Conditions: Urticaria Chronic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a Phase IV, single-site study that will examine blood cells or tissue obtained from CIU ( chronic idiopathic Urticaria) patients receiving open-label treatment with omalizumab at the current FDA-approved dose of 300 mg/month for 12 weeks in addition to standard therapy with anti-histamines. Results from the 3 Phase III studies in CIU patients provide evidence that a meaningful change in symptoms is apparent at 1-2 wks. The Minimal Important Difference (MID) is achieved by 70% of patients by 2 wks on multiple background drugs for hives. The goal is to identity the IgE bearing cell type associated with clinical symptom change.

Detailed description:
Primary Objective

This will be a study of the kinetics of clinical symptom relief during treatment of patients with CIU. The purpose is to determine if the rate of clinical remission is concordant with the rate that IgE-dependent functions of basophil change or mast cell changes during treatment.

Secondary Objectives

1. Basophil surface IgE, Fc epsilon Receptor I alpha (FcεRI) and Syk by flow cytometry
2. Dendritic cell surface IgE, FcεRI, functions
3. Basophil anti-IgE, anti FcεRI, C5a, N-Formylmethionyl-leucyl-phenylalanine (FMLP) mediated histamine along with sensitivity measures
4. Serum free IgE measures
5. Characterization of presence of serum autoantibody presence ± Syk inhibitors
6. Basophil enumeration
7. Basophil Messenger RNA (mRNA) profiling baseline at 3 timepoints (baseline, meaningful clinical changes, and 30 days)
8. To assess the rate of IgE and FcεRI change in skin mast cells at day 0, 6, 90, via a small punch biopsy as well as the Mas-Related gpr Family Member X2 (MrgX2) receptor expression

Study Design

This is a Phase IV, single-site study that will examine blood cells or tissue obtained from CIU patients receiving open-label treatment with omalizumab at the current FDA-approved dose of 300 mg/month for 12 weeks in addition to standard therapy with anti-histamines. Results from the 3 Phase III studies in CIU patients provide evidence that a meaningful change in symptoms is apparent at 1-2 wks. The MID (Minimal Important Difference) is achieved by 70% of patients by 2 wks on multiple background drugs for hives. The goal is to identity the IgE bearing cell type associated with clinical symptom change.

The study will enroll 30 patients and will consist of three phases.

Screening Visit (Week -3 to Week-2)-establish compliance with diary and review safety labs.

Standard therapy Run-in (Week -2 to Day 0)

Open-label Treatment Period (Day 0 to Week 12)

To be eligible at the screening visit (Week -1), subjects must:

1. Be \> 18 years old
2. Have a diagnosis of moderate to severe CIU, as defined by pruritus and hives for \> 3 days in a 7-day period for \> 6 consecutive weeks despite treatment with H1 antihistamine:

Must have a non-diary based daily urticaria activity score (UAS) score ≥ 2 established in the outpatient setting based on the patient's condition over 12 hours prior to the visit; the UAS is a composite score of pruritus (0-3) and number of hives (0-3) with a maximum value of 6.

This requirement may be met either at screening visit, run-in visit (Week -2), or beginning of treatment (Day 0).

Must have been on an approved dose of an H1 antihistamine for CIU such as loratadine 10 mg once a day or equivalent, for at least 7 days prior to the screening visit. Approved agents include loratadine 10 qd, desloratadine 5 mg qd, fexofenadine 180 mg qd, cetirizine 10 mg qd or levocetirizine 5 mg qd as once daily medications at the current FDA-approved dose.

Must be willing to fill out a twice-daily patient-diary to establish the patient's Urticaria Activity Score 7 (UAS7) score. The UAS is a composite diary- recorded score with numeric severity intensity ratings (0 = none to 3 = intense) for 1) the number of wheals (hives); and 2) the intensity of the pruritus (itch). The UAS7 is the sum of the daily average UAS scores (average of a.m. and p.m.) for 7 days. The maximum UAS7 value is 42.

To be eligible to begin the run-in period (Week -2 to Day 0), the patients:

Must remain on stable dose of a single H1 antihistamine at approved dose (not including antihistamine rescue medication) as established at the screening visit.

At the end of the 12-week treatment period , subjects will have last visit a final visit to collect diary, blood work, non-lesional skin biopsy and safety data.

All patients will be provided diphenhydramine (25 mg po TID) as rescue medication for pruritus relief on an as-needed basis (to a maximum of three doses in 24 hours). Patients who require treatments other than diphenhydramine (e.g., prednisone) to treat persistent/worsening disease will be discontinued from the study. Patients will also be provided an epipen and trained in its use as per American Academy of Allergy, Asthma \& Immunology (AAAAI) guidelines for omalizumab.

Primary Endpoint The time to meaningful change in diary-based clinical symptoms as measured by the Urticaria Activity Score from baseline (Wk -7 to Day -1) to the date at which an MID (5 point change in weekly UAS 7) or achievement of \> 50% reduction in daily symptom score for 3 days if in the first week. The UAS score, which is the sum of pruritus and hives, will be used to calculate the UAS7. The UAS7 score obtained 1 week prior to randomization will be used as the baseline.

Secondary Endpoints

Change in the weekly pruritus score from baseline to the 12th week in the treatment period. The pruritus score will be measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 (intense). The weekly pruritus score is the sum of average daily pruritus scores over the previous 7 days.

Change in the weekly score for number of hives from baseline to the 12th week in the treatment period. The number of hives is measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 (\> 12 hives, see below). The weekly score of number of hives is the sum of the average daily scores over the previous 7 days.

Change in the amount of rescue medication (diphenhydramine 25 mg) from baseline to the 12th week in the treatment period using the question on the rescue medication use in the patient diary.

Change in SKINDEX29 (quality of life survey instrument with 29 questions) on a 5-point Likert scale. It will be given at baseline and again at 90 days.

