A Placebo Controlled, Double-Blind Investigation of the Therapeutic Utility of Xolair (Omalizumab) for Attenuating Aspirin Induced Bronchospasm in Patients With Aspirin Exacerbated Respiratory Disease (AERD) Undergoing Aspirin Desentization
Phase: PHASE4
Conditions: Aspirin Sensitivity
Sponsor: David Lang

 
 
 
 
 
Clinical Study Protocol 
 
 
A Placebo Controlled, Double Blind Investigation of the Therapeutic 
Utility of Xolair [Omalizumab] for Attenuating Aspirin Induced 
Bronchospasm in Patients With Aspirin Exacerbated Respiratory 
Disease (AERD) Undergoing Aspirin Desensitization 
 
 
 
 
 
 
                                             Amendment 2  
 
 
Authors: 
David M. Lang, MD,  Stanley L Hazen, MD, PhD   
Phase:  
IV  
Release date: 
January 16, 2013   
 
 
 

 
 
 
 
2
TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ...........................................................................................................3 
STUDY FLOW CHART……………………………………………………………………….5 
1.  INTRODUCTION………………………………………………………………………..…6 
                   Background……...…………………………………………………………………7 
2.  STUDY OBJECTIVES ........................................................................................................10 
3.  INVESTIGATIONAL PLAN ..............................................................................................10 
3.1 
OVERALL STUDY DESIGN ...............................................................................10 
3.2 
STUDY POPULATION ........................................................................................11 
 
           Inclusion Criteria.........................................................................................12 
 
           Exclusion Criteria .......................................................................................12 
3.3 
TREATMENTS .....................................................................................................13 
3.4.      VISITS AND ASSESSMENTS………………………………………………….13 
                        Study Timetable…………………………………………………………..14 
 
            Phase A-Enrollment ...................................................................................14 
 
            Phase B-Xolair or Placebo .........................................................................14 
  
            Phase C-Aspirin Desensitization ................................................................15 
 
            Phase D-Aspirin Desensitization Treatment ..............................................15 
 
            Laboratory Tests ........................................................................................17 
3.4 
SAFETY ASSESSMENTS ....................................................................................17 
4 
DATA MANAGEMENT AND STATISTICAL METHODS ..........................................18 
5 
REFERENCES ..................................................................................................................19 
       CITATIONS ......................................................................................................................19 

 
 
 
 
3
PROTOCOL SYNOPSIS 
 
Patients with aspirin exacerbated respiratory disease (AERD) are at risk for serious 
bronchospasm when undergoing aspirin desensitization. In this study, Xolair [Omalizumab] will 
be administered for 16 weeks in a double blind, placebo controlled study to determine whether 
Omalizumab is associated with statistically significant attenuation of bronchospastic reaction 
during aspirin desensitization.  
 
Despite use of medications associated with lessening of aspirin-induced bronchospasm (1-9), 
severe bronchospasm may still occur during aspirin desensitization. For this reason, patients 
currently must undergo aspirin desensitization in a setting with the capacity for close monitoring 
and presence of personnel and equipment necessary to manage severe and rapidly progressive 
bronchospastic reaction. Aspirin desensitization is generally performed in an inpatient setting.  
Administration of Omalizumab has the potential to favorably alter this situation by blocking 
significant bronchospastic reaction, and may permit aspirin desensitization to be done in 
outpatient settings. 
  
Title of Study:   
A placebo-controlled, double-blind investigation of the therapeutic utility of Xolair 
[Omalizumab] for attenuating aspirin induced bronchospasm in patients with aspirin exacerbated 
respiratory disease undergoing aspirin desensitization  
 
Objectives:  
The primary aim of this study is to examine the effect of Omalizumab on aspirin-induced 
bronchospasm occurring during aspirin desensitization in patients with AERD.  Secondary 
objectives include assessment of aspirin dose which provokes respiratory reaction, proportion of 
subjects with declines in FEV1 of 20% and of 40%.  We also will measure change in serum and 
urinary markers of eosinophil activation in association with Omalizumab treatment and aspirin 
desensitization, and degree of change in urinary LTE4 during aspirin challenge and with aspirin 
induced bronchospasm. 
Study Rational:  
 
Aspirin desensitization offers patients with AERD opportunity for benefit including reduced 
symptoms, medication reliance, and improved quality of life; however, due to risk for serious 
bronchospasm, aspirin desensitization is not widely available or commonly performed.  We 
propose to assess the hypothesis that Omalizumab administration can reduce severity of aspirin- 
induced 
bronchospasm. 
The 
CDC 
(www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma/asthma.htm) estimates 68 per 1,000 
adult Americans 18 years and over (14 million) currently have asthma.  The corresponding 
estimate based on these data is that there are as many as 1.4 million adult Americans with AERD 
(10). If our hypothesis is confirmed, Omalizumab would have substantial utility for management 
of this large subgroup of asthmatics, and would lead to aspirin desensitization being performed 
more frequently. 
 

 
 
 
 
4
Methodology:  
This is a double-blind placebo controlled study.  
 
Number of Centers & Patients:  
Cleveland Clinic Foundation 
N = 21 
Population:  
Patients with aspirin exacerbated respiratory disease (AERD) who are candidates for aspirin 
desensitization, and who fulfill criteria for Omalizumab. 
Investigational Drug:  
Xolair (Omalizumab) 
Reference Therapy:  
Placebo  
Study Duration:  
Omalizumab will be administered for 16 weeks.  Within 1-3 weeks after this treatment is 
completed, patients will undergo aspirin desensitization.  Patients will also accomplish a visit 
one month after initiation of aspirin desensitization treatment for final assessments.  The total 
duration for subject participation is approximately 24 weeks (6 months).  
 
