Conditions: Anaphylaxis Hypotension Bronchospasm Angioedema
Keywords: Omalizumab Idiopathic Anaphylaxis Serum Tryptase Placebo-Controlled Adult Anaphylaxis Allergic Reaction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
Background:

* Omalizumab is an approved drug for the treatment of asthma by the Food and Drug Administration.
* Researchers are now studying this drug in a double-blind placebo-controlled manner to assess efficacy in patients with idiopathic anaphylaxis (recurrent hypersensitive allergic episodes for which a cause is not identified).
* The study will improve understanding of the mechanisms involved in anaphylactic reactions as a response to the downregulation (a decrease in the number of receptors on the surface of cells) in mast cell (a resident cell with several types of tissues) activation, and lead to the development of strategies to better prevent or treat anaphylaxis.

Objectives:

* To determine whether treatment with omalizumab will reduce or prevent episodes of unprovoked anaphylaxis (an acute allergic reaction) in subjects with a history of idiopathic anaphylaxis.
* To assess pharmacodynamics (physiological effects of a drug) and identify patients with undiagnosed mastocytosis (rare disorders caused by too many mast cells).
* To investigate cellular and molecular mechanisms of signaling and the effect of omalizumab on mast cells or basophils (a cell in the leukocyte family that releases histamine, which affects allergic response) and explore other regulatory pathways that may be involved with modulation of mast cell degranulation.

Eligibility:

* Patients between 18 and 70 years of age who have been diagnosed with idiopathic anaphylaxis, a diagnosis that is made only after other causes of anaphylaxis have been considered.
* Patients with documented anaphylaxis episodes (mild to severe) at least six times within the past 1 year period, at least once within the last 4 months, and with at least one of the following:

  * Elevated serum tryptase above baseline within 2 hours of the event.
  * Emergency room visit with documented anaphylaxis without a known cause established by the acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (generalized hives, itching or flushing, swollen lips-tongue-throat) and at least one of the following: (1) respiratory compromise or gastrointestinal involvement (shortness of breath, wheeze-bronchospasm, throat tightness, low oxygen levels, nausea, vomiting, or abdominal pain); or (2) reduced blood pressure or associated symptoms of end-organ dysfunction (collapse, loss of consciousness, or loss of bladder or bowel control).
  * Hospitalization for anaphylaxis.
* Patients must provide a letter of referral, with copies of pertinent medical history and laboratory tests, from the prospective participant s local physician, and have the ability to give informed consent.
* Women with childbearing potential must have a negative pregnancy test, and must agree to practice abstinence or effective birth control from the start of the protocol and for 3 months following the last injection of the study drug.

Design:

* Participants will undergo a clinical evaluation, blood tests, and a bone marrow biopsy and aspirate.
* Participants will be randomized to either drug or placebo and will receive two doses of omalizumab or a matched placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.
* Participants will remain on the assigned regimen for 6 months or until they have experienced new onset of severe adverse event on one occasion within 24 hours of study medication that are related to the study drug, whichever comes first. At that time, the participant will be discontinued from drug administration.

Detailed description:
Anaphylaxis is a severe systemic reaction caused by release of mediators from mast cells and basophils. Manifestations include cutaneous, respiratory, cardiovascular, or gastrointestinal signs and symptoms. Although anaphylaxis is frequently attributed to exposure to specific foods, drugs, and insect venoms in sensitive individuals, a causative factor is not identified in 30% to 50% of patients with recurrent anaphylactic episodes (idiopathic anaphylaxis).

Currently, therapeutic options for the treatment of idiopathic anaphylaxis are limited with variable efficacy. This pilot study will examine the hypothesis that omalizumab (Xolair ) will decrease episodes of unexplained anaphylaxis in patients with idiopathic anaphylaxis. Omalizumab is approved for use in asthma. We will examine the safety profile and efficacy of omalizumab in patients with anaphylaxis. In addition, the study will investigate whether patients with anaphylaxis have unique molecular and cellular defects in mast cells that result in these cells being more susceptible to degranulation.

The study will enroll patients with idiopathic anaphylaxis. Patients will undergo a clinical evaluation, blood tests, and a bone marrow biopsy and aspirate. Patients will be randomized to either drug or placebo and will receive, in a double-blind placebo-controlled approach, 2 doses of omalizumab or a matched placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months. Patients will remain on the assigned regimen if they have experienced anaphylactic events (post 24-hr window) determined to be unrelated to study drug or have been followed for 6 months, whichever comes first. These unrelated events would be determined by the PI not to jeopardize patient safety or restrict the use of additional therapy such as corticosteroids to control symptoms. After this point, the patient may be discontinued from drug administration until unblinding. This design ensures that no patient will have anaphylactic episodes while on placebo if other therapy is medically indicated. Research studies will be conducted to elucidate other markers or pathways of mast cell regulation.

The primary outcome will be a reduction in the number and timing of anaphylactic events during the randomized phase. Secondary outcomes will include a reduction in surface IgE receptors on basophils, identification of mutations in c-kit, and evaluation of the efficacy of omalizumab on other mediator-induced symptoms associated with anaphylaxis. The study will improve the understanding of the mechanisms involved in anaphylactic reactions as a response to the downregulation of mechanisms involved in mast cell activation that could, in turn, lead to development of strategies to better prevent or treat anaphylaxis.

Arms:
arm 1: Subjects will receive two doses of Omalizumab while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months. arm 2: Subjects will receive two doses of placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.

Interventions: intervention 1: Epinephrine intervention 2: Omalizumab (Xolair) intervention 3: Placebos
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
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A Randomized Double-Blinded, Placebo-Controlled Study of Omalizumab 
for Idiopathic Anaphylaxis 
 
NIAID Protocol Number:  
09-I-0129 
 
Sponsored by:  
National Institute of Allergy and Infectious Diseases (NIAID) 
 
Pharmaceutical Support Provided by:  
Genentech-Novartis 
 
IND Sponsor:  
Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO)/Division of Clinical Research (DCR) 
NIAID/NIH 
 
IND # 104475 
Xolair® (Omalizumab) 
Provided by: Genentech-Novartis 
  
Principal Investigator: 
Melody Carter, MD, NIAID/LAD 
 
Associate Investigators: 
Dean D. Metcalfe, MD, NIAID/LAD 
Hirsh D. Komarow, MD, NIAID/LAD 
Irina Maric, MD, CC/DLM 
Linda M. Scott, CRNP, NIAID/LAD 
Hyejeong Bolan, RN, MSN, NIAID/LAD 
Andrea Robin Eisch, RN, NIAID/LAD 
 
Collaborators: 
Lawrence B. Schwartz, M.D., Ph.D. 
 Virginia Commonwealth University, School of Medicine 
Thomas A.E. Platts-Mills, M.D. University of Virginia, School of Medicine 
 
Version 12.0: March 17, 2017 
Amendment N 
 
Clinical Monitoring 
Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO)/DCR 
NIAID/NIH 
 
 


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Confidentiality Statement 
This document is confidential and is to be distributed for review only to 
investigators, potential investigators, consultants, study staff, and applicable 
independent ethics committees or institutional review boards. The contents of 
this document shall not be disclosed to others without written authorization from 
NIAID (or others, as applicable), unless it is necessary to obtain informed 
consent from potential study participants. 
 
Statement of Compliance 
The study will be conducted in accordance with the design and specific 
provisions of this IRB approved protocol, in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki, and that are consistent with 
Good Clinical Practice (GCP) and the applicable regulatory requirement(s). The 
Principal Investigator will assure that no deviation from or changes to the protocol 
will take place without prior agreement from the Sponsor and documented 
approval from the IRB, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. The Principal Investigator will promptly report to 
the IRB and the Sponsor any changes in research activity and all unanticipated 
problems involving risk to human subjects, or others. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
Table of Contents .................................................................................................. 3 
List of Abbreviations .............................................................................................. 6 
1.0 
Précis ......................................................................................................... 9 
2.0 
Background Information and Scientific Rationale ..................................... 11 
2.1 
Background Information ......................................................................... 11 
2.1.1 
Description of the Study Agents ...................................................... 13 
2.1.2 
Summary of Relevant Clinical Studies ............................................ 14 
2.2 
Rationale................................................................................................ 14 
2.3 
Potential Risks and Benefits .................................................................. 14 
2.3.1 
Potential Risks of omalizumab ........................................................ 14 
2.3.1.1 
Anaphylaxis ............................................................................ 14 
2.3.1.2 
Malignancy ............................................................................. 15 
2.3.1.3 
Carcinogenesis, Mutagenesis, Impairment of Fertility, 
Embryotoxicity, Teratogenicity ................................................................. 15 
2.3.1.4 
Other ...................................................................................... 16 
2.3.2 
Potential Risks of other procedures................................................. 17 
2.3.2.1 
Bone Marrow Biopsy .............................................................. 17 
2.3.2.2 
Venipuncture .......................................................................... 17 
2.3.2.3 
Skin Testing ........................................................................... 17 
2.3.2.4 
Anesthesia-Conscious Sedation ............................................ 17 
2.3.2.5 
Pulmonary Function Testing ................................................... 17 
2.3.3 
Potential Benefits ............................................................................ 18 
3.0 
Study Objectives ...................................................................................... 18 
3.1 
Primary Objective .................................................................................. 18 
3.2 
Secondary Objectives ............................................................................ 18 
3.3 
Exploratory Objectives ........................................................................... 18 
4.0 
Study Design ............................................................................................ 18 
4.1 
Description of the Study Design ............................................................. 18 
4.2 
Study Endpoints ..................................................................................... 19 
4.2.1 
Primary Endpoint ............................................................................. 19 
4.2.2 
Secondary Endpoints ...................................................................... 19 
4.2.3 
Exploratory Endpoints ..................................................................... 19 
5.0 
Study Population ...................................................................................... 19 
5.1 
Participant Inclusion Criteria .................................................................. 20 
5.2 
Participant Exclusion Criteria ................................................................. 21 
5.3 
Participation of Children ......................................................................... 21 
6.0 
Study Agent .............................................................................................. 21 
6.1 
Study Agent Acquisition ......................................................................... 21 
6.2 
Study Agent Storage and Stability ......................................................... 22 
6.3 
Preparation, Administration, and Dosage of Study Agent ...................... 22 
6.3.1 
Study Agent ..................................................................................... 22 
6.3.1.1 
Description ............................................................................. 22 
6.3.1.2 
Dosing and Administration ..................................................... 22 
6.3.1.3 
Omalizumab Dosing Calculation: ........................................... 23 


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6.3.1.4 
Route of Administration .......................................................... 25 
6.3.1.5 
Dose Adjustments/Modifications/Delays ................................ 25 
6.3.1.6 
Duration of Therapy ............................................................... 25 
6.3.1.7 
Tracking of Dose .................................................................... 26 
6.3.1.8 
Use of Ancillary Medications/OTC Products/Foods ................ 26 
6.3.1.9 
Participant Access to Study Agent at Study Closure .............. 26 
6.4 
Assessment of Participant Compliance with Study Agent ...................... 26 
6.5 
Prohibited and Precautionary Medications and Procedures .................. 26 
6.6 
Rescue Medications .............................................................................. 26 
7.0 
Study Procedures/Evaluations ................................................................. 26 
7.1 
Clinical Evaluations (Appendix B) for 2 week (+/- 3 days) and 4 week (+/- 
3 days) dosing ................................................................................................. 26 
7.1.1 
Screening Visit – (Inpatient or Outpatient) ....................................... 26 
7.1.2 
First Visit- Inpatient.......................................................................... 28 
7.1.3 
Second Visit – Inpatient ................................................................... 28 
7.1.4 
Follow-up Visits – Outpatient (Visits 3, 4 and 5, see appendix for q 2 
week dosing) ................................................................................................ 28 
7.1.5 
NIH Final Treatment Visit (Visit 6) ................................................... 29 
7.1.6 
Off Treatment  Follow-up (Visit 7) ................................................... 29 
7.2 
Biohazard Containment ......................................................................... 29 
8.0 
Stored Samples ........................................................................................ 30 
8.1 
Use of Stored Samples .......................................................................... 30 
8.2 
Disposition of Stored Samples ............................................................... 30 
9.0 
Assessment of Safety .............................................................................. 31 
9.1 
Adverse Event Recording/Documentation ............................................. 31 
9.2 
Assessing Adverse Events .................................................................... 33 
9.2.1 
Adverse Event Grading (Severity) Scale ......................................... 33 
9.2.2 
Adverse Event Relationship to Study Procedures ........................... 33 
9.3 
Adverse Event Reporting Procedures .................................................... 34 
9.3.1 
Expedited Reporting to the NIAID IRB ............................................ 34 
9.3.2 
Annual Reporting to the NIAID IRB ................................................. 35 
9.3.3 
Reporting Adverse Events to Genentech ........................................ 35 
9.3.4 
Reporting Responsibilities to the Sponsor ....................................... 35 
9.3.4.1 
Adverse Events ...................................................................... 35 
9.3.4.2 
Serious Adverse Events ......................................................... 35 
9.3.4.3 
Unanticipated Problems ......................................................... 36 
9.4 
Sponsor’s Reporting Responsibilities .................................................... 36 
9.5 
Type and Duration of the Follow-up of Participants after Adverse Events
 
36 
9.5.1.1 
Reporting of Pregnancy ......................................................... 37 
9.5.1.2 
Follow-up of Participants after Adverse Events ...................... 37 
9.6 
Halting Rules for the Protocol ................................................................ 37 
9.6.1 
Unblinding of the Study ................................................................... 37 
9.6.1.1 
Scheduled Unblinding ............................................................ 37 
9.6.1.2 
Intentional, Unscheduled Unblinding for Treatment Conditions
 
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9.6.2 
Stopping Rules for an Individual Participant/Cohort ........................ 38 
9.6.3 
Premature Withdrawal of a Participant ............................................ 39 
9.7 
Data and Safety Monitoring ................................................................... 40 
    