Exploratory Endpoints

1. Basophil surface IgE, FcεRI and Syk by flow cytometry- Day 0, 1, 3, 6, 10, 20, 30 and 90 days
2. Dendritic cell surface IgE, FcεRI -Day 0, 1, 3, 6, 10, 20, 30 and 90 days
3. Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated histamine release along with sensitivity measures- Day 0, 1, 3, 6, 10, 20, 30 and 90 days
4. Serum free IgE measures (stored serum) Day 0, 1, 3, 6, 10, 20, 30 and 90 days
5. Characterization of presence of serum autoantibody presence ± Syk inhibitors -Day 0, 1, 3, 6, 10, 20, 30 and 90 days
6. Basophil enumeration by manual counting and blood histamine content - Day 0, 1, 3, 6, 10, 20, 30 and 90 days. This will determine the presence or absence of basopenia and identify subjects for mRNA profiling studies.
7. Basophil mRNA profiling baseline at 3 timepoints (baseline, meaningful clinical changes, and 30 days) in select subjects with sufficient basophil numbers ( \>1.5x 106/100 cc blood)
8. Numbers of IgE +, FcεRI + cells in non-lesional skin biopsies at day 0, 6, 90 to monitor skin mast cells well as the MrgX2 receptor expression
9. Change in circulating leukocyte population numbers that are targeted by omalizumab such as blood basophils, eosinophil and lymphocyte counts by automated analysis (week -3 to week 12).

Arms:
arm 1: Omalizumab 300mg every month for 3 doses

Interventions: intervention 1: Omalizumab
Intervention descriptions: intervention 1: omalizumab 300 mg every 4 weeks by subcutaneous injection

Protocol document:
Prot_SAP_000.pdf: 
Appendices 
 
CONFIDENTIAL 
Page 0 of 80 
 
 
 
 
 
Title  
 
Role of IgE Bearing Cells in Chronic Idiopathic Urticaria 
NCT 03111628 
 
 
Document date: May 29, 2019 
 


Protocol 
 
          Version 1.3                                                      Page 1 of 80 
 
 
Omalizumab in CIU 
 May 29, 2019 
 
  
 
 PROTOCOL SYNOPSIS 
Title  
 
Role of IgE Bearing Cells in Chronic Idiopathic Urticaria 
Short Title 
 
Omalizumab in CIU 
Protocol Number 
 
XXXXX Version 1.3 
Study Drug 
 
Omalizumab 
 
Clinical Phase 
 
Phase IV 
Principal Investigator  
 
Dr. Sarbjit S. Saini, M.D. 
 
Participating Site  
 
Johns Hopkins Asthma and Allergy Center 
 
Primary Objective 
 
This will be a study of the kinetics of clinical symptom 
relief during treatment of patients with CIU. The purpose is 
to determine if the rate of clinical remission is concordant 
with the rate that IgE-dependent functions of basophil 
change or mast cell changes during treatment.  
 
Secondary Objectives 
1) Basophil surface IgE, FcεRI and Syk by flow cytometry  
2) Dendritic cell surface IgE, FcεRI, functions  
3) Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated 
histamine along with sensitivity measures  
4) Serum free IgE measures  
5) Characterization of presence of serum autoantibody 
presence ± Syk inhibitors  
6) Basophil enumeration  
7) Basophil mRNA profiling baseline at 3 timepoints 
(baseline, meaningful clinical changes, and 30 days)  
8) To assess the rate of IgE and FcεRI change in skin mast 
cells at day 0, 6, 90, via a small punch biopsy as well as the 
MrgX2 receptor expression  
 
 


Protocol 
 
          Version 1.3                                                      Page 2 of 80 
 
 
Omalizumab in CIU 
 May 29, 2019 
 
  
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a Phase IV, single-site study that will examine blood 
cells or tissue obtained from CIU patients receiving open-
label treatment with omalizumab at the current FDA-
approved dose of 300 mg/month for 12 weeks in addition 
to standard therapy with anti-histamines. Results from the 
3 Phase III studies in CIU patients provide evidence that a 
meaningful change in symptoms is apparent at 1-2 wks. 
The MID (Minimal Important Difference) is achieved by 
70% of patients by 2 wks on multiple background drugs for 
hives. The goal is to identity the IgE bearing cell type 
associated with clinical symptom change. 
 
The study will enroll 30 patients and will consist of three 
phases. 
 
Screening Visit (Week -3 to Week-2)-establish compliance 
with diary and review safety labs. 
 
Standard therapy Run-in (Week -2 to Day 0)   
 
Open-label Treatment Period (Day 0 to Week 12) 
 
 
During the screening period (Week -3 to Week -2), each 
patient’s eligibility for the trial will be established. To be 
eligible at the screening visit (Week -1), subjects must:  
1) Be 18 years of age or older 
 
2) Have a diagnosis of moderate to severe CIU, as defined 
by pruritus and hives for > 3 days in a 7-day period for > 6 
consecutive weeks despite treatment with H1 
antihistamine: 
 
Must have a non-diary based daily urticaria activity score 
(UAS) score ≥ 2 established in the outpatient setting based 
on the patient’s condition over 12 hours prior to the visit; 
the UAS is a composite score of pruritus (0–3) and number 
of hives (0–3) with a maximum value of 6. 
This requirement may be met either at screening 
visit, run-in visit (Week -2), or beginning of 
treatment (Day 0). 
 
Must have been on an approved dose of an H1 
antihistamine for CIU such as loratidine 10 mg once a day 
or equivalent, for at least 7 days prior to the screening visit. 
Approved agents include loratadine 10 qd, desloratadine 5 
mg qd, fexofenadine 180 mg qd, cetirizine 10 mg qd or 
levocetirizine 5 mg qd as once daily medications at the 


Protocol 
 
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Omalizumab in CIU 
 May 29, 2019 
 
  
current FDA-approved dose. As per international treatment 
guidelines, daily doses up to 4-fold of the approved doe of 
the listed antihistamines will be allowed if  the patient 
demonstrates high disease activity scores based on 
screening week.  
 