Evaluation Criteria:  
The primary outcome of interest is aspirin-induced respiratory reaction, as defined by the decline 
in the forced expiratory volume in one second (FEV1) values from baseline to after ASA 
provoked reaction, in patients receiving Omalizumab vs. placebo.  Secondary outcomes include: 
dose of aspirin that provokes the first respiratory reaction, the proportion of subjects with a decline 
in FEV1 greater than 20% (significant respiratory reaction) and greater than 40% (severe 
respiratory reaction) through the course of desensitization. We also will measure:  a) changes in 
serum and urinary markers of eosinophil activation in association with 16-week trial of 
Omalizumab and aspirin desensitization; b) changes in urinary LTE4 in subjects previously treated 
with Omalizumab vs. placebo with aspirin challenge and aspirin-induced bronchospastic reaction. 

 
 
 
 
5
 
Study Timetable 
Duration of participation = Approximately 24 weeks (6 months) 
 
 
 
- 
Phase A: Entry 
- 
Phase B: Xolair/Placebo (approximately16 weeks) 
- 
Phase C: Aspirin Desensitization (1-3 weeks after Phase B) 
- 
Phase D: Aspirin Desensitization Treatment (approximately 1 month after Phase C) 
 
 
 
 
 
All visits have a window of +/- 7 days 
 
 
Study Phase 
A 
B 
B 
B 
B 
B 
B 
B 
B 
C 
D 
Injection 
schedule  
Q 2 week VS Q 
4 week 
Both 
Both 
Q 2 
wee
k 
Both 
Q 2 
wee
k 
Bot
h 
Q 2 
week 
Both 
Q 2 
week 
Both 
Both 
Time of Visit 
Screenin
g 
Baseline Week 
2 
Week 
4 
Week  
6 
Week 
8 
Week 
 10 
Week 
 12 
Week 
 14 
Desens Final 
Visit 
Inclusion/Exclusi
on criteria 
x 
 
 
 
 
 
 
 
 
 
 
Information & 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
History and 
Physical exam 
x 
 
 
Q 4 
wee
k 
only 
x 
 
 
Q 4 
wee
k 
only 
x 
x 
x 
QOL 
questionnaires 
x 
 
 
 
 
 
 
 
 
x 
x 
Spirometry 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
Laboratory 
samples 
x 
 
 
 
 
 
 
 
 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administration of 
Xolair or placebo 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 

 
 
 
 
6
1 
INTRODUCTION  
Omalizumab was recently approved by the FDA for management of patients with moderate-
severe asthma, who are not achieving the goals of asthma management despite pursuing 
appropriate avoidance measures and taking regular “controller” medications.  Based on evidence 
demonstrating its utility for improving asthma outcomes and reducing medication reliance (11, 
12), this humanized monoclonal anti-IgE antibody has been welcomed enthusiastically by the 
Allergy/Immunology community.  The anti-inflammatory effects of Omalizumab were recently 
demonstrated in a study by Djukanovic, et al (13), who carried out a randomized, double blind, 
placebo-controlled trial of 45 mild-moderate asthmatics with sputum eosinophilia ≥ 2%.  
Bronchial biopsies performed after 16 weeks of treatment revealed a significant decline in IgE in 
epithelium and submucosa in association with Omalizumab.  In addition, a significant decline in 
eosinophils in epithelium and submucosa was observed.  The latter finding is relevant for 
patients with AERD, as aspirin-provoked reaction occurs due to release of higher levels of 
leukotrienes and greater end-organ responsiveness to leukotrienes (3).  It follows that a dramatic 
decline in eosinophils encouraged by exposure to Omalizumab for 16 weeks would lead to a 
substantial and clinically significant reduction in the capacity for leukotriene release, thereby 
reducing severity of aspirin-provoked bronchospastic reaction.   
We propose to examine the impact of Omalizumab administration for 16 weeks in patients with 
AERD on attenuating aspirin induced bronchospasm.  We also will assess eosinophilic 
inflammation by measuring plasma and urine levels of 3-bromotyrosine (BrTyr) and 3, 5-
dibromotyrosine (Br2Tyr).  Previous studies (14,15) have shown that eosinophil activation 
promotes formation of brominating oxidants in allergen challenged subjects leading to post 
translational modification of proteins forming the stable molecular markers BrTyr and Br3Tyr. 
Furthermore, BrTyr levels are elevated (16) in plasma, airway lining fluid, and urine in patients 
with severe asthma.  Recent studies also demonstrate strong inverse correlations between 
systemic levels of plasma BrTyr and multiple measures of airflow limitation (Fig. 1). 
Thus, measurements of BrTyr and Br2Tyr, products specific for eosinophil peroxidase-catalyzed 
protein oxidation (17,18), can serve as a quantitative measure for assessing the efficacy of aspirin 
desensitization and Xolair (Omalizumab) effect in patients with AERD. Similarly, since 
enhanced oxidant stress following eosinophil activation syndromes and allergen challenge has 
been observed, a global systemic indicator of oxidant stress, such as urinary isoprostanes, a free 
radical generated product of arachidonic acid (19), may also prove informative as a quantitative 
index with which to monitor efficacy of Xolair (Omalizumab) effect in patients with AERD.  
 

 
 
 
 
7
BACKGROUND 
The initial report of aspirin intolerance appeared more than a century ago, only 3 years after aspirin 
was synthesized (20).  Fatal reactions from aspirin were described in the 1930s (21,22).  However, it 
was not until 1968 that Samter and Beers (23) described a clinical “triad” of nasal polyposis, bronchial 
asthma, and “life threatening reactions to acetylsalicylic acid” as a clinical syndrome. 
 
We now recognize that patients with this condition exhibit an aggressive inflammation of the 
upper and lower airways (24), for which provocation of asthma with/without nasal/ocular 
symptoms after ingestion of aspirin (and other non-steroidal anti-inflammatory drugs) is a 
marker.  Despite avoidance of aspirin and cross-reacting drugs, this subgroup of patients may 
experience refractory rhinosinusitis and asthma – frequently requiring numerous sinus-surgery 
procedures and regular administration of oral steroids.  The syndrome of aspirin sensitivity 
affects an estimated 4-10% of adult asthmatics (10).  Once aspirin sensitivity develops, it is 
present for the rest of the patient’s life.  
 