9.7.1   Safety Review and Communications Plan………………………….41 
 
9.7.2   Sponsor Medical Monitor…………………………………………......41 
10.0 
Statistical Considerations ......................................................................... 41 
10.1 
Overview and Study Objectives .......................................................... 41 
10.2 
Description of the Analyses ................................................................ 41 
10.3 
Study Hypotheses .............................................................................. 42 
10.4 
Sample Size Consideration ................................................................ 42 
10.5 
Maintenance of Trial Treatment Randomization Codes ...................... 42 
10.6 
Randomization and Blinding ............................................................... 42 
11.0 
Quality Control and Quality Assurance .................................................... 43 
12.0 
Ethics/Protection of Human Subjects ....................................................... 43 
12.1 
Conflict of Interest ............................................................................... 44 
12.2 
Rationale for Subject Selection........................................................... 44 
12.3 
Institutional Review Board .................................................................. 44 
12.4 
Informed Consent Process ................................................................. 44 
12.5 
Justification for Exclusion of Women, Minorities, and Children (Special 
Populations) .................................................................................................... 45 
12.6 
Compensation .................................................................................... 45 
13.0 
Data Management .................................................................................... 45 
14.0 
Data Handling and Record Keeping ......................................................... 46 
15.0 
Publication Policy ..................................................................................... 46 
16.0 
Record Retention ..................................................................................... 46 
17.0 
References ............................................................................................... 48 
Appendix A. Toxicity Table ................................................................................. 51 
Appendix B. Schedule of Procedures/Evaluations .............................................. 52 
Appendix C. WHO Criteria for the Diagnosis of Systemic Mastocytosis [13] ...... 57 
Appendix D. Xolair® Package Insert .................................................................... 58 
Appendix E. Physician Treatment Note .............................................................. 58 
Appendix F. Weekly Event Log ........................................................................... 59 
Appendix G. Expected symptoms and adverse events related to the underlying 
disease (IA), the study agent omalizumab or protocol procedures………………60 
 
  
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
-HCG 
human choriogonadotropin 
5-HIAA 
5-hydroxyindoleacetic acid 
ADR 
adverse drug reaction 
AE 
adverse event/adverse experience 
ALT 
alanine aminotransferase 
Anti-HTLV I/II 
antibody to HTLV virus types I and II 
anti-IgE 
antibody against human immunoglobulin E 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CIB 
clinical investigator’s brochure 
COI 
conflict of interest 
CRIMSON 
Clinical Research Information Management System 
of the NIAID 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Division of Clinical Research 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
ESR 
erythrocyte sedimentation rate 
FcRI 
high-affinity IgE receptor 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IA 
idiopathic anaphylaxis 
IgA 
immunoglobulin A 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
indolent systemic mastocytosis 
MedDRA © 
Medical Dictionary for Regulatory Activities 
N 
number (typically refers to participants) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
OCRPRO 
National Institutes of Health 
Office of Clinical Research Policy and Regulatory 
Operations 
OHRP 
Office for Human Research Protections 
OHSRP 
Office of Human Subjects Research Protections 
PAF 
platelet activating factor 
PFT 
pulmonary function test 
PI 
Principal Investigator 


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List of Abbreviations 
PK 
pharmacokinetics 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QA 
quality assurance 
RAST 
Radioallergosorbent test 
RES 
reticuloendothelial system 
SAE 
serious adverse event/serious adverse experience 
SC 
subcutaneous 
SOP 
standard operating procedure 
UP 
                
Unanticipated Problem 
UPnonAE 
 
Unanticipated Problem that is not an Adverse Event 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 


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Protocol Summary 
 
 
Full Title 
A Randomized Double-Blinded, Placebo-Controlled Study of 
Omalizumab for Idiopathic Anaphylaxis 
Short Title 
Omalizumab in the Treatment of Idiopathic Anaphylaxis 
Clinical Phase 
Phase II 
IND Sponsor  
OCRPRO/DCR/NIAID/NIH 
Conducted By 
NIAID/LAD 
Principal 
Investigator 
Melody Carter, MD 
Sample Size 
N=20 
Accrual Ceiling 
30 
Study Population 
Adults 18-70 years of age 
Accrual Period 
72 months 
Study Design 
Randomized, double-blind, placebo-controlled trial 
Study Duration 
Start Date: January 2009  End Date: January 2017 
Study Agent/ 
Intervention 
Description 
Omalizumab, FDA-approved for asthma, will be given every 2-
4 weeks to patients with idiopathic anaphylaxis. Omalizumab 
will be administered in a double-blind placebo-controlled 
manner to assess efficacy in this patient population.  
Primary Objective 
 
To determine if treatment with omalizumab will reduce 
unprovoked anaphylaxis in subjects with a history of idiopathic 
anaphylaxis. 
Secondary 
Objectives 
•Assess pharmacodynamics. 
• Determine the frequency of the D816V mutation in c-kit in 
patients with idiopathic anaphylaxis. 
• Identify patients with undiagnosed mastocytosis. 
Exploratory 
Objectives 
•Investigate cellular and molecular mechanisms of signaling 
and the effect of omalizumab on mast cells and/or basophils.  
•Explore other regulatory pathways that may be involved with 
modulation of mast cell degranulation. 
Endpoints 
Primary:  Reduction in number and timing of documented 
anaphylactic events. 
Secondary:  
• A ≥50% reduction of the IgE receptor on surface of 
basophils. 
• Document changes in mast cell mediator-type 
symptoms associated with anaphylaxis. 
• Identify persons with activating mutations of c-kit or 
other abnormal markers in mast cells. 
 
 
 
 
 
 


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1.0 Précis 
Anaphylaxis is a severe systemic reaction caused by release of mediators from 
mast cells and basophils. Manifestations include cutaneous, respiratory, 
cardiovascular, or gastrointestinal signs and symptoms. Although anaphylaxis is 
frequently attributed to exposure to specific foods, drugs, and insect venoms in 
sensitive individuals, a causative factor is not identified in 30% to 50% of patients 
with recurrent anaphylactic episodes (idiopathic anaphylaxis) [1-3].  
 
Currently, therapeutic options for the treatment of idiopathic anaphylaxis are 
limited with variable efficacy. This pilot study will examine the hypothesis that 
omalizumab (Xolair®) will decrease episodes of unexplained anaphylaxis in 
patients with idiopathic anaphylaxis. Omalizumab is approved for use in asthma. 
We will examine the safety profile and efficacy of omalizumab in patients with 
anaphylaxis. In addition, the study will investigate whether patients with 
anaphylaxis have unique molecular and cellular defects in mast cells that result 
in these cells being more susceptible to degranulation.  
 
The study will enroll patients with idiopathic anaphylaxis. Patients will undergo a 
clinical evaluation, blood tests, and a bone marrow biopsy and aspirate. Patients 
will be randomized to either drug or placebo and will receive, in a double-blind 
placebo-controlled approach, 2 doses of omalizumab or a matched placebo while 
hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up 
to 12 months. Patients will remain on the assigned regimen if they have 
experienced anaphylactic events (post 24-hr window) determined to be unrelated 
to study agent or have been followed for 6 months, whichever comes first. These 
unrelated events would be determined by the PI not to jeopardize patient safety 
or restrict the use of additional therapy such as corticosteroids to control 
symptoms.  After this point, the patient may be discontinued from drug 
administration until unblinding. This design ensures that no patient will have   
anaphylactic episodes while on placebo if other therapy is medically indicated. 
Research studies will be conducted to elucidate other markers or pathways of 
mast cell regulation. 
 
The primary outcome will be a reduction in the number and timing of anaphylactic 
events during the randomized phase. Secondary outcomes will include a 
reduction in surface IgE receptors on basophils, identification of mutations in 
c-kit, and evaluation of the efficacy of omalizumab on other mediator-induced 
symptoms associated with anaphylaxis. The study will improve the understanding 
of the mechanisms involved in anaphylactic reactions as a response to the 
downregulation of mechanisms involved in mast cell activation that could, in turn, 
lead to development of strategies to better prevent or treat anaphylaxis. 
 
 
 
 
 


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Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 Background Information and Scientific Rationale 
2.1 Background Information 
Anaphylaxis is a systemic reaction associated with release of mediators from 
mast cells and basophils [4]. Signs and symptoms of anaphylaxis include 
generalized flushing, urticaria, nasal congestion, conjunctival irritation, 
bronchospasm, angioedema of the tongue, throat, palms, and soles, 
gastrointestinal cramping, lightheadedness, and loss of consciousness. The 
clinical outcome in anaphylaxis varies from a self-limited episode to fatal 
circulatory collapse. The occurrence of anaphylaxis reported in epidemiologic 
studies suggest that 1.2% to 16.8% of the U.S. population suffer from an 
anaphylactic reaction based on the prevalence of allergic patients and that this 
population have a 0.0002% annual risk of death [5]. Common causes of 
anaphylaxis include allergic reactions to foods, drugs, and stinging insects. A 
causative factor, however, is not identified in up to 50% of the patients with 
recurrent anaphylactic episodes. Therefore, idiopathic anaphylaxis (IA) becomes 
a diagnosis of exclusion after other causes have been ruled out in these patients. 
Idiopathic anaphylaxis is categorized as frequent (2 episodes in the past 2 
months or 6 episodes in the past year) or infrequent (<6 episodes in the past 
year) [6]. 
 
Tyrosine kinases have been shown to play a key role in the initial stages of high-
affinity IgE receptor (FcRI) activation and subsequent downstream signaling 
events that lead to mediator release [7]. Animal model studies have 
demonstrated that other pathways which lead to mast cell activation may play a 
role in the pathogenesis of anaphylaxis. In mouse models of anaphylaxis, serum 
levels of sphingosine -1-phosphate, a key mediator of immune cell trafficking, 
was shown to increase mast cell responsiveness and susceptibility to 
degranulation [8]. Another mouse model demonstrated abnormal expression of 
the “regulator of G protein signaling 13” that resulted in increased mast cell 
degranulation and allergic responses [9]. More recently, it has been reported that 
platelet activating factor (PAF), a phospholipid secreted by masts cells, and PAF 
acetylhydrolase levels may correlate with severity of anaphylaxis [10]. Although, 
other pathways may be involved with mast cell degranulation, the cross-linking of 
the IgE receptor on the surface of mast cells [7] and basophils [11] remains the 
major activation pathway. 
 
In human mast cells, the influence of the D816V activating mutation in the 
tyrosine kinase KIT leads to mast cell proliferation and mastocytosis, which itself 
is associated with an increase in anaphylactic events. In a clinical study, we 
evaluated patients with idiopathic anaphylaxis to determine if some might have 
the D816V mutation. Some of these patients who had syncopal or near-syncopal 
episodes with 1 or more symptoms suggestive of mast cell degranulation also 
expressed an aberrant mast-cell population carrying the c-kit D816V mutation 
[12]. Thus, while these patients may have the characteristic aberrant morphology 
of mast cells associated with mastocytosis, they did not exhibit the skin lesions of 


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mastocytosis, had minimal pathologic changes in the bone marrow, and 
presented with recurrent anaphylactic episodes. It is therefore possible that some 
patients with idiopathic anaphylaxis may have a mutation in KIT, detectable only 
by sensitive diagnostic techniques, such as flow cytometry, or mutational 
analysis of the sorted mast cell populations obtained from bone marrow. These 
techniques are not generally available in local diagnostic laboratories. Although 
patients with the D816V mutation will not be excluded from the protocol, patients 
with mastocytosis diagnosed by the WHO criteria (see Appendix C) will not be 
enrolled in this protocol [13]. 
 
Management of anaphylaxis consists of administration of epinephrine, protection 
of airways, and support of circulation. The pattern of IA is unpredictable as well 
as the response to therapy and symptoms may cluster with periods of clinical 
remission. Attempts to control episodes of anaphylaxis with H1 and H2 
antihistamines along with systemic corticosteroids cannot be relied upon in all 
cases to mitigate anaphylactic episodes. Further, corticosteroids are associated 
with significant side effects which limit dosage and duration of therapy. High-dose 
prednisone therapy (60-100 mg/day) with daily cetirizine has been shown to 
control symptoms of anaphylaxis in patients with frequent episodes of idiopathic 
anaphylaxis. However, patients with frequent episodes of IA were less likely than 
those with infrequent episodes to respond to corticosteroid therapy and more 
often required long-term therapy [14]. After 2 to 3 months of therapy, up to 48% 
of patients from both groups were able to demonstrate remission (no episodes 
for 1 year and no prednisone) [15]. Although the empiric therapy with prednisone 
helps to reduce the severity and frequency of episodes, not all patients are able 
to discontinue prednisone [6]. This lack of targeted therapy for the treatment of 
anaphylaxis is, in part, a consequence of the relative absence of data on the 
inflammatory processes that result in systemic anaphylaxis. Thus, anaphylaxis, in 
general, has been attributed to activation of mast cells and basophils through 
antigen-induced aggregation of IgE engaged on the high-affinity receptor for IgE, 
FcRI, and subsequent release of potent inflammatory mediators such as 
histamine. However, blockade of such mediators does not prevent anaphylaxis 
and does not explain why one person allergic to an antigen has a mild reaction 
while another suffers a severe systemic reaction.  
 
Omalizumab is approved for the treatment of severe asthma, and acts through a 
mechanism that down regulates the IgE receptor on the surface of basophils, 
mast cells, and dendritic cells [16]. Recently, omalizumab has been reported to 
be useful as adjunct therapy in severe food allergy with systemic symptoms 
(n=84) [17], eosinophilic gastroenteritis (n=9) [18], rush immunotherapy (n=159) 
[19], chronic urticaria (n=20) [20], chronic autoimmune urticaria (n=12) [21], 
atopic eczema (n=11) [22], one adult with IA [23], one adult with eczema in the 
setting of Hyper-IgE syndrome [24], one child with cystic fibrosis and recurrent 
allergic bronchopulmonary aspergillosis [25], and one child with cold induced-
urticaria and anaphylaxis [26]. Similarly, we have reported that omalizumab 
prevented episodes of spontaneous anaphylaxis in 2 patients with mastocytosis 


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[27]. In the latter study, in 2 patients with unprovoked episodes of hypotension, 
omalizumab administration resulted in complete cessation of anaphylactic events 
that had previously required epinephrine and supportive therapy. In all of these 
studies there were no reported episodes of anaphylaxis as a result of 
omalizumab therapy. 
 
Omalizumab now has FDA-approval for the treatment of chronic idiopathic 
urticaria. Further analysis of adverse event data reported in the 2013 
Investigator’s brochure states “Xolair treatment was not associated with an 
increased malignancy risk based on incidence rates per 1000 patient years of 
4.14 (14/3382 patient years) for Xolair treated patients and 4.45 (11/2474 patient 
years) for placebo patients (rate ratio 0.93, 95% confidence interval 0.39-2.27). 
The overall observed incidence rate of malignancy in the Xolair clinical trial 
program was comparable to that reported in the general population”.  
A Recent trial in pediatric asthma have expanded the safety profile in children 
and was found to be efficacious in children that experienced Fall exacerbations 
of their allergic diseases [28].  
 