Must be willing to fill out a twice-daily patient-diary to 
establish the patient’s Urticaria Activity Score 7 (UAS7) 
score. The UAS is a composite diary- recorded score with 
numeric severity intensity ratings (0 = none to 3 = intense) 
for 1) the number of wheals (hives); and 2) the intensity of 
the pruritus (itch). The UAS7 is the sum of the daily 
average UAS scores (average of a.m. and p.m.) for 7 days. 
The maximum UAS7 value is 42.  
 
To be eligible to begin the run-in period (Week -2 to Day 0), 
the patients: 
 
Must have a UAS7 score ≥ 16 established over 7 consecutive 
days in the screening or run-in period. 
 
Must remain on stable dose of a H1 antihistamines (not 
including antihistamine rescue medication) as established 
at the screening visit.  
 
During the run-in period, patients will establish their 
baseline symptom scores using the diary. Patients with a 
diary-based UAS7 symptom score ≥ 16 during the 
screening or run-in periods  will be eligible to enter the 12-
week open treatment period.  The baseline UAS7 score at 
time of treatment (Day 0) must be calculated using the 
diary scores for 7 days.  Only in rare circumstances, 
(pending lab studies, in clinic UAS score < 2) will a longer 
screening period be permitted.  
 
On the first day of the treatment period (Day 0), eligible 
patients will receive 300 mg of omalizumab by sq injection. 
Baseline blood work, skin biopsy of non-lesional skin will 
also be collected. The primary endpoint will be measured 
using the daily diary scoring beginning at Day 0. For the 
duration of the 12-week, treatment period, patients must 
remain on stable doses of their pre-determined CIU H1 
antihistamine treatment.  
 
At the end of the 12-week treatment period, subjects will 
have last visit a final visit to collect diary, blood work, non-
lesional skin biopsy and safety data.  
 


Protocol 
 
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Omalizumab in CIU 
 May 29, 2019 
 
  
All patients will be provided diphenhydramine (25 mg po 
TID) as rescue medication for pruritus relief on an as-
needed basis (to a maximum of three doses in 24 hours). 
Patients who require treatments other than 
diphenhydramine (e.g., prednisone) to treat 
persistent/worsening disease will be discontinued from the 
study. Patients will also be provided an epipen and trained 
in its use as per AAAAI guidelines for omalizumab.  
 
Study Duration 
15 months (including recruitment) 
Primary Endpoint 
The time to meaningful change in diary-based clinical symptoms 
as measured by the Urticaria Activity Score from baseline (Wk -7 
to Day -1) to the date at which an MID (5 point change in weekly 
UAS 7) or achievement of > 50% reduction in daily symptom 
score for 3 days if in the first week. The UAS score, which is the 
sum of pruritus and hives, will be used to calculate the UAS7. 
The UAS7 score obtained 1 week prior to randomization will be 
used as the baseline.   
 
Secondary Endpoints 
 
Change in the weekly pruritus score from baseline to the 12th 
week in the treatment period. The pruritus score will be 
measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 
(intense). The weekly pruritus score is the sum of average daily 
pruritus scores over the previous 7 days. 
 
Change in the weekly score for number of hives from baseline to 
the 12th week in the treatment period. The number of hives is 
measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 
(> 12 hives, see below). The weekly score of number of hives is 
the sum of the average daily scores over the previous 7 days. 
 
Scoring for Wheals 
0= None 
1= Mild 1-6 hives/12 hours 
2= Moderate 7-12 hives/12 hours 
3= Severe > 12 hives/12 hours 
 
Scoring for Itch 
0= None 
1= Mild 
2= Moderate 
3= Severe 
 
 
Change in the amount of rescue medication (diphenhydramine 25 
mg) from baseline to the 12th week in the treatment period using 
the question on the rescue medication use in the patient diary. 
 


Protocol 
 
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Omalizumab in CIU 
 May 29, 2019 
 
  
Change in SKINDEX29 quality of life survey instrument 
with 29 questions on a 5-point Likert scale. It will be given 
at baseline and again at 90 days. 
 
 
 
Safety Outcome Measures 
 
The safety of omalizumab will be assessed using the 
following outcome measures: incidence and severity of 
treatment-emergent adverse events and serious adverse 
events, clinical laboratory measures, and vital signs. In 
particular we will measure CBC’s with differential at Week 
-3 and Week 12 and CMP at Week -3 and Week 12.  
 
Pharmacodynamic 
Outcome Measures 
 
PD parameters will be assayed using the blood basophil IgE 
receptor flow based assay. This assay was successfully used 
in multiple past omalizumab studies.  
Exploratory Endpoints 
 
1) Basophil surface IgE, FcεRI and Syk by flow cytometry- 
Day 0, 1, 3, 6, 10, 20, 30 and 90 days 
 
2) Dendritic cell surface IgE, FcεRI -Day 0, 1, 3, 6, 10, 20, 30 
and 90 days 
 
3) Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated 
histamine release along with sensitivity measures- Day 0, 1, 
3, 6, 10, 20, 30 and 90 days 
  
4) Serum free IgE measures (stored serum) Day 0, 1, 3, 6, 10, 
20, 30 and 90 days 
 
5) Characterization of presence of serum autoantibody 
presence ± Syk inhibitors -Day 0, 1, 3, 6, 10, 20, 30 and 90 
days 
 
6) Basophil enumeration by manual counting and blood 
histamine content - Day 0, 1, 3, 6, 10, 20, 30 and 90. This will 
determine the presence or absence of basopenia and 
identify subjects for mRNA profiling studies.  
 