The term “desensitization” has traditionally been used to describe a procedure that involves 
modification of IgE-mediated (allergic/anaphylactic) potential to a substance – usually a drug 
such as penicillin, via repetitive re-exposure in a graded-dose fashion (25).  Widal managed a 
patient in 1922 (26), with gradually increasing doses of aspirin, such that instead of reacting to 
aspirin when the previously-established provoking dose was administered, this individual was 
able to tolerate aspirin, given in advancing doses, without adverse reaction.  Zeiss and Lockey 
(27) observed the same phenomenon of aspirin “desensitization”, and ultimately this procedure 
was utilized to allow individuals with AERD who require aspirin (or an aspirin-like drug) for 
treatment of arthritis or cardiovascular conditions to safely take aspirin without adverse reaction.   
 
The aspirin desensitization procedure, in which a state of “tolerance” can be induced and  
maintained, entails administration of incremental oral doses of aspirin over the course of several 
days, until a dosage of 650 mg (2 tablets) of aspirin can be taken without adverse reaction.  
Because aspirin-provoked reaction may be delayed for 2-3 hours, the minimum interval between 
doses of aspirin is 3 hours; for this reason, the challenge may span 3-4 days.  After doses of  
aspirin are given at 8:00 a.m., 11:00 a.m., and 2:00 p.m., the challenge is suspended until the 
following day.  Patients admitted for observation to undergo the procedure are released at 
approximately 5-6 PM, and return the following morning to continue the desensitization. Aspirin 
desensitization entails provoking respiratory reaction to aspirin, then administering the same dose 
that provoked this reaction, such that an individual may have repeated reactions to the same dose.  
When an aspirin-sensitive individual no longer reacts to this dose, the aspirin dosage can be 
increased as specified in our protocol (shown below) until 650 mg of aspirin can be taken without 
untoward reaction. The sequence of aspirin doses should be regarded as a general guide.  The 
schedule is modified for each patient based on the reaction(s) to aspirin that take place during the 
procedure. The dosage at which each AERD patient will react to aspirin, the number of reactions at 
each dose, and whether reaction occurs at multiple dosage levels are quite variable.  For this reason, 
the number of challenge doses that will be required, and the duration of the desensitization, cannot be 
predicted a priori. In most cases, the procedure spans 3-4 days.  
  
 
 
 
 

 
 
 
 
8
Aspirin dosages 
30 mg 
60 mg 
100 mg 
150 mg 
325 mg 
650 mg 
End! 
 
Aspirin desensitization can be perpetuated indefinitely if aspirin is taken on a daily basis. 
 
Bronchospastic reaction in AERD patients results from enhanced release of leukotrienes 
provoked by aspirin (28), in combination with greater target organ sensitivity to leukotrienes 
(29).  Aspirin-provoked bronchospasm can be lessened by administration of anti-leukotriene 
drugs (4); however, the protection is not complete, and the response is heterogeneous (3).  The 
effect of anti-leukotrienes appears to be to shift the dose-response curve to the right, and a 
tendency to transfer aspirin-provoked reaction to the upper airway (4).  Bronchospasm has also 
been lessened in AERD patients by pre-treatment with cromolyn (5,6), nedocromil (6), 
salmeterol (7), clemastine (8), and inhaled steroid (9). However, despite use of combination 
“controller” agents, aspirin provoked reaction can be volatile and may entail life-threatening 
bronchospasm.  We have recently desensitized a patient who exhibited profound bronchospasm 
(shown in Figure 2) despite receiving oral steroid burst/taper prior to the procedure, taking 
regular inhaled steroid combined with long acting beta agonist, and montelukast at higher than 
standard dosage (30 mg/day).  This case illustrates the ongoing need for a therapeutic 
intervention that can reliably block bronchospastic reaction during aspirin 
challenge/desensitization. 
 
Because serious bronchospasm may occur at any time during aspirin desensitization, this 
procedure needs to be performed in a monitored setting.  At The Cleveland Clinic Foundation, 
this procedure is performed in our Short-Procedure Unit, where respiratory reactions can be 
promptly treated, a one-on-one physician/nurse to patient ratio can be maintained throughout the 
procedure, and emergency-resuscitative equipment and trained personnel are readily available.  
We also stipulate that aspirin-sensitive patients undergo this procedure at a time when their 
asthma is well controlled.  In order to proceed, FEV1 should be greater than 70% predicted (or 
prior best measurement).  In order to ensure the reliability of our findings, we also will be 
including two placebo doses at the start of day#1, so that individuals whose lung function 
declines due to unstable asthma (or situational factors) can be identified.  Such reactions would 
obfuscate interpretation of our findings if they were misclassified as bonafide reactions to 
aspirin. 
 
Two decades ago, the first double-blind, placebo-controlled, crossover study of aspirin treatment 
during the desensitized state was reported (30).  In two-thirds of aspirin-sensitive subjects, 
statistically significant improvement was observed in nasal/sinus symptoms and medication 
reliance for rhinosinusitis in association with regular administration of aspirin after 
desensitization was achieved.  Sweet, et al. (31) described results of a long-term assessment of 
the therapeutic utility of aspirin desensitization in 35 patients followed for an average of 3.7 
years, and compared their outcomes with 42 AERD patients who avoided aspirin while not 
undergoing desensitization and were used as controls.  Aspirin desensitization was associated 

 
 
 
 
9
with statistically-significant reduction in hospitalization rates and emergency-department 
utilization, annual numbers of outpatient visits, episodes of sinusitis and antibiotics required, 
need for polypectomy and sinus-surgery procedures. Benefit has been more dramatic for 
rhinosinusitis than for asthma.  However, aspirin desensitization may also be considered for 
patients with AERD with recalcitrant asthma; in one half of 500 AERD patients in a large 
European study (32), asthma was severe and steroid-dependent.  For this reason, such patients 
also may be viewed as candidates for aspirin desensitization treatment. 
 