In this protocol, we will enroll patients with IA to assess the efficacy of 
omalizumab in reducing episodes of anaphylaxis as well as investigate the 
common and unique features of mast cells in the pathogenesis of anaphylaxis. 
We will initiate therapy with omalizumab or a matched placebo (every 2-4 weeks) 
in hospitalized subjects for the first 2 visits (2 consecutive doses at the NIH). 
Subjects will return to the NIH for subsequent dosing. If subjects experience an 
anaphylactic event, we will obtain blood for determination of serum tryptase and 
a tube for research studies at the NIH. The final evaluation will be conducted at 
the NIH. Research studies will include flow cytometric analysis of blood and bone 
marrow cells, investigation of mutations or polymorphisms in genes involved in 
mast cell development, determination of surrogate disease markers, examination 
of mast cell growth and function, and investigation of alternative pathways 
involved in regulation of anaphylaxis.  
 
2.1.1 Description of the Study Agents 
Omalizumab:  Omalizumab (anti-IgE, E25, Xolair®) is a humanized IgG1 
monoclonal antibody that binds to the epsilon constant region of IgE and thus 
prevents the binding of IgE to its high affinity receptor (FcRI) on mast cells and 
basophils. Therefore, omalizumab decreases the concentration of free IgE 
available for binding to mast cells and basophils. By blocking the binding of IgE 
to FcRI on effector cells of immediate hypersensitivity, omalizumab inhibits the 
release of inflammatory mediators [16], inhibits allergic inflammation, improves 
asthma symptoms, and decreases the need for corticosteroid use [29]. 
Furthermore, omalizumab treatment in allergic subjects decreases FcRI surface 
expression on basophils [30], dendritic cells [31], and presumably mast cells [32]; 
and as one consequence, basophils and mast cells may be less susceptible to 
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Matched-placebo:  Matched-placebo study agent will contain the diluents used to 
reconstitute the active drug and are as follows: sucrose, L-histidine hydrochloride 
monohydrate, L-histidine, and polysorbate 20. 
  
2.1.2 Summary of Relevant Clinical Studies 
Omalizumab significantly increased the tolerance of allergen exposure in oral 
food challenges [17], and significantly reduced the occurrence of hives in patients 
with chronic urticaria in a recently completed study [20]. In patients with allergic 
eosinophilic gastroenteritis, omalizumab reduced IgE expression on basophils, 
which decreased recruitment of inflammatory cells such as eosinophils in target 
tissues; patients reported a significant reduction in symptoms scores [18]. 
Omalizumab administration led to a significant reduction in unprovoked episodes 
of hypotension in 2 patients with systemic mastocytosis [27]. In these patients, 
symptoms were reduced from 4-6 episodes per year in the first patient and 14-16 
episodes per year in the second patient, to no episodes in either patient while on 
monthly injections of omalizumab without serious adverse reactions over 
intervals of 3.5 years and 2 years, respectively. 
 
2.2 Rationale 
Omalizumab was initially approved for use in severe allergic asthma, and more 
recently has been shown to have therapeutic use in other diseases. As 
mentioned, omalizumab has been shown to have some efficacy in tolerance to 
oral food challenges [17], the reduction of systemic symptoms including 
anaphylaxis when utilized in a rush immunotherapy protocol [19], and in a 
reduction in symptom score as well as a decrease in basophil histamine release 
in responders with chronic urticaria [20]. Further, there were no serious adverse 
events associated with administration of omalizumab in these trials. Anaphylactic 
reactions are life threatening and unpredictable. Symptoms may progress over 
minutes to hours, and initial signs and symptoms are not always recognized as 
anaphylaxis as they may be non-specific, such as conjunctival injection. The 
criteria for the diagnosis of anaphylaxis, as defined in Section 5.1.1, will be used 
to identify patients for enrollment in this study. An efficacious therapy for 
management of anaphylaxis would be life-changing for persons with uncontrolled 
disease. We have shown efficacy in a brief report involving 2 patients with 
mastocytosis with the D816V mutation and no adverse effects after 2 and 3.5 
years, respectively [27]. There are no other studies that have specifically 
addressed the use of omalizumab as a primary therapy for anaphylaxis.  
 
2.3 Potential Risks and Benefits 
2.3.1 Potential Risks of omalizumab 
The following are the potential risks and adverse reactions to omalizumab: 
2.3.1.1 Anaphylaxis 


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Anaphylaxis has been reported to occur, on rare occasion, after administration of 
omalizumab in premarketing clinical trials and in post marketing spontaneous 
reports. In premarketing clinical trials, the frequency of anaphylaxis attributed to 
omalizumab use was estimated to be 0.1%. In post marketing spontaneous 
reports, the frequency of anaphylaxis attributed to omalizumab use was 
estimated to be 0.2% of patients based on an estimated exposure of about 
57,300 patients from June 2003 through December 2006 (Xolair® package insert; 
Genentech, Inc 2007). Signs and symptoms in these reported cases have 
included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of 
the throat or tongue. Some of these events have been life-threatening. 
Anaphylaxis has occurred as early as the first dose of omalizumab, but also has 
occurred beyond 1 year after beginning regularly scheduled treatment. In 
accordance with the most recent data from the FDA, 68% of the anaphylactic 
reactions occurred in the first 3 doses (39% after 1st dose, 19% after 2nd dose, 
and 10% after 3rd dose; FDA MedWatch report, July 2007). Further, only 5% of 
suspected reactions to omalizumab occurred beyond 24 hours. To distinguish 
anaphylaxis that occurs as a result of the patient’s primary disease vs. possible 
omalizumab-induced episodes of anaphylaxis, the following criterion will be used: 
anaphylaxis that occurs more than 24 hours after dosing will not be considered to 
be drug-induced.  
 
In addition, in vitro studies such as the basophil histamine release studies with 
omalizumab and subject blood samples will be undertaken to evaluate the 
possibility of a direct cause and effect. 
2.3.1.2 Malignancy 
Malignant neoplasms were observed in 20 of 4127 (0.5%) omalizumab-treated 
subjects compared with 5 of 2236 (0.2%) control subjects in clinical studies of 
asthma and other allergic disorders. The observed malignancies in omalizumab-
treated subjects were a variety of types, with breast, non-melanoma skin, 
prostate, melanoma, and parotid malignancies occurring more than once, and 5 
other types occurring once each. The majority of subjects were treated for less 
than 1 year. The significance or generalizability of these findings are not known, 
but are currently the focus of Phase 4 studies. The impact of longer exposure to 
omalizumab or use in subjects at higher risk for malignancy (e.g., elderly, current 
smokers) is not known (Xolair® package insert; Genentech, Inc 2007). 
2.3.1.3 Carcinogenesis, Mutagenesis, Impairment of Fertility, 
Embryotoxicity, Teratogenicity 
No long-term studies have been performed in animals to evaluate the 
carcinogenic potential of omalizumab. No evidence of mutagenic activity was 
observed in Ames tests using 6 different strains of bacteria with and without 
metabolic activation at omalizumab concentrations up to 5000 g/mL. 
 
The effects of omalizumab on male and female fertility have been assessed in 
cynomolgus monkey studies. Administration of omalizumab at doses up to and 
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monkeys and did not inhibit reproductive capability, including implantation, in 
female cynomolgus monkeys. This same study design was used in pregnant 
cynomolgus monkeys to study the embryotoxicity and teratogenicity of 
omalizumab. No effects on the fetus were seen at any dose. No reproductive 
toxicity studies have been performed in humans. These doses studied in 
monkeys provide a 25- to 50-fold safety factor based on mg/kg dosing, a 2- to 
16-fold safety factor based on total dose, and 2- to 5-fold safety factor based on 
area under the curve (AUC) over the range of adult clinical doses (Xolair® 
package insert; Genentech, Inc 2007). 
 
Female subjects on study are required to use contraception up to 3 month after 
the last dose of study agent. Potentially fertile female subjects will have human 
choriogonadotropin (-HCG) serum or urine pregnancy tests done prior to every 
omalizumab injection. Omalizumab will only be administered after a member of 
the study team confirms a negative pregnancy test result. These procedures will 
assure that during the period of study agent dosing, all fertile female subjects will 
have a serum pregnancy test performed a minimum of once every 4 weeks. This 
frequency is commensurate with the potential risk of the drug as noted above. 
Omalizumab did not elicit reproductive toxicity or inhibit reproductive capabilities 
in male cynomolgus monkeys, therefore male subjects do not need to practice 
contraceptive restrictions but will need to report any pregnancy that occurs with a 
partner during the study.  
 
2.3.1.4  Other 
Since this drug has not yet been used to treat anaphylaxis, there is the possibility 
of unexpected side effects and unforeseen risks including worsening of 
symptoms. A 5-year safety study found a slightly higher rate of cardiac and 
cerebral blood vessel problems occurred in patients being treated with Xolair 
compared to those patients not treated with Xolair. These included problems 
such as  transient ischemic attacks or TIAs; heart attacks; sudden, unexpected 
chest pain;  pulmonary hypertension; and blood clots in the lungs and veins. 
Although the data are suggestive of a serious safety signal, due to weaknesses 
in how the safety study was designed and carried out, the exact increased level 
of these risks with Xolair cannot be determined. 
 
To further evaluate the cardiac and cerebral risks noted in the 5-year safety 
study, a review was conducted of a combined analysis of 25 randomized double-
blind clinical trials comparing Xolair to placebo. An increased risk of cardiac and 
cerebral-related problems in patients treated with Xolair was not noted in this 
combined analysis, but the low number of these events, the young patient 
population, and the short duration of follow-up prevented reviewers from making 
any definite conclusions about the absence of a risk.    
 
Since this trial is being conducted for 6 months, the risk for these side effects 
should be minimal.  Because of this possibility, we will collect safety data at all 


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scheduled visits at the Clinical Center and maintain communication with referring 
physicians to monitor such side effects while patients are enrolled on protocol. 
 
2.3.2 Potential Risks of other procedures 
2.3.2.1 Bone Marrow Biopsy 
Subjects will undergo a bone marrow biopsy and aspiration for analyses 
including for the D816V mutation in KIT as described in Section 7.1.2. This 
procedure is associated with pain and will result in a small bruise. Anesthesia-
conscious sedation will be offered if needed (see below).  Infection from the 
needle puncture is rare, but if this does occur, appropriate treatment will be 
given. Bleeding at the biopsy site for greater than 2 minutes will be treated with 
pressure at the site. Pain will be treated with therapy appropriate for severity. 
2.3.2.2 Venipuncture 
The potential risks of the needle stick for blood drawing include pain, fainting, 
infection, and bruising or small hematoma. The bruising may last up to 72 hours, 
and a hematoma is treated with local pressure. Infection from the needle 
puncture is rare, but if this does occur, appropriate treatment will be given. 
2.3.2.3 Skin Testing 
Skin testing with allergen extracts is a standard medical procedure that rarely 
leads to complications. The procedure may lead to mild itching and swelling of 
the skin. For epicutaneous skin testing, itching and swelling are self-limited and 
subside within 1-2 hours. The testing leaves no permanent mark on the skin. 
Skin testing may rarely lead to anaphylaxis. The rate of systemic reactions to 
skin testing has been reported to be 1 reaction per 3000 patients [33]. Although 
the risk of anaphylaxis from skin testing is extremely low, medications for 
treatment of anaphylaxis will be on hand and a physician will be available in the 
hospital when skin testing is performed. Subjects will stay in the clinic for 
30 minutes after the skin testing to monitor for anaphylaxis.  RAST testing may 
also be done as an alternative to skin testing. The risks associated with this 
procedure are the same for venipuncture, section 2.3.2.2. 
2.3.2.4 Anesthesia-Conscious Sedation 
In most cases, a bone marrow procedure is done under local anesthesia. 
Sedation may be required for the performance of the bone marrow biopsy in 
subjects with a history of prior difficultly with this procedure or extreme anxiety 
associated with invasive procedures such as syncope. In general, sedation is 
considered safe; however, there are a number of possible risks including nausea, 
vomiting, and changes in vital signs (heart rate, breathing rate, and blood 
pressure). Therefore, this procedure will be conducted in the intensive care unit 
and administered by specially trained physicians until recovery is complete. A 
separate consent specific for conscious sedation will be obtained prior to the use 
of sedation. 
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Pulmonary Function testing is a standard medical procedure that rarely leads to 
complications. 
2.3.3 Potential Benefits 
The subjects in the study will benefit from a thorough medical evaluation. 
Omalizumab has not been used in a controlled clinical trial in subjects with 
anaphylaxis. Subjects may or may not benefit from the experimental therapy. 
Subjects may experience a significant reduction in anaphylactic events during the 
period of omalizumab therapy. 
 
3.0 Study Objectives 
3.1 Primary Objective 
The primary objective of this study is to determine if treatment with omalizumab 
over 6 months will produce a reduction in the number and timing of anaphylactic 
events in subjects with a history of frequent idiopathic anaphylaxis. 
3.2 Secondary Objectives 
Secondary objectives of this study include the following: 
1. Assess the pharmacodynamics of subcutaneously administered 
omalizumab in subjects with anaphylaxis (free IgE, basophil activation 
studies). 
2. Examine the effects of omalizumab in the immunopathogenesis of 
anaphylaxis. 
3. Identify subjects with the D816V mutation.  
3.3 Exploratory Objectives 
Exploratory objectives of this study include the following: 
1. Investigate cellular and molecular mechanisms of mast cell signaling and 
the effect of omalizumab on mast cells and/or basophils.  
2. Explore other regulatory pathways that may be involved with suppression 
of mast cell degranulation. 
 
4.0 Study Design 
4.1 Description of the Study Design 
This is randomized, double-blind, placebo-controlled Phase 2, off-label* study 
(change in indication, dose and schedule) of commercially available omalizumab 
and matched placebo in 20 subjects with unprovoked anaphylaxis (10 in each 
group). Specifically, we intend to use the dosing calculation table in the package 
insert.  This dose has been used safely in other studies where omalizumab was 
used for off-labeled disease such as chronic urticaria [20, 21]. The first 2 doses 
will be given at the NIH as an inpatient, then continue on the same interval 
dosing (every 4 weeks  or bi-weekly, depending on the subject’s weight and IgE 
levels) thereafter for up to 6 months with drug being administered at the Clinical 


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Center’s Day Hospital. All subjects will then be followed for 6 months or if they 
have experienced anaphylactic events (post 24-hr window) determined to be 
unrelated to study agent, whichever comes first. These unrelated events would 
be determined by the PI not to jeopardize patient safety or restrict the use of 
additional therapy such as corticosteroids to control symptoms.  After this point, 
the patient may be discontinued from drug administration until unblinding. These 
discontinued subjects will complete the follow-up to allow ascertainment of the 
endpoint. Because of the waiting period for mutational analysis (~4 weeks), 
subjects will return to begin therapy after the diagnosis of mastocytosis 
(exclusion criteria) has been ruled out. 
 