7) Basophil mRNA profiling baseline at 3 timepoints 
(baseline, meaningful clinical changes, and 30 days) in 
select subjects with sufficient basophil numbers ( >1.5x 
106/100 cc blood) 
 
8) Numbers of IgE +, FcεRI + cells in non-lesional skin 
biopsies at day 0, 6, 90  to monitor skin mast cells well as 
the MrgX2 receptor expression  


Protocol 
 
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Omalizumab in CIU 
 May 29, 2019 
 
  
 
9) Change in circulating leukocyte population numbers that 
are targeted by omalizumab such as blood basophils, 
eosinophil and lymphocyte counts by automated analysis 
(week -3 to week 12).  
 
10) Change in urine prostaglandins and eicosanoids 
pretreatment ( Days-21, -14,  0,) relative to post-treatment 
timepoints 1, 3, 6, 10, 20, 30 and 90. 
Inclusion Criteria 
Male or female, ages 18 years or older 
 
Females must be surgically sterile or postmenopausal or using a 
highly effective form of birth control throughout the duration of 
the study such as an oral contraceptive, or double barrier method 
contraception condom with spermatocide or IUD.  Females in 
certain categories (not sexually active, vasectomized partner, 
tubal occlusion) will be admitted at the discretion of the 
investigator on a case-by-case basis.   
  
Females must have a negative urine pregnancy test at screening 
and other visits specified in this protocol unless documented to 
have a hysterectomy or be postmenopausal. 
 
Clinical history of CIU at the time of screening, as defined by 
pruritus and hives for > 3 days in a 7-day period for > 6 
consecutive weeks despite treatment with H1 antihistamine. 
 
CIU diagnosis > 3 months (by history) 
 
No underlying etiology clearly defined for urticaria (main 
manifestation cannot be physical urticaria). 
 
Non-diary based UAS scores ≥ 2 at either the screening visit 
(Week -3), at the run-in visit (Week -2), or on Day 1. 
 
A diary-based UAS7 score ≥ 16 established during the screening 
or run-in periods despite stable doses of H1 antihistamine. 
 
Compliance with study procedures during run-in period (e.g., 
completion of the study diary). 
 


Protocol 
 
          Version 1.3                                                      Page 7 of 80 
 
 
Omalizumab in CIU 
 May 29, 2019 
 
  
Exclusion Criteria 
Pregnant females, confirmed by a positive Human Chorionic 
Gonadotropin (HCG) test, or females with plans to become 
pregnant or breastfeed during the duration of the study.  
 
Recent history of drug or alcohol abuse (within 3 years prior to 
screening visit). 
 
Inability or unwillingness of a participant to give written informed 
consent or comply with study protocol. 
 
Use of any investigational drugs within 30 days of screening.  
 
Active atopic dermatitis or other skin disease associated with 
pruritus during the time of the study, which require treatment 
with topical corticosteroids. 
 
Clinically relevant major systemic disease (making interpretation 
of the study results difficult) including a history of anaphylaxis.  
 
Inability to comply with study and follow-up procedures 
 
Patients may not take during treatment period or have been taking 
within the past one-month any of the following 
medications/treatments: regular (daily/every other day) 
hydroxychloroquine, sulfasalazine, dapsone, methotrexate, 
cyclosporin, IVIG, or other monoclonal antibody therapies. 
 
Patients may not take doxepin during screening, run-in, or 
treatment period or have been taking doxepin within the past 2 
weeks regularly (daily/every other day) prior to screening.  
 
Patients may not use cutaneous corticosteroid (intranasal, inhaled, 
and ophthalmic steroids are permitted) during the screening, run-
in, or treatment phases.  
 
Patients may not use oral or systemic steroids during the study or 
within 4 weeks prior to enrollment. 
 
Patients may not take H2 antihistamines and leukotriene receptor 
antagonists within 7 days before screening, during the screening, 
run-in, or treatment phases. The exception will be if they are 
already on these medications for the treatment of GERD, asthma 
or allergic rhinitis. 
 
Contraindications to diphenhydramine 
 
Any clinically relevant abnormal findings in clinical chemistry, 
hematology, physical examination, pulse, blood pressure at 
baseline, which, in the opinion of the investigator, could put the 
patient at risk because of his/her participation in the study. 
 
Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, 


Protocol 
 
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Omalizumab in CIU 
 May 29, 2019 
 
  
in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s 
ability to comply with study requirements or may compromise the 
quality of the data obtained from the study. 
Safety Plan 
 
Patient will be instructed to recognize the signs and symptoms of 
any severe hypersensitivity reaction, and to contact a healthcare 
provider in case of any such symptoms. All will be provided with 
an epipen as per usual standard of care with omalizumab 
recipients.  
 
Patients with CIU can have angioedema as part of their 
symptoms. When that angioedema poses a risk to the airway, the 
emergent use of systemic corticosteroids is indicated. Patients 
who require treatment with systemic corticosteroids will be 
discontinued from the study and followed for safety assessment 
for the remainder of the study. Patients will be provided 
emergency contact information and advised to contact a 
physician during the entire trial, in case of angioedema.  
 
Safety data including laboratory tests will be reviewed internally 
on a periodic basis during the conduct of the study. 
 


Protocol 
 
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Omalizumab in CIU 
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Investigational 
Product(s)/Intervention(s), 
Dosage and Mode of 
Administration 
Patients will receive the study drug (Omalizumab) which is 
supplied by the manufacturer and is administered 
subcutaneously as the per package insert. 
 
Study Procedures 
Phlebotomy; Skin biopsies. 
Statistical Considerations 
Our plan is to look at multiple cellular parameters in 
Omalizumab treated patients and relate cellular changes to 
the timing of the MID for itch (>5 points) or hives (> 5 
points) with the primary outcome being the percentage of 
patients achieving a 50% rise in basophil anti-IgE functions 
at the time of reaching a clinical MID.  
 