In summary, AERD may appear only after years of progression of rhinosinusitis and asthma.  
The aggressive upper and lower airways inflammation characteristic of this condition continues 
despite avoidance of aspirin and aspirin-like drugs.  Aspirin desensitization can be carried out as 
a means to reduce symptoms and medication reliance.  This procedure can be justified based on 
the substantial improvement in health service utilization and quality-of-life that will result.  
Following the procedure, patients typically continue to require regular medication for asthma and 
nasal/sinus symptoms, albeit at lower doses and reduced frequency of administration.  The 
economic savings associated with aspirin-desensitization treatment accrue from reduced rates of 
hospitalization and sinus-surgery procedures; re-operative intervention can be reduced from an 
average of once every three years (before desensitization) to once every ten years during long-
term daily treatment with aspirin.   An intervention that would make aspirin desensitization more 
widely available, by reducing risk (for severe bronchospasm) associated with this procedure, has 
substantial potential for improving health care outcomes and quality of life for AERD patients. 
 
 
 
0
0.5
1
1.5
2
2.5
3
8:00
AM
9:00
AM
10:00
AM
11:00
AM
12
Noon
1:00
PM
2:00
PM
3:00
PM
4:00
PM
5:00
PM
6:00
PM
7:00
PM
8:00
PM
 9:00
PM
FEV1 (liters)
Day One
Day Two
Day Three
Day Four
 

 
 
 
 
10
Figure 2:  Serial FEV1 measurements are displayed for JN, who underwent successful aspirin 
desensitization but had severe bronchospastic responses to graded dose aspirin challenge.  On day 1(shown 
in red), 60 mg aspirin challenge dose was associated with 64% decline in FEV1, which continued to 
decline further despite administration of nebulized beta agonist and then nebulized beta agonist combined 
with anticholinergic agent.  Repeated nebulized beta agonist and nebulized corticosteroid were 
administered along with intramuscular epinephrine, oral anti-leukotriene, intravenous magnesium and 
intravenous corticosteroid.  Lung function improved over several hours.  On day 2 (shown in yellow), 60 
mg dose was repeated and this provoked 59% decline in FEV1.  Protracted bronchospasm continued for 
the rest of day 2 despite administration of nebulized, oral, and intravenous medications.  On day 3, 60 mg 
aspirin dose was tolerated without untoward reaction, and then aspirin dosage was advanced per protocol 
without further reactions.  This patient continues to take aspirin daily, and has experienced benefit in the 
course of AERD in recent months. 
 
2 
STUDY OBJECTIVES 
 
PRIMARY AIM:   
To assess the impact of Omalizumab on aspirin-induced bronchospasm occurring during aspirin 
desensitization in patients with AERD. 
 
PRIMARY OUTCOME OF INTEREST:  
Aspirin-induced respiratory reaction as defined by the decline in the forced expiratory volume in 
one second (FEV1) values from baseline to after ASA provoked reaction. 
 
SECONDARY OUTCOMES OF INTEREST: 
1. Dose of ASA that provokes the first respiratory reaction. 
2. Proportion of subjects with a decline in FEV1 greater than 20% (significant respiratory reaction) 
through the course of the desensitization process. 
3. Proportion of subjects with a decline in FEV1 greater than 40% (severe respiratory 
reaction) through the course of the desensitization process. 
4. Change in plasma and urinary markers of eosinophil activation in association with 16-week 
trial of Omalizumab and aspirin desensitization, compared with placebo. 
5. Change in urinary LTE4 in subjects previously treated with Omalizumab vs. placebo with 
aspirin challenge and aspirin-induced bronchospastic reaction. 
3 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN 
 Design:   
The study will be a randomized double-blind placebo-controlled evaluation of the impact of 
Omalizumab on aspirin desensitization in patients with AERD.  Patients who are candidates for 
aspirin desensitization will be offered the opportunity to participate in this study, and will 
receive either Omalizumab or identical placebo. Subjects will receive 4 injections every 4 
weeks or 8 injections every 2 weeks (+/- 7 days) for approximately 16 weeks (based on serum 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
11
IgE and body weight according to Xolair label), after which aspirin desensitization will be 
performed. 
 
Vital signs (including pulse oximetry) will be measured and recorded at baseline, prior to each 
dose of aspirin, and prn symptoms.  Serial spirometry will be measured at baseline each 
morning, every hour during the course of the desensitization procedure, and prn respiratory 
symptoms. The completion time for each challenge day will vary based upon the timing of 
aspirin-provoked reaction and response to treatment; however, we anticipate that on most days 
the challenge will conclude between 5:00 and 6:00 PM -- 3 hours following the last dose of 
aspirin, or after recovery from aspirin provoked bronchospasm.   
 
AERD patients (N = 21) will be randomized  2:1 to receive either Omalizumab or placebo for a 
period of approximately 16 weeks prior to aspirin desensitization procedure. 
 
We will also address the hypothesis that the potential for eosinophil activation and leukotriene 
release during aspirin induced reaction will be significantly reduced in association with 
Omalizumab by performing serial measurements of plasma and urinary Borty, F2Isoprostanes 
and serial measurements of urinary LTE4. 
 
Aspirin-provoked reaction in patients with AERD occurs due to heightened leukotriene release 
and greater end-organ responsiveness to leukotrienes (28,29).  Omalizumab administration for 
16 weeks is associated with a significant decline in eosinophils in epithelium and submucosa 
(13).  We hypothesize that a substantial and clinically significant reduction in the capacity for 
leukotriene release will be promoted by the dramatic decline in eosinophils resulting from 
treatment with Omalizumab, and that this will significantly reduce severity of aspirin-provoked 
bronchospastic reaction.  We will measure serum and urinary markers of eosinophil activation, 
as well as urinary LTE4 at the following time points to confirm our hypothesis: 
Measurements of plasma and urinary markers will be performed: 
 At baseline, prior to randomization to Omalizumab/placebo (plasma and urine) 
 At baseline, prior to aspirin desensitization procedure 
 3 hours after aspirin dose 1-3 (urine) 
 3 hours post reaction specimen (plasma and urine) 
 After completion of aspirin desensitization  
o  3 hours following dose of 650 mg (plasma and urine) 
 1 month follow-up visit after taking aspirin 650 mg BID daily (plasma and urine).  
 