*The labeled indication for omalizumab is the treatment of patients with moderate 
to severe persistent asthma who have a positive skin test or in vitro reactivity to a 
perennial aeroallergen and whose symptoms are inadequately controlled with 
inhaled corticosteroids. Omalizumab has been shown to decrease the incidence 
of asthma exacerbations in these patients. 
 
4.2 Study Endpoints 
4.2.1 Primary Endpoint 
The primary endpoint for this study is a reduction in the number and timing of 
anaphylactic events during the 6 month randomized phase. 
4.2.2 Secondary Endpoints 
The secondary endpoints for this study include the following: 
1. Quantify at least a 50% reduction of the IgE receptor on the surface of 
basophils after 6 months therapy using flow cytometry and correlate with 
surface expression of IgE on basophils. 
2. Document the changes in mast cell mediator-type symptoms associated 
with anaphylaxis (flushing, vomiting, diarrhea, syncope, pruritus) before 
and during the 6 months of therapy. 
3. Identify persons with the D816V mutation in c-kit or other abnormal 
markers in mast cells with data from flow cytometry and genetic analysis. 
4.2.3 Exploratory Endpoints 
The exploratory endpoint for this study is to determine if other pathways are 
involved in the induction of anaphylaxis in these subjects. Exploratory objectives 
of this study include the following: 
• Investigate cellular and molecular mechanisms of mast cell signaling and 
the effect of omalizumab on mast cells and/or basophils.  
• Explore other regulatory pathways that may be involved with suppression 
of mast cell degranulation. 
5.0 Study Population 
Volunteers to participate in this study must satisfy all of the following inclusion 
criteria, but have none of the exclusion criteria. 


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5.1 Participant Inclusion Criteria 
Volunteers must satisfy all of the following inclusion criteria to be eligible for this 
study. 
 
1. Subject must be at least 18 years of age and no older than 70 years of 
age. 
2. Diagnosis of idiopathic anaphylaxis, a diagnosis of exclusion, assigned 
after other causes of anaphylaxis and other diseases in the differential 
diagnoses have been considered [6].  
3. Anaphylaxis episodes (mild-severe) at least 6 times within the past 1 year 
period, documented according to medical records, physician report, or 
patient report, and 1 episode within the last 4 months, and with at least 1 
of the following: 
a. Elevated serum tryptase above baseline within 2 hours of the 
event. 
b. Emergency room visit with documented anaphylaxis without an 
etiology established by the acute onset of an illness (minutes to 
several hours) with involvement of the skin, mucosal tissue, or both 
(e.g., generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) [Grade 1]* and at least 1 of the following:  
i. Respiratory compromise or gastrointestinal involvement 
(e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia, nausea, vomiting, or 
abdominal pain [Grade 2]*). 
ii. Reduced blood pressure or associated symptoms of end-
organ dysfunction (e.g., hypotonia [collapse], syncope, or 
incontinence [Grade 3]*).  
c. Hospitalization for anaphylaxis: hospital records with documented 
anaphylaxis without known cause established by the acute onset of 
an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, 
swollen lips-tongue-uvula) [Grade 1]*) and at least one of the 
following:  
i. Respiratory compromise or gastrointestinal involvement 
(e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia, nausea, vomiting, or 
abdominal pain [Grade 2]*). 
ii. Reduced blood pressure or associated symptoms of end-
organ dysfunction (e.g., hypotonia [collapse], syncope, or 
incontinence [Grade 3]*).  
4. Letter of referral, with copies of pertinent medical history and laboratory 
tests, from prospective study participant’s local physician. 
5. Ability to give informed consent. 
6.  Women of childbearing potential must have a negative -HCG serum or 
urine pregnancy test prior to each injection, and must agree to practice 
abstinence or effective contraception from initiation of the protocol and for 


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3 months following the last infusion of the study agent (effective 
contraception methods include abstinence, surgical sterilization of either 
partner, barrier methods such as diaphragm, condom, cap, or sponge, or 
hormonal contraception). 
 
*Severity grading of anaphylaxis [34] 
 
5.2 Participant Exclusion Criteria 
A volunteer who satisfies any of the following exclusion criteria will be ineligible to 
participate in this study. 
 
1. Presence of conditions which, in the judgment of the investigator or the 
referring physician, may put the subject at undue risk for study 
participation or travel (such as an acute infection, severe 
thrombocytopenia, coronary artery disease, uncontrolled hypertension, 
congestive heart failure, chronic beta blocker therapy such as atenolol or 
metoprolol, or myeloproliferative disease). 
2. History of malignancy 
3. Known cause for anaphylaxis or flushing 
4. Diagnosis of mastocytosis 
5. Inability to provide informed consent 
6. Inability or refusal to undergo a bone marrow biopsy and aspirate 
7. HIV positive or other known immunodeficiency 
8. Active or chronic hepatitis 
9. Use of any other investigational agent within 30 days of the study 
10. Current use of chronic oral corticosteroids or other immunosuppressant 
medications  
11. Pregnant or nursing women 
12. Positive pregnancy test 
13. IgE levels and subject’s weight that cause dosing to be above dosing 
guidelines.  
 
5.3 Participation of Children 
Children under the age of 18 of age will not be included in the study due to the 
new data from the FDA (boxed warning) regarding the new risks of omalizumab 
and anaphylaxis. If this drug is proven safe and efficacious in the adult 
population, we will consider the addition of children with a protocol amendment. 
 
6.0 Study Agent 
6.1 Study Agent Acquisition 
The study agent (omalizumab) and placebo-matched control will be obtained 
from Genentech-Novartis under the OCRPRO Sponsored Trial.  


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6.2 Study Agent Storage and Stability 
Study agent will be stored by the NIH Pharmacy per package insert. The study 
agent will be prepared in the NIH pharmacy the day of the injection since the 
drug has to be used within 4 hours of preparation. Unused materials will be 
returned to Genentech at the end of the study dosing period. 
 
6.3 
Preparation, Administration, and Dosage of Study Agent 
6.3.1 Study Agent 
6.3.1.1 Description 
Omalizumab (rhuMAb-E25) is a recombinant DNA-derived, humanized IgG1 
monoclonal antibody that selectively binds to human immunoglobulin E (anti-IgE) 
(Xolair® package insert; Genentech, Inc 2007. The placebo-matched control will 
be supplied by Genentech, Inc. and will be an inert product formulated to 
duplicate the visual appearance as well as physical properties of the drug.  
6.3.1.2 Dosing and Administration 
The current package insert for using omalizumab is based upon clinical data 
targeting a reduction in serum IgE to ≤10 IU/mL, and utilizes specifically a dose 
of 0.008-0.025 mg/kg/IU/mL (IgE) every 2-4 weeks in asthma patients. To 
simplify dosing calculations for practitioners, the package insert contains a 
dosing nomogram, based on the subject’s serum IgE and weight, which provides 
drug dosing in this range (Appendix D, Tables 1 and   2). Upper limit of dosing is 
375 mg administered subcutaneously. Current understanding of omalizumab 
pharmacodynamics in asthma and allergic rhinitis suggests that the package 
insert dose is sufficient to decrease the serum free IgE level by 10- to 30-fold and 
results in a free serum IgE level of 10 IU/mL. Omalizumab has not been used 
extensively in anaphylaxis and the pharmacokinetics of the drug in anaphylaxis 
has not been investigated.  
 
The omalizumab package label limits the maximum dose. Due to this restriction 
and the requirement for dosing in proportion to the serum IgE, the US package 
labeling limits omalizumab administration to subjects with high IgE values. For 
example, the omalizumab package label notes that for a patient weighing more 
than 70 kg, omalizumab should not be used when serum IgE is greater than 
400 IU/mL. Anaphylaxis occurs over a wide distribution of serum IgE values, with 
some individuals having IgE levels greater than would permit dosing in the 
current omalizumab dosing scheme in U.S. Thus, the enrollment of anaphylaxis 
subjects with serum IgE and body mass values that are within the ranges 
provided by the US package insert will be dosed according to the package insert 
as shown in Tables 1 and 2. Those subjects whose serum IgE and body mass 
values are outside of the range of current US package insert will be dosed 
according to the European dosing guideline (Table 3). Finally, subjects with 
serum IgE values of <30 IU/mL will receive 150 mg of omalizumab every 4 
weeks. 


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Subsequent dosing (every 2 or 4 weeks) will be administered at the NIH. 
Patients’ whose dosing guideline cannot be determined from the values provided 
below in US Standard dosing shown in Table 1 or 2, will be dosed according to 
the guidelines provided in European dosing in Table 3. 
 
Skin testing to determine allergic sensitivity to omalizumab will not done prior to 
dosing at this time since a specific antigen has not been identified and in 
accordance with the Joint Task Force of the Academy of Allergy, Asthma, & 
Immunology and Asthma and Immunology on omalizumab-associated 
anaphylaxis, it is not currently recommended prior to dosing [35] 
 
 
 
 
6.3.1.3 Omalizumab Dosing Calculation: 
Tables 1 and 2 provide omalizumab dosing calculation information obtained from 
the US package insert. Omalizumab will be dosed at either 4 week intervals, as 
described in Table 1, or at 2 week intervals, as described in Table 2. Doses for 


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individuals whose IgE levels fall outside of the ranges provided in Table 1 or 2 
will be dosed according to European guidelines provided in Table 3. 
 
 
 
 
 


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6.3.1.4 Route of Administration  
The drug or placebo-matched product will be injected subcutaneously every 2-4 
weeks x 2 total doses at NIH (first two doses as an inpatient and subsequent 
doses in the day hospital), then every 2-4 weeks thereafter (up to 12 months) 
based on initial dosing schedule. The placebo dose will be based on the same 
criteria as the active drug in order to have a uniform volume of the injection 
material. 
 
6.3.1.5 Dose Adjustments/Modifications/Delays 
The dose may be withheld in the event of serious related or unrelated illness or 
adverse event (e.g., drug related or cardiac arrest). There will be no other 
dosage modifications. 
 
6.3.1.6 Duration of Therapy 
Subjects may remain on the assigned regimen (post 24-hour drug administration 
period) if they have experienced anaphylactic events determined to be unrelated 
to study agent or have been followed for 6 months, whichever comes first. These 
unrelated events would be determined by the PI not to jeopardize patient safety 
or restrict the use of additional therapy such as corticosteroids to control 
symptoms.  After this point, the patient may be discontinued from drug 
administration until unblinding. This design ensures that no patient will have 
repeated anaphylactic episodes while on placebo if other therapy is medically 


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indicated. If significant efficacy is demonstrated, we will initiate communication 
with the subject’s insurance company for financial support to continue therapy.  
6.3.1.7 Tracking of Dose 
Dose will be documented on the medication form or in CRIS. 
6.3.1.8 Use of Ancillary Medications/OTC Products/Foods  
There are no known contraindications with medications or food and omalizumab. 
6.3.1.9 Participant Access to Study Agent at Study Closure  
We will communicate our findings to the patient’s primary physician and 
insurance company if significant efficacy is demonstrated for continued support 
for maintenance, off-label therapy. 
 
6.4 
Assessment of Participant Compliance with Study Agent 
See Appendix F, which will be completed by the study team. 
 
6.5 
Prohibited and Precautionary Medications and Procedures  
No formal drug interaction studies have been preformed with omalizumab. The 
concomitant use of omalizumab and allergen immunotherapy has been 
evaluated in patients receiving rush immunotherapy [19]. Subjects will not be 
allowed to initiate chronic systemic corticosteroid therapy for anaphylaxis while 
on the study. If chronic systemic corticosteroids are needed the subject will be 
removed from the study. Short term corticosteroid use for emergent therapy is 
permitted as well as inhaled corticosteroids for respiratory illnesses such as 
asthma. 
 
6.6 
Rescue Medications 
Use of epinephrine and other drugs for treatment of anaphylaxis are allowed as 
needed for anaphylaxis events. 
7.0 Study Procedures/Evaluations 
7.1 
Clinical Evaluations (Appendix B) for 2 week (+/- 3 days) and 4 week 
(+/- 3 days) dosing 
7.1.1 Screening Visit – (Inpatient or Outpatient) 
If a patient is deemed eligible based on supporting documents, no screening visit 
is necessary. We will not repeat laboratory tests that have been obtained prior to 
the first patient visit, if completed within 3 months of the study, with the exception 
of a pregnancy test for women of childbearing potential, if not done within the 
past 30 days. Determination of eligibility based on prior bone marrow biopsy 
studies will be at the discretion of the study PI. 
 