 
. 
 
 
 


Protocol 
 
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Omalizumab in CIU 
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Table of Contents 
  
PROTOCOL SYNOPSIS ........................................................................................................ 1 
1. 
BACKGROUND AND RATIONALE ................................................................ 17 
1.1 
BACKGROUND ................................................................................................................... 17 
1.2 
RATIONALE FOR SELECTION OF STUDY POPULATION ....................................... 19 
1.3 
INTERVENTION(S) ............................................................................................................. 19 
1.4 
RATIONALE FOR SELECTION OF INTERVENTION(S) AND REGIMEN .............. 20 
1.4.1 
Clinical Studies ..................................................................................................................... 20 
1.5 
RISKS ..................................................................................................................................... 21 
1.5.1 
Risks of Investigational Product(s)/Intervention(s) ....................................................... 21 
1.5.2 
Risk of Study Procedures .................................................................................................... 21 
1.5.3 
Risk of Concomitant Medications, Prophylactic Medications and Rescue Medications 
 
 ......................................................................................................................................... 22 
1.6 
BENEFITS .............................................................................................................................. 22 
1.6.1 
Benefits of Intervention(s) ................................................................................................... 22 
2. 
OBJECTIVES ....................................................................................................................... 23 
2.1 
PRIMARY OBJECTIVE(S) ................................................................................................... 23 
2.2 
SECONDARY OBJECTIVE(S) ............................................................................................ 23 
2.3 
EXPLORATORY OBJECTIVE(S) ........................................................................................ 24 
3. 
STUDY DESIGN .................................................................................................... 25 
3.1 
STUDY ENDPOINTS ........................................................................................................... 27 
3.1.1 
Primary Endpoint(s) ............................................................................................................ 27 
3.1.2 
Secondary Endpoint(s) ........................................................................................................ 27 
3.1.3 
Exploratory Endpoint(s) ..................................................................................................... 28 


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Omalizumab in CIU 
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3.2 
STUDY COMPLETION ....................................................................................................... 28 
4. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ............................ 29 
4.1 
INCLUSION CRITERIA ...................................................................................................... 29 
4.2 
EXCLUSION CRITERIA ..................................................................................................... 29 
4.3 
PARTICIPANT WITHDRAWAL CRITERIA ................................................................... 30 
4.4 
PARTICIPANT WITHDRAWAL FROM STUDY ........................................................... 31 
5. 
INTERVENTION MATERIAL(S), OTHER STUDY PRODUCTS 
(CONTROLS/PLACEBOS) ................................................................................... 32 
5.1 
INTERVENTION(S) ............................................................................................................. 32 
5.2 
FORMULATION, PACKAGING, AND LABELING ...................................................... 32 
5.3 
PREPARATION, ADMINISTRATION, AND DOSAGE ............................................... 32 
5.4 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT(S)/INTERVENTION(S)32 
5.5 
ASSESSMENT OF COMPLIANCE WITH INTERVENTION MATERIAL(S) ............ 33 
5.6 
DISCONTINUATION OF INTERVENTION MATERIAL(S) ....................................... 33 
6. 
OTHER MEDICATIONS ..................................................................................... 34 
6.1 
CONCOMITANT MEDICATIONS ................................................................................... 34 
6.2 
PROPHYLACTIC MEDICATIONS ................................................................................... 34 
6.3 
RESCUE MEDICATIONS ................................................................................................... 34 
6.4 
PROHIBITED MEDICATIONS .......................................................................................... 34 
7. 
STUDY VISITS AND PROCEDURES ............................................................... 35 
7.1 
ENROLLMENT AND RANDOMIZATION .................................................................... 35 
7.2 
SCREENING VISIT(S) ......................................................................................................... 35 
7.3 
MAIN STUDY VISIT(S) ....................................................................................................... 36 
7.4 
VISIT WINDOWS ................................................................................................................ 41 
8. 
SAFETY PROCEDURES ....................................................................................... 42 


Protocol 
 
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8.1 
STOPPING RULES ............................................................................................................... 42 
8.1.1 
Study Stopping Rules .......................................................................................................... 42 
8.1.2 
Individual Stopping Rules .................................................................................................. 42 
8.1.3 
Additional Study Procedures ........................................... Error! Bookmark not defined. 
8.1.4 
Premature Discontinuation of Investigational Product(s)/Intervention(s) with    
continued study participation/follow-up ........................................................................ 42 
8.1.5 
Premature Termination Follow-up .................................................................................... 42 
8.1.6 
Participant Replacement ..................................................................................................... 42 
8.2 
ADVERSE EVENTS ............................................................................................................. 43 
8.2.1 
Adverse Event Definition ................................................................................................... 43 
8.2.2 
Serious Adverse Event (SAE) Definitions ........................................................................ 43 
8.2.3 
‘Expected’ verses ‘Unexpected’ Adverse Event Definition ........................................... 44 
8.3 
MANAGEMENT OF ADVERSE EVENTS ....................................................................... 44 
8.3.1 
Collecting Procedure ........................................................................................................... 44 
8.3.2 
Recording and Reporting Procedure ................................................................................. 45 
8.3.2.1 Notifying the Medical monitor ............................................................................................... 45 
8.3.2.2 Notifying the Institutional Review Board .............................................................................. 45 
8.3.3 
Grading and Attribution ........................................................................................................ 45 
8.3.3.1 Grading criteria ...................................................................................................................... 45 
8.3.3.2 Definition of Attribution ........................................................................................................ 46 
8.4 
MANAGEMENT OF SERIOUS ADVERSE EVENTS ..................................................... 47 
8.4.1 
SAE Collecting Procedure ................................................................................................... 47 
8.4.2 
SAE Recording and Reporting Procedure ........................................................................ 47 
8.4.2.1 Reporting Pregnancy .............................................................................................................. 47 