- 
We will obtain samples at initiation of aspirin desensitization to assess impact of 
Omalizumab exposure compared with placebo for the prior 16 weeks. 
- 
Serial samples of urine will be obtained on day 1 of desensitization to examine the 
impact of aspirin challenge doses (without and with reaction) in patients who have 
received Omalizumab compared with placebo.  Samples will be obtained on day 2 
in those in whom respiratory reaction did not occur on day 1. 
- 
Samples obtained at desensitization will also be compared in subjects randomized 
to Omalizumab vs. placebo; these specimens will also be used as “baseline” for 
aspirin desensitization treatment. 
- 
Final samples of blood and urine will be obtained at visit 11, after 1 month of 
aspirin desensitization treatment, to assess the effect of aspirin desensitization 
treatment with and without prior administration of Omalizumab. 

 
 
 
 
12
3.2 
STUDY POPULATION 
We intend to offer participation to all patients with AERD seen at the Cleveland Clinic 
Foundation 
 Patients will fulfill the following criteria, according to Xolair label: 
o AERD – confirmed by history and clinical course 
o Atopic as determined by immediate hypersensitivity skin testing or RAST. 
o IgE level = 30-700 IU/ml 
o Candidate for aspirin desensitization 
Participants will be randomized 2:1 (14:7) to receive either Omalizumab or placebo for a period 
of 16 weeks prior to aspirin desensitization procedure. 
Inclusion criteria 
 Age ≥ 18 years. 
 Fulfill diagnostic criteria for AERD and be a candidate for aspirin desensitization 
o 
Chronic asthma – frequently moderate-severe or severe 
 patients will have a  history compatible with variable airflow obstruction (33). 
o 
Chronic rhinosinusitis – usually requiring previous sinus surgery procedure(s). 
 Sinusitis will have been confirmed by computed tomography presently and/or       
in the past. 
o 
History of adverse reaction to aspirin and/or aspirin-like drugs (e.g., ibuprofen, 
naproxen, etc.) compatible with AERD.    
 Candidate for Xolair [Omalizumab] 
o 
Moderate-severe persistent asthma 
o 
IgE = 30-700 IU/ml 
o 
IgE mediated (allergic) potential to inhalant allergen(s) by cutaneous or in vitro 
testing. 
Exclusion criteria  
 Women of childbearing potential not using appropriate contraception method(s)  
 Women currently breastfeeding  
 Women who desire to become pregnant during the time of participation in this study 
 Men who desire to get someone pregnant during participation in this study 
 Known sensitivity to Xolair [Omalizumab] 
 Treatment with Xolair (Omalizumab) in the past 12 months 
 IgE level < 30 IU/ml, or > 700 IU/m. 
 No evidence of atopy by immediate hypersensitivity skin testing 
 Use of any other investigational agent in the last 30 days 
 Age < 18 year. 
 Current tobacco habituation 
 Presence of emphysema 
 Ethanolism or drug abuse within last 12 months 
 Presence of significant medical condition including malignancy, neurologic, kidney, 
gastrointestinal, liver or cardiovascular disease 

 
 
 
 
13
 Contraindication for aspirin administration, including but not limited to: severe anemia, 
thrombocytopenia, recent gastrointestinal hemorrhage. CBC will be obtained if not recently 
performed 
 Extensive travel commitments during the study that would interfere with study measurements 
or clinic visits 
3.3 
TREATMENTS 
INVESTIGATIONAL THERAPY AND REFERENCE THERAPY 
Patients with AERD who are candidates for aspirin desensitization will be offered the 
opportunity to participate.  Once enrolled, patients will receive either Omalizumab (administered 
according to Xolair label) or identical placebo. Subjects will receive 4 injections every 4 weeks 
or 8 injections every 2 weeks (+/- 7 days) for approximately 16 weeks, after which aspirin 
desensitization will be performed.  Desensitization procedure will be carried out per protocol, as 
detailed above.  Aspirin provoked reaction necessitates treatment with reversal of bronchospasm, 
followed by re-introduction of the same dose.  Dosage advancement may proceed if this dose is 
then tolerated without untoward reaction.  As more than 1 reaction may occur, the desensitization 
procedure typically spans 3-4 days. 
TREATMENT, ASSIGNMENT, BLINDING AND RANDOMIZATION 
Patients will be randomized 2:1 to receive either Omalizumab or placebo for a period of 16 
weeks prior to aspirin desensitization procedure.  Randomization will be performed by John 
Petrich of the Pharmacy Department. 
 
The randomization code may be broken by the investigator only in a medical emergency. Should 
this be required, the reasons for this will be documented. 
CONCOMITANT THERAPY 
Participants may receive medications as appropriate for management of AERD, including but not 
limited to agents to treat asthma and rhinosinusitis. Efforts will be made to maintain medications 
at constant doses during participation, and to avoid adding additional medications or modifying 
dose of current medications -- unless required for exacerbation of asthma and/or rhinosinusitis. 
Subjects will diligently avoid aspirin and aspirin-like drugs prior to desensitization. 
INTERRUPTION OR DISCONTINUATION OF TREATMENT 
Every patient has the right to discontinue study participation at any time, and patients may be 
discontinued from the study for any reason beneficial to his/her wellbeing. All data generated up 
to the time of discontinuation from the study will be analyzed and the reason(s) for 
discontinuation will be recorded.  
TREATMENT COMPLIANCE 
In order to continue participation in the study, patients must be adherent with the recommended 
schedule for administration of drug/placebo for 16 weeks.  Also, patients should schedule aspirin 
desensitization within the 2-3 week period following the final scheduled dose of drug/placebo.   