1. Medical History and physical examination.  


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2. Blood tests in each subject will consist of a complete blood count with 
differential, acute care panel, hepatic panel, mineral panel, prothrombin 
time (PT) as medically indicated, partial thromboplastin time (PTT) as 
medically indicated, total serum IgE, serum tryptase level, hepatitis 
profiles, HIV test, anti-HTLV I/II, and for women of childbearing potential, a 
-HCG serum or urine pregnancy test. Additional tests will be ordered as 
clinically indicated for each subject's condition. Tests may include 
urinalysis, urine for 5-hydroxyindoleacetic acid (5-HIAA), 
radioallergosorbent (RAST) testing for specific allergens and/or skin 
testing. Additional blood will be collected for research studies as needed 
(section 4.2.2). The total volume of blood drawn for all testing and during 
all visits will not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over 
any 8-week period for adult patients (i.e. those persons 18 years of age or 
older). This information may be obtained from a prior procedure at the 
Clinical Center; however these tests will be carried out if not obtained in 
the last 3 months prior to enrollment. 
3. Bone marrow biopsy and aspirate analysis will include routine diagnostic 
processing and staining of the biopsy and aspirate, tryptase staining of 
biopsy for mast cells, flow cytometric analysis of the aspirate for abnormal 
mast cell markers CD2, CD25 or basophil activation studies for 
degranulation studies, and c-kit mutational analysis (if not done prior to 
enrollment). It is anticipated that most subjects will complete this 
evaluation as in-patients. Bone marrow biopsy and aspirate will be 
performed on the 3SW-N procedure unit (sedation will be available on an 
as-needed basis) by an Associate Investigator (PI) or hematology consult 
service.  
a. Genetic testing  
Mutations in c-kit may be most reliably identified in the mononuclear 
fraction of a bone marrow aspirate. We also will investigate the 
presence of polymorphisms or mutations in other genes that regulate 
mast cell activation. 
This process entails counseling by study investigators as to the 
significance of positive vs. negative findings. Unanticipated genetic 
information such as paternity or differences unrelated to a disease 
process, will not be divulged to the participants in this study and all 
medical information will remain highly confidential as part of the 
research records. Information regarding genetic polymorphisms and 
gene mutations on tested blood specimens will only be given to 
participants on request. This information will not be shared with any 
employer or insurance company unless requested by the subject. 
Such information will only be released when the participant’s DNA 
base change in KIT or other polymorphisms associated with mast cell 
growth and differentiation has been confirmed by the appropriate 
genetic sequencing tests performed in our laboratory. Only the 
individuals performing the genetic testing on the blood samples will 
have access to the blood samples of the respective participants. All 


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information pertaining to the study of genes will be maintained in 
locked study files. 
4. Skin testing will be performed as medically indicated in subjects where a 
new causative mechanism for anaphylaxis needs to be ruled out prior to 
enrollment in the treatment protocol.  
5. Pulmonary function tests (PFTs) will be performed prior to skin testing, if 
medically indicated. The subject is instructed to blow hard for ~ 6 seconds 
into a tube connected to a spirometer to measure the forced expiratory 
volume during 1 second (FEV1). An FEV1 value of >70% of predicted is 
required to undergo skin testing. 
6. Consultations will be requested as medically indicated.  
7. Upon completion of testing, the subject will receive the first dose of 
omalizumab or matched placebo according to directions on the package 
insert. All subjects will be observed for approximately 24 hours as in-
patients. 
 
7.1.2 First Visit- Inpatient 
1. Medical history and Physical examination.  
2. Blood tests in each subject will consist of a total serum IgE (as needed), 
serum tryptase level (as needed), research blood (as needed), and for 
women with child-bearing potential, a -HCG serum (as indicated) or urine 
pregnancy test (as indicated). Additional tests will be ordered as clinically 
indicated by each subject's condition.  
3. Consultations will be requested as medically indicated.  
4. The subject will receive the first dose of omalizumab or matched placebo. 
All subjects will be observed for approximately 24 hours as in-patients.  
5. There will be standard nursing orders to include: Epi-Pen at bedside, vital 
signs should be monitored once per shift, or as needed based on the 
patient’s condition, and other standard orders as appropriate. 
7.1.3 Second Visit – Inpatient 
1. Medical history and Physical examination.  
2. Blood tests in each subject will consist of a serum tryptase level, research 
blood (as needed), and for women with child-bearing potential, a -HCG 
serum or urine pregnancy test. Additional tests will be ordered as clinically 
indicated by each subject's condition.  
3. Consultations will be requested as medically indicated.  
4. The subject will receive the second dose of omalizumab or matched 
placebo. All subjects will be observed for approximately 24 hours as in-
patients. (Women will receive the second dose upon receiving the results of 
pregnancy testing.)  
7.1.4 Follow-up Visits – Outpatient (Visits 3, 4 and 5, see appendix for q 2 
week dosing) 
1. Interval history and physical examination. 


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2. Upon completion of serum or urine pregnancy testing for women of 
childbearing potential, the subject will receive the next scheduled dose of 
omalizumab or matched placebo, and will be observed in the Clinical 
Center for a period of approximately 2 hours 
3. Research blood (at 16 weeks (visit 5 for Q4 week dosing or visit 9 for Q2 
week dosing)). 
7.1.5 NIH Final Treatment Visit (Visit 6) 
1. Focused History and physical examination.  
2. Blood tests in each subject: complete blood count with differential, acute 
care panel, hepatic panel, , serum tryptase levels, hepatitis profiles, anti-
HTLV I/II, and for women of childbearing potential, a -HCG serum or 
urine pregnancy test. Additional tests will be ordered as clinically indicated 
for each subject's condition. Additional blood may be collected for 
research studies. 
3. The subject will receive the next scheduled dose of omalizumab or 
matched placebo, and will be observed in the Clinical Center for a period 
of approximately 2 hours 
7.1.6 Off Treatment  Follow-up (Visit 7) 
After completion of study agent administration, patients will be monitored by their 
referring physicians who will continue to document any anaphylactic events.  All 
patients will be scheduled to return to the NIH 6 months (+/- 30 days) after 
receiving the final dose of study agent or early withdrawal from the protocol due 
to adverse events or medical conditions determined to be a safety issue by the 
research team.   The following indications may dictate a follow-up visit to the NIH: 
1) an adverse event (Grade 3) possibly attributed to study agent, 2) Change in 
clinical status that may be associated with study agent such as non-anaphylactic 
adverse events. If necessary, the subject will return to the NIH within 1 month for 
a  follow-up visit which may include:  
1. History and physical examination.  
2. Blood tests in each subject: complete blood count with differential, acute 
care panel, hepatic panel (as indicated), IgE, serum tryptase levels, 
hepatitis profiles (as indicated), anti-HTLV I/II (as indicated), and for women 
of childbearing potential, a serum or urine -HCG test for pregnancy. 
Additional tests will be ordered as clinically indicated for each subject's 
condition. Additional blood may be collected for research studies. 
3. Possible bone marrow procedure for correlation of downregulation of the 
IgE receptor on the surface of basophils to bone marrow mononuclear cells 
or mast cells.  
 
7.2 
Biohazard Containment 
Because HIV and other blood-borne pathogens can be transmitted through 
contact with contaminated needles, blood, and blood products; appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of 


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blood, and in the shipping and handling of all specimens for this study, as 
currently recommended by the Centers for Disease Control and Prevention and 
the National Institutes of Health. 
 
8.0 Stored Samples 
8.1 
Use of Stored Samples 
During this study, extra blood and bone marrow aspirate samples will be 
collected and stored for future research. Samples may be used and tested at a 
later time but the results of the investigational tests will not be available in the 
medical records. If the subject is interested in learning about them, someone 
from the study team will discuss the results with the subject. The subject may 
also request that those results be shared with the subject’s private doctor. 
 
For a select group of enrolled patients, blood samples that are labeled according 
to a code with no personally identifiable information will be sent to outside 
collaborators, Lawrence B. Schwartz, M.D., Ph.D. and Thomas A.E. Platts 
Mills, M.D. for measurement of serum fractionated tryptase levels and galactose-
a-1,3-galactose (alpha-gal) assays. 
 
To protect each subject’s privacy, all of the subject’s samples will be labeled with 
a code that only the study team can link to that subject. Any identifying 
information about the subject will be kept confidential to the extent permitted by 
law. In the future, other investigators (both at NIH and outside) may wish to study 
these samples. When the study team shares the samples, they will all be labeled 
with a code. Some general information about the subject such as the subject’s 
gender, age, health history, or ethnicity may also be shared with other 
investigators. The study team will not sell any samples and the samples will be 
used only for research purposes. If the future studies require additional 
information, the study team will contact the subject for separate consent. 
 
In the future, other investigators (both at NIH and outside) may wish to study 
these samples and/or data. In that case, IRB approval must be sought prior to 
any sharing of samples. Any clinical information shared about the sample would 
similarly require prior IRB approval. 
 
8.2 
Disposition of Stored Samples 
1. Access to stored samples will be limited using [either a locked room or a 
locked freezer]. Samples and data will be stored using codes assigned by 
the investigators. Data will be kept in password-protected computers. Only 
investigators will have access to the samples and data.  
2. Samples acquired will be tracked (Biological Specimen Inventory System 
BSI ).  


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3. Any loss or unanticipated destruction of samples of >25% (for example, 
due to freezer malfunction) or that compromises the scientific integrity of 
the data collected for the study will be reported to the NIAID IRB. 
9.0 Assessment of Safety 
9.1 
Adverse Event Recording/Documentation 
At each contact with the subject, information regarding adverse events will be 
elicited by appropriate questioning and examinations and will be immediately 
recorded on a source document. Source documents will include: progress notes, 
laboratory reports, consult notes, phone call summaries, survey tools, and data 
collection tools. Source documents will be reviewed in a timely manner by the 
research team. All grades of adverse events that are possibly, probably, or 
definitely related to study agent will be recorded on an appropriate case report 
form (CRF). All AEs will be recorded on a CRF regardless of attribution. The start 
date, the stop date, the severity of each reportable event, and the PI’s judgment 
of the AEs relationship to the study agent/intervention will also be recorded on 
the CRF. For the purposes of this study CRIMSON will serve as both source and 
CRF. 
 
9.1.1   Definitions 
Adverse Event (AE) 
An adverse event is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the research. 
 
Adverse Reaction (AR) 
An adverse event that is caused by an investigational agent (drug or biologic). 
 
Suspected Adverse Reaction (SAR) 
An adverse event for which there is a reasonable possibility that the 
investigational agent caused the adverse event. ‘Reasonable possibility’ means 
that there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction which implies a high degree of certainty. 
 
Serious Adverse Event (SAE) 
A Serious Adverse Event is an AE that results in one or more of the following 
outcomes: 
• death 
• a life threatening (i.e., an immediate threat to life) event 
• an inpatient hospitalization or prolongation of an existing hospitalization 
• a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• a congenital anomaly/birth defect 


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• a medically important event* 
 
* Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life threatening or result in death or 
hospitalization but they may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed above.  
 
Unexpected Adverse Event 
An AE is unexpected if it is not listed in the Investigator’s Brochure or Package 
Insert (for marketed products) or is not listed at the specificity or severity that has 
been observed.  It is the responsibility of the IND Sponsor to make this 
determination. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A SUSAR is a Suspected Adverse Reaction that is both Serious and 
Unexpected.   
 
Unanticipated Problem (UP) 
An Unanticipated Problem is any event, incident, experience, or outcome that is 
 
1.  unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research 
protocol and informed consent document; Investigator’s Brochure or other 
study documents; and 
b. the characteristics of the subject population being studied; and 
2. possibly, probably, or definitely related to participation in the research; and 
3. places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. (Per the IND Sponsor, an AE with a serious outcome will be 
considered increased risk.) 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE) 
Unanticipated problem that is not an Adverse Event (UPnonAE): An 
unanticipated problem that does not fit the definition of an adverse event, but 
which may, in the opinion of the investigator, involve risk to the subject, affect 
others in the research study, or significantly impact the integrity of research data.  
Such events would be considered a non-serious UP. For example, we will report 
occurrences of breaches of confidentiality, accidental destruction of study 
records, or unaccounted-for study drug 
 
Protocol Deviation: Any change, divergence, or departure from the IRB 
approved study procedures in a research protocol. Protocol deviations are 
designated as serious or non-serious and further characterized as 
 


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1. Those that occur because a member of the research team deviates from 
the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
 
Serious Protocol Deviation: A deviation that meets the definition of a Serious 
Adverse Event or compromises the safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB 
requirements, or regulatory requirements for the protection of human subjects. 
Non-compliance is further characterized as 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 
9.2 
Assessing Adverse Events 
9.2.1 Adverse Event Grading (Severity) Scale 
The NCI Cancer Therapy Evaluation Program Common Terminology Criteria for 
Adverse Events version 3.0 (CTCAE) will be used to grade adverse events which 
can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3
.pdf (see Appendix A)  
 
All other laboratory and clinical AEs that occur in a subject will be assessed for 
severity and classified into 1of the categories below. 
• Grade 1 (Mild): The event requires minimal or no treatment and does not 
interfere with the subject’s daily activities. 
• Grade 2 (Moderate): The event results in a low level of inconvenience or 
concern with the therapeutic measures. Moderate events may cause 
some interference with functioning. 
• Grade 3 (Severe): The event interrupts a subject’s usual daily activity and 
may require systemic drug therapy or other treatment. Severe events are 
usually incapacitating. 
• Grade 4 (Life Threatening): Any adverse drug experience that places the 
subject or participant, in the view of the investigator, at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction 
that had it occurred in a more severe form, might have caused death. 
• Grade 5 (Death) 
 
9.2.2 Adverse Event Relationship to Study Procedures 


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For all collected AEs, the clinician who examines and evaluates the subject will 
determine the adverse event’s causality based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below. 
• Definitely Related: There is clear evidence to suggest a causal 
relationship, and other possible contributing factors can be ruled out. The 
clinical event, including an abnormal laboratory test result, occurs in a 
plausible time relationship to drug administration and cannot be explained 
by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The 
event must be pharmacologically or phenomenologically definitive, with 
use of a satisfactory rechallenge procedure if necessary.  
• Probably Related: There is evidence to suggest a causal relationship, 
and the influence of other factors is unlikely. The clinical event, including 
an abnormal laboratory test result, occurs within a reasonable time 
sequence to administration of the drug, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition.  
• Possibly Related: There is some evidence to suggest a causal 
relationship (e.g., the event occurred within a reasonable time after 
administration of the trial medication). However, the influence of other 
factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an adverse drug event may 
rate only as “possibly related” soon after discovery, it can be flagged as 
requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• Unlikely: A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the trial medication) and in which other drugs 
or chemicals or underlying disease provides plausible explanations (e.g., 
the subject’s clinical condition, other concomitant treatments).  
• Unrelated: The AE is completely independent of study agent 
administration, and/or evidence exists that the event is definitely related to 
another cause. There must be an alternative, definitive cause documented 
by the clinician.  
9.3 
Adverse Event Reporting Procedures 
9.3.1 Expedited Reporting to the NIAID IRB 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, 
and serious or continuing non-compliance will be reported within 7 calendar days 
of investigator awareness. Serious Adverse Events that are possibly, probably, or 
definitely related to the research will be reported to the NIAID IRB within 7 
calendar days of investigator’s awareness, regardless of expectedness. 
 


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9.3.2 Annual Reporting to the NIAID IRB 
The following items will be reported to the NIAID IRB in summary at the time of 
Continuing Review: 
 
- 
Serious and non-serious unanticipated problems  
- 
Expected serious adverse events that are possibly, probably, or 
definitely related to the research 
- 
Serious adverse events that are not related to the research 
- 
All adverse events, except expected AEs and deaths granted a 
waiver of reporting.  
- 
Serious and Non-Serious Protocol deviations  
- 
Serious, continuing, and minor non-compliance 
- 
Any trends or events which in the opinion of the investigator should 
be reported 
Any protocol-specific reporting requirements as per sponsor and 
pharmaceutical support/provider. 
9.3.3 Reporting Adverse Events to Genentech 
Adverse events (SAE/AEs) that are possibly, probably, or definitely related to 
study agent will be reported to Genentech using the same time intervals for 
reporting to the IRB outlined above in section 9.5.1.1.  
 