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8.4.2.2 Unexpected, Non-Serious Adverse Events ............................................................................. 48 
8.4.2.3 SAE Reporting Criteria and procedures ................................................................................. 48 
8.4.2.4 Notifying the medical monitor ................................................................................................ 48 
8.4.2.5 Notifying the Institutional Review Board .............................................................................. 48 
8.5 
Protocol Deviations ................................................................................................................. 49 
8.5.1 
Protocol Deviation Definition ............................................................................................ 49 
8.5.2 
Management of Protocol Deviations ................................................................................. 49 
8.5.2.1 DETECTING PROTOCOL DEVIATIONS ......................................................................... 49 
8.5.2.2 reporting protocol deviations .................................................................................................. 49 
9. 
SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN .................... 50 
9.1 
SAMPLE SIZE AND POWER CALCULATIONS ........................................................... 50 
9.2 
DATA ANALYSIS ................................................................................................................ 51 
9.2.1 
Study Participant Baseline Characteristics and Demographics .................................... 51 
9.2.2 
Primary Endpoint Analysis ................................................................................................ 51 
9.2.3 
Secondary Endpoint Analyses ........................................................................................... 51 
9.2.4 
Exploratory Endpoint Analyses ......................................................................................... 52 
9.2.5 
Safety Analysis ..................................................................................................................... 53 
9.2.6 
Pharmacodynamic Data Anaylses ..................................................................................... 53 
9.2.7 
Medical History .................................................................................................................... 53 
9.2.8 
Medication Use ..................................................................................................................... 53 
9.2.9 
Study Completion ................................................................................................................ 54 
9.3 
INTERIM ANALYSES ......................................................................................................... 54 
9.4 
DEVIATIONS FROM STATISTICAL PLAN ................................................................... 54 
10. 
IDENTIFICATION AND ACCESS TO SOURCE DATA ............................... 55 


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10.1 
IDENTIFYING SOURCE DATA ........................................................................................ 55 
10.2 
UPDATING SOURCE DOCUMENTATION ................................................................... 55 
10.3 
PERMITTING ACCESS TO SOURCE DATA .................................................................. 55 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 56 
12. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE .......................................................................................... 57 
12.1  
STATEMENT OF COMPLIANCE ..................................................................................... 57 
12.2  
INFORMED CONSENT AND ASSENT ........................................................................... 57 
12.3 
PRIVACY AND CONFIDENTIALITY .............................................................................. 57 
13. 
REFERENCES ......................................................................................................... 58 
List of Appendices  
Appendix 1: Schedule of Events ........................................................................................................... 63 
Appendix 2: Patient Diary ................................................................................................................... 66 
Appendix 3: In Clinic UAS ................................................................................................................. 71 
Appendix 4: Serious Adverse Event Report Form ............................................................................... 73 
Appendix 5: Skindex ............................................................................................................................ 77 
Appendix 6: Protocol Deviation Form ................................................................................................. 80 
 
 


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Glossary of Abbreviations  
AE 
Adverse Event 
BHR 
Basophil Histamine Release 
BID 
Two Times a Day 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CIU 
Chronic Idiopathic Urticaria 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
FEV1 
Forced Expiratory Flow in 1 Second 
G6PD 
Glucose-6-phosphate Dehydrogenase 
GCP 
Current Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroid 
INR 
International Normalized Ratio 


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IRB 
Institutional Review Board 
IVIG 
Intravenous Immunoglobulin 
LABA 
Long-Acting-beta-2-Agonists 
LDH 
Lactate Dehydrogenase 
MAO 
Monoamine Oxidase 
MOP 
Manual of Operations 
PD 
Pharmacodynamic 
PEF 
Peak Expiratory Flow 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
QD 
Once a Day 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TID 
Three times a Day 
UAS 
Urticaria Activity Score 
ULN 
Upper Limit of Normal 


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BACKGROUND AND RATIONALE 
Background 
Overview of CIU 
Episodes of urticaria affect up to 25% of the US population during their lifetime (1, 2). While 
many short-lived, urticarial reactions have identifiable causes such as allergens or infections, 
there is a large class of reactions for which the underlying cause is unknown (3). Recurrent 
urticaria for greater than 6 weeks is termed chronic urticaria (CU), and in the vast majority of 
cases (>90%) no trigger is found and thus is termed chronic idiopathic urticaria (CIU). The 
annual prevalence of CIU is approximately 1% (4, 5).  CIU is a widely recognized disorder in 
multiple continents (North America, Asia, Europe) and multiple disease guidelines have been 
issued in these various regions supporting the global burden of this ailment (6-9). CIU also 
affects both children and adults and nearly twice as many females in the adult population (4, 
10-14). Although CIU skin reactions are rarely life-threatening and are limited in duration for an 
average of 2-3 years in 80% of cases, the pruritus that accompanies the disease has an impact on 
quality of life that is similar to heart disease (15). 
Mechanisms active in CIU  
 It is well-accepted that CIU subjects suffer from recurrent episodes of hives virtually anywhere 
on body that are extremely pruritic and related to excessive histamine presence in the skin (16). 
The pathology observed in CIU lesional skin biopsies, is of mast cells that are degranulated and 
presence of skin infiltrating basophils, and blood basopenia (17, 18). However, the identifiable 
triggers for these two cells remain unknown. The skin pathology in CIU lesions closely 
resemble that found in skin biopsies of allergen triggered skin late-phase reactions but lacks an 
identifiable trigger (19, 20). Over the last decades, two theories have been explored for the cause 
of this condition. The first suggests an autoimmune trigger for either mast cells or basophils and 
the second focuses on the cell that might be controlling the reaction, the mast cell or the 
basophil. In the 1980s it was noted that there was a higher frequency of thyroid autoantibodies 
among CIU patients as compared to the normal population (21). This observation gave rise to 
the idea that autoimmunity may also be a trigger for CIU lesions given the absence of external 
triggers. Subsequently, a subset of CIU patients was identified with circulating IgG anti-IgE (5-
10% of patients) or anti-FcεRI antibodies  (35-40 % of patients) (22, 23). This seemed a 
remarkable discovery since either type of antibody could be the trigger for driving secretion 
from either mast cells or basophils. However, additional studies have raised a number of issues 
with this explanation such as (3, 24): 1) the lack of specificity of autoantibodies for CIU given 
that such IgG antibodies occur in other skin diseases, SLE, RA and healthy subjects 2) antibody 
titers are stable in remission and do not follow disease symptoms 3) the lack of distinct clinical 
phenotype, skin biopsy, or therapeutic response in those with autoantibodies 4) the lack of a 
standardized autoantibody detection assay despite nearly two decades of work. The success of 
omalizumab (Xolair, anti-IgE antibody) therapy in CIU patients provides support that this 
disease depends on IgE dependent pathways. However, the clinical response kinetics to 
omalizumab therapy did not differ among the subset of CIU subjects (25-30%) with serologic 
evidence of functional autoantibodies (CIU Index assay-basophil histamine release assay), 
raising questions about the pathogenic role of such autoantibodies (25-27). The second area of 