 
 
 
 
14
3.4 
VISITS AND ASSESSMENTS 
Study Timetable 
 
Duration of participation = approximately 24 weeks (6 months) 
- 
Phase A: Entry 
- 
Phase B: Xolair/Placebo (approximately 16 weeks) 
- 
Phase C: Aspirin Desensitization (1-3 weeks after Phase B) 
- 
Phase D: Aspirin Desensitization Treatment (approximately 1 month after Phase C) 
 
All visits have a window of +/- 7 days 
* Informed consent may take place prior to Phase A, while the patient is completing an 
outpatient visit. 
Phase A - Enrollment 
Visit 1:  
- 
Verify that inclusion criteria are fulfilled 
- 
History and Physical exam 
- 
Baseline spirometry performed 
- 
Baseline QOL obtained 
Study Phase 
A 
B 
B 
B 
B 
B 
B 
B 
B 
C 
D 
Injection schedule  
Q 2 week VS Q 4 
week 
Both 
Both 
Q 2 
wee
k 
Both 
Q 2 
week 
Both 
Q 2 
week 
Both 
Q 2 
wee
k 
Both 
Both 
Time of Visit 
Screenin
g 
Baseline Week 
2 
Week 
4 
Week  
6 
Week  
8 
Week 
 10 
Week 
 12 
Week 
 14 
Desens Final 
Visit 
Inclusion/Exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Information & 
Informed consent 
X* 
 
 
 
 
 
 
 
 
 
 
History and 
Physical exam 
x 
 
 
Q 4 
week 
only 
x 
 
 
Q 4 
wee
k 
only 
x 
x 
x 
QOL questionnaires 
x 
 
 
 
 
 
 
 
 
x 
x 
Spirometry 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
Laboratory samples 
x 
 
 
 
 
 
 
 
 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administration of 
Xolair or placebo 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 

 
 
 
 
15
- 
Baseline specimens of blood and urine for eosinophil activation markers (plasma 
bromotyrosine (BrTyr) and dibromotyrosine (Br2Tyr), and urinary BrTyr and 
F2Isoprostanes (F2IsoP) obtained. 
- 
Urine for LTE4 
- 
IgE level obtained if not performed previously. 
- 
Urine pregnancy test   
 
Phase B – Xolair/Placebo  
Baseline: 
– Xolair/ placebo initiated (anticipate q 2 weekly administration for most subjects) 
– Spirometry  
– Injectable epinephrine dispensed. 
 
Week 4, 8, and 12 (receiving injections every 4 weeks +/- 7 days): 
– Xolair/ placebo dosing  
– Spirometry  
 
– Physical Examination (weeks 4 and 12) 
 
Week 2, 4, 6, 8, 10, 12, 14 (receiving injections every 2 weeks +/- 7 days):  
– Xolair/ placebo dosing  
– Spirometry at weeks 4, 8, 12 
– Physical Examination (weeks 6 and 14) 
 
Phase C – Aspirin Desensitization  
 spans 3-4 days 
Day 1 
– History and Physical exam 
– Vital signs (including pulse oximetry) will be measured and recorded at baseline, 
prior to each dose of aspirin, and prn symptoms 
- 
Spirometry performed at baseline, hourly,  and prn symptoms during aspirin 
desensitization procedure, per protocol  
- 
QOL obtained to assess benefit on Omalizumab vs. placebo compared with baseline. 
- 
Blood and urine for eosinophil activation markers and urinary LTE4 obtained prior to 
aspirin challenge: these will reflect post-Omalizumab and baseline desensitization 
specimens. 

 
 
 
 
16
- 
Two placebo doses will be given to ensure that lung function is stable (< 10% 
variability in FEV1 compared with baseline) prior to proceeding with aspirin 
challenge. 
- 
Urinary LTE4, BrTyr, and F2IsoP obtained 3 hours post aspirin dose 1. 
Day 2 
– History and Physical exam 
– Vital signs (including pulse oximetry) will be measured and recorded at baseline, 
prior to each dose of aspirin, and prn symptoms 
- 
Spirometry performed at baseline, hourly,  and prn symptoms  during aspirin 
desensitization procedure, per protocol  
- 
Urinary LTE4, BrTyr, and F2IsoP obtained 3 hours post aspirin doses 2 and 3. 
- 
Plasma BrTyr, Br2Tyr, and urinary BrTyr, F2IsoP and LTE4 obtained 3 hours post 
reaction ( if no reaction following doses 1-3) 
Day 3 or 4 – post desensitization sample (3 hours after 650 mg ASA dose) 
– History and Physical exam 
– Vital signs (including pulse oximetry) will be measured and recorded at baseline, 
prior to each dose of aspirin, and prn symptoms 
- 
Spirometry performed at baseline, hourly,  and prn symptoms  during aspirin 
desensitization procedure, per protocol  
- 
Plasma BrTyr, Br2Tyr, and urinary BrTyr, F2IsoP and LTE4 obtained 3 hours post 
reaction ( if no reaction following doses 1-4) 
-   Blood and urine for eosinophil activation markers and urine for LTE4, BrTyr, and 
F2IsoP obtained: these are post-aspirin desensitization samples. 
 
Phase D – Aspirin Desensitization Treatment 
Final Visit  
-     1 month (+/- 7 days) post-desensitization: final assessments and labs obtained 
- 
History and Physical exam 
- 
Progress spirometry performed to assess change with aspirin desensitization 
treatment. 
- 
Blood and urine for eosinophil activation markers: Plasma BrTyr, Br2Tyr, and 
urinary BrTyr, F2IsoP. 
- 
urine for LTE4 
- 
QOL obtained to assess benefit on aspirin desensitization treatment. 
- 
urine pregnancy test 
 

 
 
 
 
17
Laboratory Tests 
Primary Aim 
Our primary aim is assess the impact of Omalizumab on aspirin-induced bronchospasm 
occurring during aspirin desensitization in patients with AERD.  The primary outcome of interest 
is bronchospastic reaction induced by aspirin.  This will be quantified by the decline in the 
forced expiratory volume in one second (FEV1) values from baseline to after aspirin-provoked 
reaction. 
 
Secondary Aim 
We will assess whether Omalizumab attenuates aspirin induced bronchospasm by examining the 
dose of aspirin provoking respiratory reaction, and by analyzing the proportion of subjects who 
experience bronchospastic reaction with declines in FEV1 ≥ 20% and ≥ 40%, respectively, in 
Omalizumab and placebo groups.  
 