9.3.4 Reporting Responsibilities to the Sponsor 
9.3.4.1 Adverse Events 
Line listings, frequency tables, and other summary AE data will be submitted to 
the IND Sponsor when needed for periodic safety reviews, review of IND annual 
reports, review of IND safety reports, and preparation of final study reports. 
 
9.3.4.2 Serious Adverse Events 
SAEs (whether or not they are also UPs) must be reported on the SAE/UP Report 
Form and sent to the Sponsor Clinical Safety Office (CSO) by fax or e-mail 
attachment. Deaths and immediately life threatening SAEs must be reported 
within 1 business day after the site becomes aware of the event. All other SAEs 
must be reported within 3 business days of site awareness.  
 


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SPONSOR CLINICAL SAFETY OFFICE CONTACT INFORMATION:  
 
Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
 
Phone 301-846-5301 
Fax 301-846-6224 
                                 E-mail: rchspsafety@mail.nih.gov 
 
9.3.4.3 Unanticipated Problems 
Non-Serious AEs that are UPs must also be reported on the SAE/UP Report 
Form and sent to the CSO by fax or e-mail attachment no later than 7 calendar 
days of site awareness of the event. The UPs that are not AEs are not reported 
to the Sponsor CSO. 
 
9.4 
Sponsor’s Reporting Responsibilities 
Serious and unexpected suspected adverse reactions (SUSARs) as defined in 
21 CFR 312.32 and determined by the IND Sponsor will be reported to FDA and 
all participating Investigators as IND Safety Reports.  
 
The IND Sponsor will also submit an IND Annual Report of the progress of the 
investigation to the FDA as defined in 21 CFR 312.33. 
 
9.5 
Type and Duration of the Follow-up of Participants after Adverse 
Events 
AEs may be observed by the Investigator and/or study staff, elicited from the 
subject and/or family member, reported on subject diary cards, or volunteered by 
the study subject. Adverse events that had previously been reported by the study 
subject will also be reassessed for duration, intensity, and possible reoccurrence. 
Assessment of safety will include clinical observation and monitoring of 
hematological, chemical, and immunologic parameters. 
 
Any AE that occurs between the times a study participant signs the informed 
consent form and the time s/he departs the study at the end of the final follow-up 
visit (or at the time of early discontinuation of the subject from the study for any 
reason) will be captured and recorded. 
 
Primary care of the subject’s initial medical condition will continue to be under the 
auspices of his or her local medical provider. A letter describing the study will be 
sent to the subject’s primary care physician. The local medical provider will be 
instructed verbally and with written guidelines to contact the NIH investigators 
immediately for any adverse event. A toll-free number will be available to provide 
24-hour access to the Principal Investigator or designee. The subject’s primary 


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care provider(s) will be encouraged to call the PI should any change in condition 
be noted as compared to the subject’s baseline status. Should the occasion 
arise, subjects may also be treated at the NIH Clinical Center. 
 
9.5.1.1 Reporting of Pregnancy 
The investigators will report within 15 days of the site’s awareness this reportable 
event to the IRB & Genentech. All pregnancies will be followed until outcome, if 
subject is willing, and any congenital abnormality will be reported to the Sponsor 
and IRB. 
 
9.5.1.2 Follow-up of Participants after Adverse Events 
All SAEs and non-serious AEs reported in this study will be followed until 
resolution or until the investigator and the clinical/medical monitor are in 
agreement that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after 
the patient discontinues participation in the study. Subjects with SAEs that are 
possibly, probably, or definitely related to drug may be asked to return for a visit 
in 30  10 days. These events will be reported to the FDA annually.  
 
9.6 
Halting Rules for the Protocol 
The protocol will be suspended for new enrollment if two grade 3 severe adverse 
events documented to be associated with the administration of study agent within 
24 hours of the study agent that requires an emergency room visit or 
hospitalization for anaphylaxis in 2 or more subjects. An urgent review will be 
requested of the DSMB to determine if the safety of the remaining participants is 
compromised and if the study should continue. Grade 2 or below serious possibly 
or probably-related adverse events will not stop the protocol. Medical events 
determined to be unrelated to study agent administration will not be a reason to 
halt the protocol; however, a report will be sent to the DSMB and the FDA for 
documentation of such events. 
 
9.6.1 Unblinding of the Study 
9.6.1.1 Scheduled Unblinding 
The study will be unblinded after all 20 volunteers have been enrolled and 
completed the Day 180 study visit. Enrolled subjects that do not complete 180 
days due to anaphylactic events deemed associated with study agent or those 
with more than 2 events will be followed until the end of their projected study 
period. At that time, efficacy data from Study Days -180 and Day 180 will be 
reviewed, along with the safety data collected through Study Day 180. 
9.6.1.2 Intentional, Unscheduled Unblinding for Treatment Conditions 
Prior to breaking the treatment blind, consultation with the PI or the Medically 
Accountable Investigator will be done. The research pharmacist will keep the 


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treatment code list locked in a secure area and can be reached 24 hours a day to 
rapidly access subject unblinding codes if necessary. If a subject’s drug 
assignment is unblinded, the information will be provided to only the individuals 
needing it for treatment decisions, with documentation of the event and the 
reason for unblinding recorded in the subject’s research record. The PI should 
immediately report all cases involving emergency unblinding to the Sponsor.  
 
The PI must report all case of unblinding, intentional or unintentional, to the IRB, 
DSMB, Genentech, and the FDA in writing within 2 business days after the 
unblinding. 
 
If a serious adverse event (SAE) has resulted in unblinding, this information will 
be included in the SAE Report Form. Incidences of unblinding in and of 
themselves will be reported to the OCRPRO Clinical Safety Office. 
 
A detailed report of the event that resulted in the unblinding will be sent to the, 
NIAID Intramural DSMB, FDA, Genentech, and the NIAID IRB. 
 
Every 6 months, the DSMB will review the data from this trial. The Board may 
view unblinded anaphylaxis event data (i.e., broken down by treatment group) to 
assess safety of the study agent. If there is some signal that the active arm is 
associated with a greater rate of anaphylaxis than the control arm, 
recommendations regarding termination might be considered; no formal 
statistical boundaries for harm are specified. Since this is a double-blind, 
placebo-controlled drug treatment trial, we will continue to elicit the advice of the 
DSMB for safety and ethical issues. The DSMB will monitor this protocol on a 
regular schedule and it is within their jurisdiction to evaluate efficacy during these 
reviews, if appropriate. Furthermore, due to the size of this study (n=20) and 
time-line for dosing (6 months), the evaluation of efficacy is not statistically 
powered for interim data. 
 
9.6.2 Stopping Rules for an Individual Participant/Cohort 
At any time during the study, subjects may choose to withdraw from the study.  
 
Study agent may be discontinued with a new onset adverse event of Grade 3 or 
greater (see Appendix A) on one occasion within 24 hours of study medication 
that occurs in a particular subject and determined by PI to be related to the study 
agent. 
 
An event will be established by the acute onset of an illness (minutes to several 
hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized 
hives, pruritus or flushing, swollen lips-tongue-uvula) [Grade 1] and at least one 
of the following: 1) Respiratory compromise or gastrointestinal involvement (e.g., 
dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia, nausea, vomiting, or abdominal pain [Grade 2]) or 2) Reduced blood 
pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia 


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[collapse], syncope, or incontinence [Grade 3]). If these criteria are not met, the 
episode will not count as an event.  
 
Study agent will also be discontinued if an adverse event occurs that in the 
opinion of the investigator may compromise the patients’ well being. 
 
If the patient is unable or unwilling to keep scheduled appointments for receiving 
their injections of study agent or follow-up safety visits, subjects  will be 
discontinued from the study. 
 
Study agent will be discontinued and the patient withdrawn from the study if 
he/she develop a malignancy while on study medication. 
 
During the primary evaluation phase, subjects will continue with the randomized 
assignment for 6 months, or if they have experienced anaphylactic events 
determined to be unrelated to study agent or have been followed for 6 months, 
whichever comes first. Since the primary disease is idiopathic anaphylaxis, 
patients may experience anaphylactic events that are associated with their 
underlying disease. Patients will continue to receive study agent, if determined to 
the best of our ability that these events are unrelated to study agent 
administration. These unrelated events would be determined by the PI not to 
jeopardize patient safety or restrict the use of additional therapy such as 
corticosteroids to control symptoms.   
 
In the event that the subject is withdrawn from the study due to an AE, the event 
must be recorded on the CRF as such. The subject should be monitored and 
treated by the investigator until the abnormal parameter or symptom has 
resolved or stabilized. It is up to the clinician to determine that the AE has either 
resolved or stabilized, after which no further follow-up is necessary. There should 
also be documentation to support this determination. 
 
9.6.3 Premature Withdrawal of a Participant 
Subjects who withdraw from the study prior to taking at least 1 dose of study 
medication are not required to complete additional visits. Subjects who receive 
study agent and either withdraw voluntarily from the study or who meet study 
criteria for withdrawal may be asked to return to the NIH Clinical Center for 
additional outpatient follow-up visits, including a focused history and physical 
exam, research blood tests and safety laboratory tests (CBC, ESR, CHEM-20, 
serum -HCG, urinalysis). The timing of these additional visits may correspond to 
those which may have been previously scheduled for administration of the study 
agent or may occur at other times according to the availability of the patient and 
discretion of the PI. Such subjects are not required to complete the additional 
research tests and procedures typically performed at the sixth month visit but 
may do so according to patient availability and the discretion of the PI.   
 


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9.7 
Data and Safety Monitoring 
The NIAID Intramural Data and Safety Monitoring Board (DSMB) will review the 
IRB approved protocol, informed consent documents, the data and safety 
monitoring plan and any stopping guidelines prior to study initiation.  During the 
course of the study, the DSMB will review cumulative study data twice per year to 
evaluate safety, efficacy, study conduct, and the scientific validity and integrity of 
the trial. As part of this responsibility, DSMB members must be satisfied that the 
timeliness, completeness, and accuracy of the data submitted to them for review 
are sufficient for evaluation of the safety and welfare of study subjects. The 
DSMB will convene if stopping criteria are met or other safety issues arise that 
the Principal Investigator and/or NIAID Clinical Director or designee would like 
the DSMB to address. 
 
The PI or study coordinator will provide the DSMB Executive Secretary with a 
sealed copy of the randomization codes needed for the DSMB review of the 
safety data. The Principal Investigator will notify the DSMB based on the 
reporting schedule for SAEs of all cases of unblinding, intentional or 
unintentional, so that the DSMB can assess the potential impact of the unblinding 
on the overall integrity of the study.  
 
The DSMB will also assess the performance of overall study operations and any 
other relevant issues, as necessary. Following each review, the DSMB will 
provide its recommendations to the study sponsor, including whether the study 
should continue without change, be modified, or terminated. The Principal 
Investigator will submit all written DSMB recommendations to the IRB upon 
receipt. 
 
9.7.1 
Safety Review and Communications Plan 
A Safety Review and Communication Plan (SRCP) has been developed for the 
protocol. The SRCP is an internal communications document between the PI and 
the CSO, which delineates the safety oversight responsibilities of the PI, the 
CSO, and other stakeholders. The SRCP also includes the overall plan for 
conducting periodic safety surveillance assessments. 
9.7.2 
Sponsor Medical Monitor (SMM) 
A medical monitor, representing the IND Sponsor (OCRPRO), has been 
appointed for oversight of safety in this clinical study. The SMM will be 
responsible for performing safety assessments as outlined in an SRCP. 
 
 


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10.0 
Statistical Considerations 
10.1 
Overview and Study Objectives 
Eligible subjects will be randomized to receive either placebo or omalizumab in a 
double-blind fashion with a target of 10 subjects enrolled in each study arm. 
During the primary evaluation phase, subjects will continue with the randomized 
assignment for 6 months.. After 6 months, patients will be discontinued from the 
randomized regimen, and followed for an additional 6 months. 
 
10.2 
Description of the Analyses 
The primary analysis will employ an exact Wilcoxon Rank Sum Test; this analysis 
is based completely on a ranking of the 20 subjects. The ranking procedure is as 
follows. Patients are first sorted according to numbers of events in the 6-month 
drug period. Ties are broken among patients with the same number of events, by 
further ranking patients by time of their first event (a patient with a later first event 
is considered better than a patient with an earlier first event). For example, if 
there are 5 patients with 0 events, they all get the rank of 1. If there are 3 patients 
with exactly one event, the one with the latest event time is ranked 6, the one 
with the middle event time is ranked 7, and the one with the earliest event is 
ranked 8.  This process continues for patients with 2 events, then those with 3 
events and so on. To test the hypothesis that the drug reduces anaphylaxis 
events after the first 24 hours, the primary analysis will exclude events in this 
time period. However, as a sensitivity analysis, the Wilcoxon Rank Sum Test 
primary analysis method, described above, will be conducted again, including 
these early data. The primary analysis will be conducted as a 2-sided α=.05 test.  
The p-values associated with alternate analyses of the primary endpoint, 
analyses of secondary endpoints, and exploratory analyses are considered 
descriptive. 
 
A key secondary analysis of the primary endpoint will analyze the number of 
events during the 6 months prior to randomization minus the number of events 
occurring in 6 months after randomization; this analysis will be done by the 
Wilcoxon Rank Sum Test.  Exploratory analyses will also be done comparing the 
number of events in the 3 study periods: 6 months prior to randomization, 6 
months after randomization, and the 6 months after drug discontinuation. 
 
The Cox model using the Wei-Lin-Weissfeld approach to multiple events, with an 
optimal linear combination for the test of the treatment effect, will also be 
performed.  This alternate analytic method would serve as an additional 
sensitivity analysis. 
 
Secondary endpoints will be analyzed descriptively, and with comparisons made 
by t-tests, Wilcoxon Rank Sum Tests, or Fishers Exact test, where appropriate. 
 