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interest is the role of the basophil (28).  The blood basophil is selectively recruited to the skin 
lesions of CIU patients and is capable of secreting histamine that can drive the skin reaction, yet 
it is hard to reconcile with the long-standing view that the skin mast cell drives the disease (29). 
But studies have shown that IgE-mediated basophil reactivity tracks well with the remissions 
and exacerbations of this disease (30-32). We have identified 2 patterns of basophil reactivity 
based on the degree of histamine release after optimal IgE receptor activation: CIU-non-
responders (CIU NR) which release less than 10% of total cellular content and CIU-responders 
(CIU-R) which release greater than 10% of histamine content (33). We have established the 
stability of these 2 functional phenotypes in active disease and improvement with disease 
remission (30, 32).  Blood basopenia is a unique feature of this disorder since it was first 
reported in the 1960’s (34). Evidence also exists that blood basopenia is related to disease 
severity and improves with symptom improvement and in remission (31, 32, 35). Indeed, the 
concordance between basophil functionality and the disease is far better than the relationship 
between the presence of autoantibodies and disease (30). Further, systemic corticosteroids 
rapidly suppress CIU disease symptoms and all classes of basophil mediators release, but not 
skin mast cell degranulation.  Systemic corticosteroids therapy leads to a rise in blood basophil 
numbers in CIU whereas in normal subjects basophil numbers fall (35), favoring the idea that 
steroids impair basophil migration to the CIU skin lesions.  
 
While skin mast cell degranulation is generally accepted in CIU, the trigger remains unclear. 
Evidence supports that skin mast cell numbers are not increased in skin biopsies (18, 36-38) and 
serum tryptase levels, an indicator of total body mast cell number, are within the normal range 
(39, 40). Older studies support that increased skin mast cell releasability to stimuli such as 48/80 
and codeine (41, 42) occurs in CIU. Recently, MrgX2 has been identified as the receptor for 
numerous stimuli (48/80, codeine, and multiple drugs) on human and murine mast cells (43). A 
recent report has identified increased MrgX2 in skin mast cells in CIU(38). 
 
Without a clear mechanism or knowledge of the principle cell type responsible for CIU disease, 
treatments are relegated to symptomatic relief (44). The purpose of this proposed research is to 
determine what cell type(s) strongly influence expression of this disease. This will be done by 
using an observation made possible by the recent introduction of omalizumab, a monoclonal 
IgG anti-IgE therapeutic antibody, into the treatment regimen for CIU (25-27, 45). 
 
Omalizumab therapy in CIU 
 
Omalizumab has shown success in H1 refractory CIU cases and was approved by the FDA in 
April 2014 for this indication. It has undergone 3 Phase III studies that support a fixed dose of 
150 mg or 300 mg every 4 weeks is effective in 70% of anti-histamine refractory CIU recipients 
(25-27). However, it carries the high costs of a biologic agent, requires subcutaneous injection in 
a physician’s office, and requires an EpiPen prescription due to the risk of drug-related 
anaphylaxis of 0.2%. The efficacy of omalizumab therapy in CIU has raised questions as to the 
role of IgE in this non-allergic skin disease. A recent study has shown changes in blood 
basophils but not skin mast cells at an early timepoint associated with clinical symptom 
improvement. The results for omalizumab have been surprising. The surprise occurs at two 
levels, first, that an anti-IgE therapeutic would have such dramatic effects in this disease and 
second, that the effects occur so rapidly (25-27, 45, 46).  
 
Results from the 3 Phase III studies in CIU provide evidence that a meaningful change in 
symptoms is apparent at 1-2 weeks (25-27). Based on pooled Phase III trial data, approximately 


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70% of CIU subjects treated with 300 mg/month omalizumab for 12 weeks will have a 70% 
reduction in their pretreatment UAS7 (Urticaria Activity Score for 7 days: scale is 0-3 for itch 
and 0-3 for number of hives; maximal daily score is 6 (average of AM and PM scores), and 
maximum UAS7 is 42); 60% will have an 80% reduction in symptoms (UAS7< 6), and 40% are 
fully asymptomatic (UAS7=0) (47). The MID (Minimal Important Difference) is achieved by 
70% of patients by 2 weeks in patients on multiple drugs for hives versus a median time of 4-5 
weeks on placebo injections (26). Therefore, this protocol is designed to make an assessment of 
the clinical symptoms at a high frequency in the early 2 weeks during treatment along with the 
blood and skin tissue biopsy studies. 
 