We also will measure markers of eosinophil activation and urinary LTE4, to confirm our 
hypothesis that aspirin-provoked reaction will be significantly attenuated by prior 
administration of Omalizumab for 16 weeks. We anticipate that systemic markers of eosinophil 
activation will be elevated in all AERD subjects at baseline, and that a reduction will be 
observed in Omalizumab-treated patients in the baseline sample at time of desensitization 
compared with placebo.  This may also be observed in the level of urinary LTE4 compared 
with initial sample at study entry, and compared with placebo-treated subjects -- among whom 
this should be relatively unchanged.  If a dramatic decline in eosinophils (and consequent 
reduction in potential for leukotriene release) is achieved with Omalizumab treatment for 16 
weeks (13), we would expect this to also be reflected in significant reduction in the rise in 
urinary markers of eosinophil activation and oxidant stress (BrTyr and F2IsoP), as well as 
LTE4, with aspirin-induced respiratory reaction in subjects randomized to Omalizumab 
compared to placebo. At the one month follow up visit, we expect that we will find a reduction 
in systemic markers of eosinophil activation in placebo-treated patients compared with baseline 
sample obtained at study entry in association with aspirin desensitization treatment, but that 
this will be less marked compared with those randomized to prior treatment with Omalizumab. 
 
Markers of eosinophil activation and urinary LTE4 will be measured as previously reported (14, 
18, 19, 34).  
 
3.5 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, as described in the study manual. 
 
An adverse event is any undesirable sign, symptom or medical condition occurring after starting 
study drug (or therapy). Medical conditions/diseases present before starting study treatment are 
only considered adverse events if they worsen after starting study treatment.  
A serious adverse event is an undesirable sign, symptom or medical condition which: 1. is fatal 
or life-threatening, 2. required hospitalization, 3. results in persistent or significant 
disability/incapacity, 4. is medically significant, in that it may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above.  

 
 
 
 
18
4 
DATA MANAGEMENT AND STATISTICAL METHODS   
Safety Assessment:   
Investigators will enter information required by the protocol into the Case Report Forms (CRFs). 
Non-obvious errors or omissions will be entered on Data Query Forms, which will be returned to 
the investigational site for resolution. The assessment of safety will be based mainly on the 
frequency of adverse events, which includes all serious adverse events. Adverse events will be 
summarized by presenting for each treatment group the number and percentage of patients 
having any adverse event, having an adverse event in each body system, and having each 
individual adverse event.  Any other information collected (e.g. severity or relatedness to study 
medication) will be listed as appropriate. 
 
Statistical Methods: 
Unequal-variances t-tests will be used to compare the change in FEV1 (and the aspirin provoking 
dose) between subjects who receive placebo and those who receive Omalizumab.  If distributional 
assumptions are not met, the nonparametric Wilcoxon Rank Sum test will be used.  Pearson’s chi-
square test will be used to test if the proportion of subjects with a decline in FEV1 > 20% is 
significantly different between subjects who receive placebo and those who receive Omalizumab.  
A significance level of 0.05 will be used for all analyses.  SAS 9.1 software, SAS Institute, Cary, 
NC will be used to perform all analyses. 
Interim Analysis 
An interim analysis will be conducted based on enrolled patient data through the last completed 
study visit. Primary and secondary outcome measures will be reviewed as part of the analysis.  If 
there are no clinically meaningful findings, the interim analysis report will be submitted to the 
FDA with the annual report.  If there are meaningful clinical findings, the PI will send a letter to 
the subjects detailing these findings.  If the study continues, the statistician will further evaluate 
the sample size. 
 
Sample Size Calculation:   
No previous studies have been done to examine the impact of Omalizumab in the ASA 
desensitization process.  Stevenson, et.al (1), conducted a study on the impact of Montelukast in 
inhibiting aspirin response in AERD patients.  We believe the standard deviation for the change in 
FEV1 values for both subject groups will be similar in magnitude to those previously observed (1); 
for this reason, we have based our sample calculations on these estimates.  The standard deviation 
for the change in FEV1 values is assumed to be equal to 6.7 and 7.8 for the placebo and 
Omalizumab groups, respectively. The minimum mean difference in the change in FEV1 between 
the two groups that can be detected, with randomization proceeding 2:1 to Omalizumab and placebo 
groups, and with 14 and 7 AERD patients in each group (assuming an attrition rate of 3 subjects, or 
14-15%), respectively, is 12.8%, with a power of 90%. Secondary outcomes of interest noted above 
will also be examined; however, the proposed enrollment may not entail sufficient power to assess 
these in a definitive fashion.  
The objective of this trial is to study the therapeutic utility of Omalizumab for attenuating aspirin 
induced bronchospasm occurring during aspirin desensitization. Data will be summarized with 
respect to demographic and baseline characteristics and efficacy and safety observations. 
Exploratory analyses will be performed using descriptive statistics.  

 
 
 
 