 


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10.3 
Study Hypotheses 
The administration of omalizumab for episodes of unprovoked anaphylaxis in 
idiopathic anaphylaxis will lead to a decrease in free serum IgE levels, a 
reduction of FcRI expression, and result in decreased episodes of anaphylaxis. 
10.4 
Sample Size Consideration 
A simulation study was conducted to estimate statistical power of the primary 
analysis will be conducted as a two-sided =.05 test. The power is a function of 
the hazard ratio (HR); a HR of 5, for example, means that subjects in 1 group 
would be expected to have 5 times as many events as those in the other group 
during the same time period. The simulations indicated that  with a sample size 
of 10 per group, the power is likely to be greater than 90% if the true HR=5 and 
greater than 80% if the true HR=4. The actual power depends somewhat on the 
assumed true gamma distribution of exponential waiting times. Simulations were 
conducted on 2 pairs of means and standard deviations of exponential 
parameters: (0.20, 0.06) and (0.15, 0.05), where for the first parameter set, the 
true expected time to the first event is 0.20 years for an average person, but that 
some individuals will have true expected time to first event smaller than 0.10 
years and some larger than 0.30 years. The simulated parameters are 
approximately consistent with the eligibility requirement that enrolled subjects 
had at least 6 events in the year prior to randomization. The powers did not vary 
substantially for these parameter sets. In short, if the true HR is very large, 
namely in the range of 4 to 5, the statistical power is likely to be at least 80%, 
with this sample size in this population. 
 
10.5 
Maintenance of Trial Treatment Randomization Codes 
The maintenance of randomization codes will be under the jurisdiction of the 
Pharmacy and by the DSMB Executive Secretary.   
 
10.6 
Randomization and Blinding 
The randomization sequence will be obtained by computer-generated random 
numbers [36] and will be provided by the study pharmacist. Study numbers 1 
through 20 will be used for the sequential enrollments with subjects being 
randomized simultaneously to all cohorts. The study number is assigned after 
completion of the eligibility checklist in the electronic study database and will be 
the next sequential number. To reduce the potential for participant dropouts 
during the period between randomization and initial dosing of the study agent, 
randomization will occur on Day 0 after eligibility is confirmed and the study 
consent is signed. The study pharmacist is responsible for maintaining security of 
the treatment assignments. The subject, the clinical staff, and the Principal 
Investigator will be blinded to treatment allocation. The pharmacist with primary 
responsibility for drug dispensing will keep the randomization code. To maintain 
blinding, any discussion of the treatment assignment between the clinicians and 


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the pharmacy staff is prohibited until after the assignments are permitted to be 
known to all. In addition, the placebo-matched controlled drug will be formulated 
by the parent company (Genentech-Novartis) for consistency between the drug 
and matched placebo. The nursing staff administering the product will be from a 
rotating inpatient nursing pool at the NIH for the first 2 doses and subsequent 
dosing at the NIH will be the same product for the remainder of the study. 
 
11.0 
Quality Control and Quality Assurance 
Following written standard operating procedures, the monitors (RCHSPP) will 
verify that the clinical trial is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, GCP, FDA (21 CFR 
312.50), and the applicable regulatory requirements.  
 
The investigational site will provide direct access to all source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by local and regulatory authorities. 
 
Quality control procedures will be implemented beginning with the data entry 
system and data quality control checks that will be run on the database will be 
generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
12.0 
Ethics/Protection of Human Subjects 
Monitors (RCHSPP) under contract to the NIAID will visit the clinical research site 
to monitor all aspects of the study in accordance with appropriate regulations. 
The objectives of a monitoring visit will be: 1) to verify the prompt reporting of 
data points, including SAEs; 2) to verify the existence of signed informed 
consent; 3) to examine individual subject CRF and source documents; 4) to 
ensure protection of study subjects, compliance with the protocol, and accuracy 
and completeness of records. The monitors also will inspect the clinic site 
regulatory files to ensure that regulatory requirements [Office for Human 
Research Protections (OHRP)/ICH-GCP and FDA] are being obeyed. During the 
monitoring visits, the principal investigator (and/or designee) and other study 
personnel will be available to discuss the study progress and monitoring visit. 
The principal investigator (and/or designee) will make study documents (e.g., 
consent forms) and pertinent CRF and supporting data readily available for 
inspection by the local IRB, the site monitors, and the NIAID staff for confirmation 
of the study data. 
 
A specific protocol monitoring plan will be discussed with the principal 
investigator and study staff prior to enrollment. The plan will outline the frequency 
of monitoring visits based on such factors as study enrollment, data collection 
status, and regulatory obligations. 


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12.1 Conflict of Interest 
 
The investigators conducting this clinical trial have completed the appropriate 
forms that relate to potential conflicts of interest according to NIAID guidelines.  
Specifically, assets, income, liabilities, outside positions, agreements, 
arrangements, gifts and travel reimbursements of the investigators, their spouses 
and their minor children have been reported according to the guidelines.  No 
reportable conflicts of interest have been identified for any of the investigators 
conducting this trial. 
 
12.2 
Rationale for Subject Selection 
This protocol is open to males and females from all ethnic and racial groups. The 
study will be listed on ClinicalTrials.gov, Clinical Center research studies and the 
NIAID patient website. Past, present and future LAD patients, that meet the 
protocol requirements, will be contacted to see if they are interested in 
participating. If recruitment goals are not met, a recruitment plan will be 
developed by the Clinical Center Office of Patient Recruitment. 
 
12.3 
Institutional Review Board 
A copy of the protocol, informed consent forms, and other information to be 
completed by participants, such as survey instruments or questionnaires, and 
any proposed advertising or recruitment materials will be submitted to the IRB for 
written approval. 
 
The investigator must submit and obtain approval from the IRB for all subsequent 
amendments to the protocol, informed consent documents, and other study 
documentation referenced above. The investigator will be responsible for 
obtaining IRB approval of the annual Continuing Review throughout the duration 
of the study. 
 
12.4 
Informed Consent Process 
When subjects arrive at the NIH Clinical Center, they will be consented by one of 
the study team investigators using the Standard Consent. Each subject must 
understand fully the contents of the consent form.   The informed consent will be 
given to the subject in advance so that they can thoroughly read the consent and 
ask any questions they may have prior to consent being obtained.  Upon 
Admission to the CC the informed consent will be obtained prior to drug 
administration or any other study procedure and a copy will be given to the 
subject for their records.  According to Title 21 CFR 50.20, the information that is 
given to the subject or the representative shall be in language understandable to 


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the subject or the representative.  A short form will be used to obtain consent as 
described in 45 CFR §46.117(b) (2). 
 
Assent or Informed Consent Process (in Case of a Minor) 
All subjects will be ≥18 years of age and can legally provide informed consent. 
 
12.5 
Justification for Exclusion of Women, Minorities, and Children 
(Special Populations) 
Exclusion of Women: Pregnant or breast feeding mothers are excluded from 
this study. 
 
Exclusion of Minorities: None will be excluded. 
 
Exclusion of Children: Children under the age of 18 years will be excluded due 
to new data concerning anaphylaxis and the FDA Boxed warning.  
 
12.6 
Compensation 
Compensation (money) is not provided as a part of this study.   The subjects will 
be reimbursed for their transportation costs as is permitted by the NIAID travel 
policy. 
13.0 
Data Management 
The Investigator is responsible for ensuring that the data collected are complete, 
accurate, and recorded in a timely manner.  Source documentation (the point of 
initial recording of information) should support the data collected in CRIMSON 
and must be signed and dated by the person recording and/or reviewing the 
data.  Data should be reviewed by the Investigator and signed as required with 
written or electronic signature, as appropriate. Source documents include all 
recordings of observations or notations of clinical activities, and all reports and 
records necessary for the evaluation and reconstruction of the clinical trial.  
Source documents include, but are not limited to, the subject’s medical records, 
laboratory reports, ECG tracings, x-rays, radiologist’s reports, subject’s diaries, 
biopsy reports, ultrasound photographs, progress notes, pharmacy records, and 
any other similar reports or records of procedures performed during the subject’s 
participation in the study. Data from CRIMSON Data System will be collected 
directly from subjects during study visits and telephone calls, or will be abstracted 
from subjects’ diaries and medical records.  The subject’s medical record must 
record his/her participation in the clinical trial and, after unblinding what 
medications (with doses and frequency) or other medical interventions or 
treatments were administered, as well as any adverse reactions experienced 
during the trial.  
 
 


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14.0 
Data Handling and Record Keeping 
• Data will be coded, so that subjects will not be able to be identified by 
persons not listed as investigators. . 
 
• Data will be stored in a secure area, with limited access. 
 
• Data will be collected on a monthly basis from subjects using the weekly 
event log and physician (both NIH and home) will document each visit on 
the physician treatment note. (See Appendixes E and F) 
15.0 
Publication Policy 
Following completion of the study, the investigator may publish the results of this 
research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a 
condition for publication. This policy requires that all clinical trials be registered in 
a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting 
similar policies. It is the responsibility of the NIAID Division or Branch to register 
this trial in an acceptable registry either on or before the onset of patient 
enrollment. 
 
Publication of the results of this trial will be governed by NIAID publication 
policies. Any presentation, abstract, or manuscript will be made available for 
review (according to division requirements if any), prior to submission.  
16.0 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the 
ICH Good Clinical Practice Guideline.  All essential documentation for all study 
subjects are to be maintained by the investigators in a secure storage facility for 
a minimum of three years, per DHHS (45 CFR 46.115(b)). The FDA requires 
study records to be retained for up to two years after marketing approval or 
disapproval (21 CFR 312.62), or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational agent for a 
specific indication]. These records are also to be maintained in compliance with 
IRB/EC, state, and federal medical records retention requirements, whichever is 
longest. All stored records are to be kept confidential to the extent provided by 
federal, state, and local law. It is the investigator’s responsibility to retain copies 
of source documents until receipt of written notification to the contrary from the 
Office of Clinical Research Policy and Regulatory Operations (OCRPRO), 
Division of Clinical Research (DCR) of the National Institute of Allergy and 
Infectious Diseases (NIAID). No study document should be destroyed without 
prior written agreement between OCRPRO/NIAID and the Principal Investigator. 
Should the investigator wish to assign the study records to another party and/or 
move them to another location, the investigator must provide written notification 


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of such intent to OCRPRO/NIAID with the name of the person who will accept 
responsibility for the transferred records and/or their new location. NIAID must be 
notified in writing and written NIAID permission must be received by the site prior 
to destruction or relocation of research records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17.0 
References 
1. 
Khan, D.A. and M.W. Yocum, Clinical course of idiopathic anaphylaxis. 
Ann Allergy, 1994. 73(4): p. 370-4. 
2. 
Thong, B.Y., et al., Anaphylaxis in adults referred to a clinical 
immunology/allergy centre in Singapore. Singapore Med J, 2005. 46(10): 
p. 529-34. 
3. 
Webb, L.M. and P. Lieberman, Anaphylaxis: a review of 601 cases. Ann 
Allergy Asthma Immunol, 2006. 97(1): p. 39-43. 
4. 
Lieberman, P., Anaphylaxis and anaphylactoid reactions. 5th ed. 
Middleton Allergy: Principles and Practice, ed. J.W.F. Ellis EF, C.E.R., 
Adkinson NF, Busse WW. 1998, St Louis: Mosby. 1079-1089. 
5. 
Neugut, A.I., A.T. Ghatak, and R.L. Miller, Anaphylaxis in the United 
States: an investigation into its epidemiology. Arch Intern Med, 2001. 
161(1): p. 15-21. 
6. 
Greenberger, P.A., Idiopathic anaphylaxis. Immunol Allergy Clin North 
Am, 2007. 27(2): p. 273-93, vii-viii. 
7. 
Gilfillan, A.M. and C. Tkaczyk, Integrated signalling pathways for mast-cell 
activation. Nat Rev Immunol, 2006. 6(3): p. 218-30. 
8. 
Olivera, A., et al., The sphingosine kinase-sphingosine-1-phosphate axis 
is a determinant of mast cell function and anaphylaxis. Immunity, 2007. 
26(3): p. 287-97. 
9. 
Bansal, G., et al., Suppression of immunoglobulin E-mediated allergic 
responses by regulator of G protein signaling 13. Nat Immunol, 2008. 9(1): 
p. 73-80. 
10. 
Vadas, P., et al., Platelet-activating factor, PAF acetylhydrolase, and 
severe anaphylaxis. N Engl J Med, 2008. 358(1): p. 28-35. 
11. 
Macglashan, D., Jr., IgE receptor and signal transduction in mast cells and 
basophils. Curr Opin Immunol, 2008. 20(6): p. 717-23. 
12. 
Akin, C., et al., Demonstration of an aberrant mast-cell population with 
clonal markers in a subset of patients with "idiopathic" anaphylaxis. Blood, 
2007. 110(7): p. 2331-3. 
13. 
Valent P, H.H., Li CY, Longley BJ, Metcalfe DD, Parwaresch RM, Bennett 
JM, ed. Mastocytosis. World Health Organization Classification of 
Tumours: Pathology and Genetics: Tumours of Haematopoietic and 
Lymphoid Tissues, ed. S.L. Kleihues P. 2001, IARC Press: Lyon. 291. 
14. 
Wong, S., M.S. Dykewicz, and R. Patterson, Idiopathic anaphylaxis. A 
clinical summary of 175 patients. Arch Intern Med, 1990. 150(6): p. 1323-
8. 
15. 
Wong, S., et al., Outcome of prophylactic therapy for idiopathic 
anaphylaxis. Ann Intern Med, 1991. 114(2): p. 133-6. 
16. 
Milgrom, H., et al., Treatment of allergic asthma with monoclonal anti-IgE 
antibody. rhuMAb-E25 Study Group. N Engl J Med, 1999. 341(26): p. 
1966-73. 
17. 
Leung, D.Y., et al., Effect of anti-IgE therapy in patients with peanut 
allergy. N Engl J Med, 2003. 348(11): p. 986-93. 


