedema) 
(during the last 4 weeks) 
Never 
Rarely 
Occasionally 
Often 
Very 
often 
6.   Do you have difficulty falling 
asleep? 
□ 
□ 
□ 
□ 
□ 
7.   Do you wake up during the night? 
□ 
□ 
□ 
□ 
□ 
8.   Are you tired during the day 
because you are not sleeping 
well at night? 
□ 
□ 
□ 
□ 
□ 
9.   Do you have trouble concentrating? 
□ 
□ 
□ 
□ 
□ 

39 
 
 
Never 
Rarely 
Occasionally 
Often 
Very 
often 
10. Do you feel depressed? 
□ 
□ 
□ 
□ 
□ 
11. Do you have to limit your choices of 
food or beverages? 
□ 
□ 
□ 
□ 
□ 
12. Do the swelling episodes place a 
burden on you? 
□ 
□ 
□ 
□ 
□ 
13. Are you afraid that a swelling 
episode could occur suddenly? 
□ 
□ 
□ 
□ 
□ 
14. Are you afraid that the frequency of 
the swelling episodes might 
increase? 
□ 
□ 
□ 
□ 
□ 
15. Are you ashamed to go out in public 
because of the swelling episodes? 
□ 
□ 
□ 
□ 
□ 
16. Do the swelling episodes make you 
embarrassed or self-conscious? 
□ 
□ 
□ 
□ 
□ 
17. Are you afraid that the treatment of 
the swelling episodes could have 
negative long-term effects for you? 
□ 
□ 
□ 
□ 
□ 
 
This document must not be copied or used without the permission of MOXIE GmbH. For scientific or commercial use or in case a 
translation / cross cultural adaptation is intended, please check the terms and conditions on www.moxie-gmbh.de. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Angioedema Quality of Life Questionnaire – American English Version 2012 

40 
 
AE-QoL 
 
Quality of Life Questionnaire for Patients with Recurrent Swelling Episodes 
 
 
Instructions for evaluation of the AE-QoL 
(German Version) 
 
 
The structure of AE-QoL 
 
The German version of AE-QoL consists of four dimensions and a total score: 
 
Dimensions 
Item 
Functioning 
1. Impairment of work 
2. Impairment of physical activity 
3. Impairment of spare time activities 
4. Impairment of social relations 
Fatigue/Mood 
6. Difficulties of falling asleep 
7. Waking up during the night 
8. Feeling tired during the day 
9. Difficulties in concentrating 
10. Feeling downhearted 
Fears/Shame 
12. Feeling burdened at having swellings 
13. Fear of new suddenly appearing swellings 
14. Fear of increased frequency of swellings 
15. Ashamed to visit public places 
16. Embarrassed by the apppearence of swellings 
17. Fear of long term negative drug effects 
Nutrition 
5. General limitations in foods and eating 
11. Limitations in the selection of food and beverages 
Total Score 
Items 1 to 17 
 
Angioedema Quality of Life Questionnaire – American English Version 2012 

41 
 
The AE-QoL scale scores as well as the AE-QoL total score are calculated by using 
the following formula: 
 
(Σ items – min Σ items / max Σ items – min Σ items) x 100 
 
For example: Scale “Functioning”: 
Item 1: answer 3 
Item 2: answer 2 
Item 3: answer 4 
Item 4: answer 5 
Σ items: (3+2+4+5) = 14 
min Σ items: (1+1+1+1) = 4 
max Σ items: (5+5+5+5) = 20 
Enter values in formula: (14 - 4 / 20 – 4) x 100 = 62.5% 
 
The AE-QoL scale scores correspond to the mean of the items within each scale. If 
some items are missing, the total of the items within the scale is divided by the 
number of the non missing items. The same holds for the AE-QoL total score. 
 
An AE-QoL scale score should not be calculated if more than one item is missing in 
that dimension. The AE-QoL total score should not be calculated if more than 25% of 
items (>4 items) are missing. 
 
Please not that only calculating the raw scale scores (mean of the item scores within 
each scale) and the raw total score score (mean of all item scores) would be easier 
than the above described procedure. However, in case of missing answers, an 
interindividual as well as an intraindividual comparison of AE-QoL results would be 
limited. The above described linear transformation of all raw scores into percentage 
scores (indicating the location of the raw scores in relation (in percent) to its 
maximum possible score) solves this problem and makes it possible to judge and 
compare AE-QoL results even when single items are missing.  The linear 
transformation of raw scores results in minimal and highest possible scale and total 
scores of 0 and 100, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE-QoL German Version 1.0 

42 
 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 3: 
Visual Acuity Score 

43 
 
Visual Acuity Score 
Subject Number: 
Visit Number 
Date: 
Read By: 
 
 
Draw a line where you feel best describes your overall health 
state at your most recent angioedema event with 100 being 
the best imaginable state, and 0 being the worst imaginable 
state. 
 
 
 
 
 
 
 
 
 
 
 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 

44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 4: 
Laboratory Testing Study Grid 

45 
 
Laboratory Testing Study Grid 
 
 
Study Periods 
Screening 
Treatment 
Follow- 
Up 
Visit Number 
1A 
1B 
2 
3 
4 
5 
6 
7 
8 
9 
C1 Esterase 
Inhibitor Panel- if 
needed (UWHC) 
x 
Chronic Urticaria 
Index 
(Research lab) 
x 
 
Urine Mast Cell 
Meditators 
(UWHC) 
x 
CD63/CD203 
(Research lab) 
x 
x 
x 
x 
Tryptase 
(Research lab) 
x 
x 
x 
x 
Bradykinin 
(Research lab) 
x 
x 
x 
x 
PAF (Research lab) 
x 
x 
x 
x