19
5 
REFERENCES 
CITATIONS 
 
1) 
Stevenson DD, Simon RA, Mathison DA, Christiansen SC. Montelukast is only partially 
effective in inhibiting aspirin responses in aspirin sensitive asthmatics.  Ann Allergy Asthma 
Immunol 2000; 85: 477. 
2) 
Pauls JD, Simon RA, Daffern PJ, Stevenson DD.  Lack of effect of the 5-Lipoxygenase 
inhibitor zileuton in blocking oral aspirin challenges in aspirin sensitive asthmatics.  Ann 
Allergy Asthma Immunol  2000; 85:  
3) 
Lang DM.  Anti-Leukotriene agents and aspirin-sensitive asthma – Are we removing the 
second bassoonist or skating to where the puck is gonna be? Ann Allergy Asthma and 
Immunol 2000; 85: 5-8. 
4) 
Berges-Gimeno M, Simon R, Stevenson D.  The effect of leukotriene-modifier drugs on 
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5) 
Yoshida S, Amayasu H, Sakamoto H, et al.  Cromolyn sodium prevents 
bronchoconstriction and urinary LTE4 excretion in aspirin-induced asthma.  Ann Allergy 
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6) 
Robuschi M, Gambaro G, Sestini P, et al.  Attenuation of aspirin-induced 
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7) 
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8) 
Szczeklik A, Serwonska M.  Inhibition of idiosyncratic reactions to aspirin in asthmatic 
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9) 
Lang DM. Blocking aspirin-induced bronchospasm.  Ann Allergy Asthma Immunol 2005; 
95: 307-308. 
10) 
Hamad A, Sutcliffe A, Knox A. Aspirin-induced asthma: clinical aspects, pathogenesis 
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11) 
Busse W, Corren J, Lanier B, McAlary M, Fowler-Taylor A, Della Cioppa G, van As A, 
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Soler M, Matz J, Townley R, Buhl R, O'Brien J, Fox H, Thirlwell J, Gupta N, Della 
Cioppa G. The anti-IgE antibody Omalizumab reduces exacerbations and steroid requirement 
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13) 
Djukanovic R, Wilson S, Kraft M; et al. Effects of treatment with anti-immunoglobulin E 
antibody Omalizumab on airway inflammation in allergic asthma.  Am J Respir Crit Care 
Med. 2004; 170:583-93.  
14) 
Wu W, A.  d’Avignon, Y.H. Chen, and S.L. Hazen.  3-Bromotyrosine and 3,5-
dibromotyrosine are major products of protein oxidation by eosinophil peroxidase:  Potential 
markers for eosinophil-dependent tissue injury in vivo.  Biochemistry. 1999; 38:3538-3548  
15) 
Wu W, M. Samoszuk, S. Comhair; M.J. Thomassen, C. Farver, R. Dweik, M. Kavuru, 
S.C.  Erzurum and S.L. Hazen. Eosinophils generate brominating oxidants in allergen-
induced asthma. J. Clin. Invest.  2000; 105: 1455-1463   
16) 
MacPherson JC, S.A. Comhair, S.C. Erzurum, D.F. Klein, M.F. Lipscomb, M.S. Kavuru, 
M.  Samoszuk and S.L. Hazen. Eosinophils are a major source of NO-derived oxidants in 
severe asthma:  Characterization of pathways available to eosinophils for generating reactive 
nitrogen species. J. Immunology. 2001; 166:5763-5772  

 
 
 
 
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17) 
Denzler L, M. Borchers, J.R. Crosby, G. Cieslewicz, E.M. Hines, J.P. Justice, S. Cormier, 
K. Lindenberger, W. Song, W. Wu, S.L. Hazen, G. Gleich, J.J.  Lee and N.A. Lee. 
Ovalbumin-challenge models of asthma in mice do not elicit eosinophil degranulation and 
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Brennan ML, W. Wu, X. Fu, Z. Shen, W. Song, H. Frost, L. Narine, E. Lenkiewicz, M.T. 
Borchers, A.J. Lusis, J.J. Lee, N.A. Lee, H.A. Abu-Soud, H. Ischiropoulos, and S.L. Hazen.  
A tale of two controversies: i) Defining the role of peroxidases in nitrotyrosine formation in 
vivo using eosinophil peroxidase and myeloperoxidase deficient mice; and ii) Defining the 
nature of peroxidase-generated reactive nitrogen species. J.Biol.Chem. 2002; 277:17415–
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21) Dysart BR.  Death following ingestion of 5 grains of acetylsalicylic acid.  JAMA 1933; 
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22) Francis N, Gent OT, Bullen SS. Death from 10 grains of aspirin. J Allerg 1935; 6: 504. 
23) Samter M, Beers RF.  Intolerance to aspirin: Clinical studies and consideration of its 
pathogenesis.  Ann Intern Med 1968; 68: 975-83. 
24) 
Szczeklik A, Stevenson DD.  Aspirin-induced asthma: Advances in pathogenesis and 
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25) 
Solensky R.  Drug allergy: desensitization and treatment of reactions to antibiotics and 
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26) Widal M, Abrami P, Lermeyez J.  Anaphylaxie et idiosyncrasie. Presse Med 1922; 30: 189-
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27) 
Zeiss R, Lockey R. Refractory period to aspirin in a patient with aspirin induced asthma. 
J Allergy Clin Immunol 1976; 57:440-8. 
28) 
Christie PE, Tagari P, Ford-Hutchinson AW; et al.  Urinary leukotriene E4 
concentrations increase after aspirin challenge in aspirin sensitive asthmatic subjects.  Am 
Rev Resp Dis  1991; 143: 1025-9. 
29) 
Arm JP, O’Hickey SP, Spur BW, Lee TH.  Airway responsiveness to histamine and 
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30) 
Stevenson D, Pleskow  W, Simon, R; et al. Aspirin sensitive rhinosinusitis: a double 
blind cross over study of treatment with aspirin.  J Allergy Clin Immunol 1984; 73:500-7 
31) 
Sweet J, Stevenson D, Simon R, Mathison D. Long term effects of aspirin desensitization 
treatment for aspirin sensitive rhinosinusitis asthma.  J Allergy Clin Immunol 1990; 85:59-65  
32) 
Szczeklik A, Nizankowska E, Duplaga M.  Natural history of aspirin induced asthma.  
Eur Resp J  2000; 16: 432-6.Arm J.  What can desensitization do for patients with aspirin-
induced asthma?  J Resp Dis  1999; 20: 647. 
33) 
Expert Panel Report 2: Guidelines for the diagnosis and 
      management of asthma. US Department of Health and Human Services. Publication No. 97-              
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34) 
Manning PJ, Rokach J, Malo J, et al.  Urinary leukotriene E4 levels during early and late 
asthmatic responses.  J Allergy Clin Immunol 1990; 86: 211-20. 

 
 
 
 
21
Signature of Investigator(s) and Study Personnel 
 
  type/print name   
(Investigator) David M. Lang, 
MD 
signature  
 
date 
 
type/print name   
(Statistician) 
signature  
 
date 
 
  type/print name   
Head of investigational site 
signature  
 
date 
 
 
  type/print name   
Medical Director 
signature  
 
date 
 
  type/print name   
(Regional Scientific Director) 
signature  
 
date