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18. 
Foroughi, S., et al., Anti-IgE treatment of eosinophil-associated 
gastrointestinal disorders. J Allergy Clin Immunol, 2007. 120(3): p. 594-
601. 
19. 
Casale, T.B., et al., Omalizumab pretreatment decreases acute reactions 
after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J 
Allergy Clin Immunol, 2006. 117(1): p. 134-40. 
20. 
Gober LM, S.P., Eckam JA, Saini SS, Effect of Anti-IgE (Omalizumab) in 
Chronic Idiopathic Urticaria Patients. J Allergy Clin Immunol, 2008. 121: p. 
S147. 
21. 
Kaplan, A.P., et al., Treatment of chronic autoimmune urticaria with 
omalizumab. J Allergy Clin Immunol, 2008. 122(3): p. 569-73. 
22. 
Belloni, B., et al., Low-dose anti-IgE therapy in patients with atopic 
eczema with high serum IgE levels. J Allergy Clin Immunol, 2007. 120(5): 
p. 1223-5. 
23. 
Jones, J.D., S.R. Marney, Jr., and J.M. Fahrenholz, Idiopathic anaphylaxis 
successfully treated with omalizumab. Ann Allergy Asthma Immunol, 
2008. 101(5): p. 550-1. 
24. 
Bard, S., et al., Eczematous dermatitis in the setting of hyper-IgE 
syndrome successfully treated with omalizumab. Arch Dermatol, 2008. 
144(12): p. 1662-3. 
25. 
van der Ent, C.K., H. Hoekstra, and G.T. Rijkers, Successful treatment of 
allergic bronchopulmonary aspergillosis with recombinant anti-IgE 
antibody. Thorax, 2007. 62(3): p. 276-7. 
26. 
Boyce, J.A., Successful treatment of cold-induced urticaria/anaphylaxis 
with anti-IgE. J Allergy Clin Immunol, 2006. 117(6): p. 1415-8. 
27. 
Carter, M.C., et al., Omalizumab for the treatment of unprovoked 
anaphylaxis in patients with systemic mastocytosis. J Allergy Clin 
Immunol, 2007. 119(6): p. 1550-1. 
28. 
Busse, W.W., et al., Randomized trial of omalizumab (anti-IgE) for asthma 
in inner-city children. N Engl J Med, 2011. 364(11): p. 1005-15. 
29. 
Busse, W., et al., Omalizumab, anti-IgE recombinant humanized 
monoclonal antibody, for the treatment of severe allergic asthma. J Allergy 
Clin Immunol, 2001. 108(2): p. 184-90. 
30. 
MacGlashan, D.W., Jr., et al., Down-regulation of Fc(epsilon)RI 
expression on human basophils during in vivo treatment of atopic patients 
with anti-IgE antibody. J Immunol, 1997. 158(3): p. 1438-45. 
31. 
Prussin, C., et al., Omalizumab treatment downregulates dendritic cell 
FcepsilonRI expression. J Allergy Clin Immunol, 2003. 112(6): p. 1147-54. 
32. 
Beck, L.A., et al., Omalizumab-induced reductions in mast cell Fce psilon 
RI expression and function. J Allergy Clin Immunol, 2004. 114(3): p. 527-
30. 
33. 
Valyasevi, M.A., D.E. Maddox, and J.T. Li, Systemic reactions to allergy 
skin tests. Ann Allergy Asthma Immunol, 1999. 83(2): p. 132-6. 
34. 
Brown, S.G., Clinical features and severity grading of anaphylaxis. J 
Allergy Clin Immunol, 2004. 114(2): p. 371-6. 


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35. 
Cox, L., et al., American Academy of Allergy, Asthma & 
Immunology/American College of Allergy, Asthma and Immunology Joint 
Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin 
Immunol, 2007. 120(6): p. 1373-7. 
 
 
36.     Diem K, Lentner C. page 131. In, Documenta Geigy, Scientific Tables.  
Diem K, Lentner C, editors. 7th ed. Publisher, Basle Switzerland:Ciba 
Geigy 1970. 
 


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Appendix A. Toxicity Table 
 
The NCI Cancer Therapy Evaluation Program Common Terminology Criteria for 
Adverse Events version 3.0 (CTCAE) will be used to grade adverse events. 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B. Schedule of Procedures/Evaluations 
Each treatment visit may occur within (+/-) 3 days of the scheduled time and the 
6 month off-treatment visit may occur within (+/-) 30 days of the scheduled time. 
 
Schedule of Evaluations – 4 week dosing 
 
Preparation and Screening – the following screening procedures may be 
performed up to 4 weeks prior to the study agent administration. Screening may 
be either on an inpatient or outpatient basis. 
 
* Women of childbearing potential must have a negative -HCG serum or urine 
pregnancy test prior to each injection. 
 
†A serum tryptase and research blood will be obtained subsequent (within 24 
hours) to any anaphylactic event in association with study agent administration.  
 
 
Screening Visit - Day -30 to -1  
Admission to the Clinical Center or outpatient clinic for screening (duration 2-3 
days) 
Inpatient 5SE or Outpatient OP11 
Informed consent 
Medical history and physical exam 
Screening blood work 
Bone marrow biopsy (as needed, at the discretion of the PI)  
Pulmonary Function Tests (PFTs), if indicated for skin testing 
Research blood draws as needed 
Consultations will be requested as medically indicated 
 
Visit #1 - Day 0 (1st injection) 
Admission to 5SE (duration may be up to 2-3 days) 
Medical history and physical exam 
Blood draws as needed prior to study agent injection 
Initial study agent injection 
Observation for approximately 24 hours for adverse reactions 
Consultations will be requested as medically indicated 
Epi-Pen provided with teaching and take home instructions on the signs and 
symptoms of anaphylaxis and when to seek medical care. Subjects will be 
advised to bring Epi-Pen to subsequent visits for staff to check and to carry it with 
them until otherwise advised. 
 
Day 1 
Observation 
Discharge 
 
Visit #2 – Week 4 (2nd injection) 


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Admission to 5SE (duration may be up to 2-3 days) 
Focused history and physical 
Blood draw 
Study agent injection 
Observation for aproximately 24 hours 
Consultations will be requested as medically indicated 
Subjects will be reminded to bring Epi-Pen to subsequent visits for staff to check 
and to carry it with them until otherwise advised. 
 
Week 4, Day +1 
Observation 
Discharge 
 
Omalizumab or Placebo-matched control (Study agent) Administration *  
All injections administered in the Clinical Center will include an observation 
period of 2 hours. 
 
Visit #3 – Week 8 (3rd injection) 
Study agent administration at the NIH.  
 
Visit #4 – Week 12 (4th injection)  
Study agent administration at the NIH.  
. 
Visit #5 – Week 16 (5th injection) 
Research blood draws 
Study agent administration at the NIH. 
. 
Visit #6 – Week 20 (6th injection) 
(Final Treatment Visit) 
Admission to day hospital 
Focused history and physical 
Blood draw 
Study agent injection 
Observation for 2 hours post injection 
Subjects will be reminded to bring Epi-Pen to subsequent visits for staff to check 
and to carry it with them until otherwise advised. 
 
Visit #7 – 6 months post treatment follow up (+/- 30 days) 
The subjects will be monitored by their referring physicians, who will 
continue to document any anaphylactic events, until their follow-up study 
visit 6 months after drug completion.  The subject will return to the NIH for 
a final follow-up visit which may include:  
1) History and physical examination.  
2) Blood tests in each subject: complete blood count with differential, 
acute care panel, hepatic panel (as needed), IgE, serum tryptase 
levels, hepatitis profiles (as needed), anti-HTLV I/II (as needed), 


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and for women of childbearing potential, a -HCG serum or urine 
test for pregnancy, and research blood (as needed). Additional 
tests will be ordered as clinically indicated for each subject's 
condition.  
3) Possible bone marrow biopsy 
 
The above schedule will be followed as closely as possible. However, subjects 
will be allowed a (+/-) 3 day interval unless otherwise noted to meet the schedule 
timeline for the administration of study agent. Admissions to the th NIH Clinical 
Center may be extended as necessary to accommodate the subject schedule. 
 
 
Schedule of Evaluations – 2 week dosing 
 
 
Preparation and Screening – the following screening procedures may be 
performed up to 4 weeks prior to the study agent administration. Screening may 
be either on an inpatient or outpatient basis. 
 
Screening Visit - Day -30 to -1 
Admission to the Clinical Center or outpatient clinic for screening (duration 2-3 
days) 
Inpatient 5SE or Outpatient OP11 
Informed consent 
Medical history and physical exam 
Screening blood work 
Bone marrow biopsy (as needed, at the discretion of the PI)  
Pulmonary Function Tests (PFTs), if indicated for skin testing 
Research blood draws as needed 
Consultations will be requested as medically indicated 
 
Visit #1 - Day 0 (1st injection) 
Admission to 5SE (duration may be up to 2-3 days) 
Medical history and physical exam 
Blood draws as needed prior to study agent injection 
Research blood draws as neededInitial study agent injection 
Observation for approximately 24 hours for adverse reactions 
Consultations will be requested as medically indicated 
Epi-Pen provided with teaching and take home instructions on the signs and 
symptoms of anaphylaxis and when to seek medical care. Subjects will be 
advised to bring Epi-Pen to subsequent visits for staff to check and to carry it with 
them until other wise advised. 
 
Day 1 
Observation 
Discharge 


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Visit #2 – Week 2 (2nd injection) 
Admission to 5SE (duration may be up to 2-3 days) 
Focused history and physical 
Blood draw 
Research blood draws as needed 
Study agent injection 
Observation for approximately 24 hours for adverse reactions 
Consultations will be requested as medically indicated 
Subjects will be reminded to bring Epi-Pen to subsequent visits for staff to check 
and to carry it with them until otherwise advised. 
 
Week 2, Day +1 
Observation 
Discharge 
 
Omalizumab or Placebo-matched control (Study agent) Administration *  
All injections administered at the Clinical Center and include an observation 
period of approximately 2 hours. 
 
Visit #3 – Week 4 (3rd injection) 
Study agent administration at the NIH 
 
Visit #4 – Week 6 (4th injection) 
Study agent administration at the NIH 
 
Visit #5 – Week 8 (5th injection) 
Study agent administration at the NIH 
 
Visit #6 – Week 10 (6th injection) 
Study agent administration at the NIH 
 
Visit #7 – Week 12 (7th injection) 
Study agent administration at the NIH 
 
Visit #8 – Week 14 (8th injection) 
Study agent administration at the NIH 
 
Visit #9 – Week 16 (9th injection) 
Study agent administration at the NIH 
Research blood draws 
 
Visit #10 – Week 18 (10th injection) 
Study agent administration at the NIH 
 
Visit #11 – Week 20 (11th injection) 


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Study agent administration at the NIH 
 
Visit #12 – Week 22 (12th injection) 
(Final Treatment Visit) 
Admission to day hospital 
Focused history and physical 
Blood draw 
Research blood draws as needed 
Study agent injection 
Observation for approximately 2 hours post injection 
Subjects will be reminded to bring Epi-Pen to subsequent visits for staff to check 
and to carry it with them until otherwise advised. 
 
Visit #13 – 6 months post treatment follow up (+/- 30days) 
The subjects will be monitored by their referring physicians, who will 
continue to document any anaphylactic events, until their follow-up study 
visit 6 months after drug completion. The subject will return to the NIH  for 
one final follow-up visit which may include:  
4) History and physical examination.  
5) Blood tests in each subject: complete blood count with differential, 
acute care panel, hepatic panel as needed, IgE, serum tryptase 
levels, hepatitis profiles as needed, anti-HTLV I/II as needed, and 
for women of childbearing potential, a -HCG serum or urine test 
for pregnancy, and research blood as needed. Additional tests will 
be ordered as clinically indicated for each subject's condition.  
6) Possible bone marrow biopsy 
7) The final visit may include counseling by study investigators as to 
the significance of positive vs. negative findings if data is available. 
 
The above schedule will be followed as closely as possible. However, subjects 
will be allowed a (+/-) 3 day interval unless otherwise noted to meet the schedule 
timeline for the administration of study agent. Admissions to the th NIH Clinical 
Center may be extended as necessary to accommodate the subject schedule. 
 
 
 
 
 
 


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Appendix C. WHO Criteria for the Diagnosis of Systemic Mastocytosis [13] 
 
 
 
1 major criterion + 1 minor criterion or 3 minor criteria 
 
▪ Major Criteria: 
– Characteristic multifocal dense infiltrates of mast cells 
in bone marrow biopsy 
▪ Minor Criteria: 
– Morphology of mast cells: Spindle shaped 
– the D816V mutation in c-kit  
– Flow cytometric co-expression of CD117, CD2 and 
CD25 by the bone marrow mast cell population 
– Serum tryptase >20 ng/mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D. Xolair® Package Insert  
 
URL: http://www.gene.com/gene/products/information/pdf/xolair-prescribing.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E. Physician Treatment Note 


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Appendix F. Weekly Event Log 


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Appendix G.  Expected symptoms and adverse events related to the 
underlying disease (IA), the study agent omalizumab or protocol 
procedures. 
 
Idiopathic Anaphylaxis (IA) 
Omalizumab 
Procedure 
Generalized flushing 
Anaphylaxis: 
Pain 
Urticaria 
Hypotension 
Bruise 
Nasal congestion 
Syncope 
Infection 
Conjunctival irritation 
Urticaria 
Bleeding 
Bronchospasm 
Malignancy 
Fainting 
Angioedema (tongue, throat, 
palms, soles) 
Angioedema (throat or tongue) Infection 
Gastrointestinal cramping 
Bronchospasm 
Bruising 
Lightheadedness 
Mutagenesis 
Small hematoma 
Loss of consciousness 
Impairment of Fertility 
Mild itching 
Circulatory collapse 
Embryotoxicity 
Swelling of the skin 
Hives 
Teratogenicity 
Anaphylaxis 
Itching 
Carcinogenesis 
Nausea 
Shortness of breath 
Increase in hear diseases 
Vomiting 
Diarrhea 
Lung problems 
Changes in vital signs 
Vomiting 
Cerebrovascular disease(eg. 
stroke) 
Itchy eye, nose, throat 
Hypotension 
Arthritis/Arthralgia 
Runny nose 
Laryngospasm 
Pain (general) 
Tightness in the throat or 
chest 
Hoarseness 
Leg pain 
Coughing 
Uterine cramps 
Fatigue 
Sneezing 
Urinary incontinence 
Dizziness 
Shortness of breath 
 
Fracture 
Hives  
 
Arm pain 
Flushing 
 
Pruritus 
Lightheadedness 
 
Dermatitis 
Asthma exacerbation 
 
Earache 
Injection site local reaction 
 
Rash (urticaria or other forms) 
Shock 
 
Fever 
Swelling in the throat 
 
Lymphadenopathy 
Death 
 
Injection site reaction 
 
 
Viral infections 
 
 
Upper respiratory tract 
infection 
 
 
Sinusitis 
 
 
Headache 
 
 
Pharyngitis 
 
 
Blood Clots 
 
 
Cartiovascular Disease 
 


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