Current approaches to CIU per guidelines and unmet needs 
Based on recent guidelines, Omalizumab is the only FDA-approved adjunctive agent beyond 
first-line oral, non-sedating antihistamines (48). This is important because up to 50% of patients 
fail to respond to a non-sedating oral antihistamine (49).  Current guideline recommended add-
on therapies include H2 blockers, leukotriene receptor antagonists, older generation sedating 
antihistamines (48). In more severe CIU cases, systemic steroids are recommended and in 
steroid-dependent cases, there are several other agents that have been reported to be beneficial 
such as cyclosporine, sulfasalazine, dapsone, plaquenil, and mycophenolate mofetil but all carry 
significant toxicities and require frequent, costly laboratory monitoring (CBC, renal function, 
G6PD)(50, 51).  Thus, there is an unmet need to improve the understanding of the pathogenesis 
of CIU to lead to improved, less toxic therapies.   
  
Rationale for Selection of Study Population  
Results from the 3 Phase III studies in CIU provide evidence that a meaningful change in 
symptoms is apparent at 1-2 weeks (25-27). The MID (Minimal Important Difference) is 
achieved by 70% of patients by 2 weeks in patients on multiple drugs for hives versus a median 
time of 4-5 weeks on placebo injections (26). Therefore, this protocol is designed to make an 
assessment of the clinical symptoms at a high frequency in the early 2 weeks during treatment 
along with the blood and skin tissue biopsy studies. The goal is to identify which cell type(s) 
strongly influence expression of this disease using a monoclonal therapeutic anti-IgE antibody 
that is FDA approved in CIU subjects not controlled on treatment with anti-histamines.  
Intervention(s)  
Omalizumab is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that 
selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of 
approximately 149 kiloDaltons. Xolair is produced by a Chinese hamster ovary cell suspension 
culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable 
in the final product.  


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Rationale for Selection of Intervention(s) and Regimen  
 
We propose a single-site study with 12 weeks of open label therapy with omalizumab 300 
mg/month with no placebo arm. We favor the higher dose of approved drug given it’s faster 
onset of clinical benefit and open label therapy to gain the greatest possible participation from 
eligible subjects given the widespread knowledge of the efficacy of omalizumab in CIU. 
Omalizumab is currently FDA approved, and a standard of care option for patients who have 
anti-histamine refractory urticaria. We propose to treat for 12 weeks as there is ample evidence 
for clinical benefit within this time frame and the likelihood to impact skin mast cell IgE 
receptors expression based on prior studies  after 8 weeks (52). 
This is a study of the kinetics of clinical symptom relief during treatment with omalizumab of 
patients with chronic idiopathic urticaria. The purpose is to determine whether the rate of 
clinical remission is concordant with the rate that IgE-dependent functions of basophil change 
during treatment. In addition, skin mast cell expression of FcεRI and IgE in the non-lesional 
skin will be monitored to determine if the rate of change in these two parameters is consistent 
with prior measurements (52) or uniquely faster in these individuals. Previous studies of 
omalizumab therapy in CIU have not examined the changes in cellular functions with a 
temporal granularity being proposed in this study. Notably, the earliest assessment of basophil 
functions in previous studies occurred at 1 month, a time point in which basophil function has 
generally decreased in most patients (53). We are interested in judging whether the kinetics for 
early clinical symptoms matches the changes to the blood basophil phenotype. 
Other IgE-bearing cell types known to be impacted by omalizumab treatment include the 
peripheral blood dendritic cell. We have previously shown that these cells change in allergic 
patients in a time-frame similar to basophils. IgE receptor function of dendritic cells includes 
impacting their ability to release various cytokines induced by toll receptor activation. To date, 
TLR9 receptors activation of pDCs is impaired in subjects with CIU(54). 
 
In addition, we will examine whether IgE receptor alteration of skin mast cells via omalizumab 
has an impact on MrgX2 expression. Our proposed hypothesis is that omalizumab in CIU will 
reduce IgE levels and IgE receptor bearing leukocyte expression in a time dependent fashion 
with clinical symptom improvement and most rapidly on those cells (basophils) implicated in 
disease pathogenesis thus reducing the signs and symptoms in CIU refractory to control with 
antihistamines.  
 
Clinical Studies  
Omalizumab has undergone extensive clinical trials in subjects with allergic asthma and chronic 
idiopathic urticaria. It is currently FDA approved for both of these indications with allergic 
asthma approval occurring in 2003 and CIU in 2014.  In the clinical studies completed in 
subjects with chronic uriticaria, omalizumab was generally well tolerated(25-27). Dose ranging 
studies identified that flat dosing schedule was efficacious with maximal efficacy seen at 300 mg 
as compared to either a single dose of 75 mg or 600 mg.  The clinical efficacy of omalizumab in 
CIU has been evaluated in 3 phase III randomized, double-blind, placebo-controlled studies. 
Two of the studies evaluated CIU subjects on standard dosed antihistamines with doses of 75 


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mg, 150 mg and 300 mg injected every 4 weeks for either 12 or 24 weeks. The third study tested 
only the 300 mg dose or placebo injection every 4 weeks for 24-week studies in patients 
refractory to usual CIU care per guidelines (up to 4 –fold standard dose of non-sedating 
antihistamines, ± H2 blocker, ± leukotriene receptor antagonists.).  All three studies 
demonstrated efficacy in reducing the UAS7 score and weekly itch score. Differences between 
treatment groups for secondary variables (weekly hive score, angioedema) also favored either 
the 150 mg or 300 mg dose of omalizumab . As per the PI, the mechanism of action, besides 
lowering IgE receptors through binding of IgE, remains unknown.  
Risks 
Risks of Intervention(s)  
Omalizumab:  In CIU patients ≥12 years of age, the most commonly observed adverse 
reactions: from 3 placebo-controlled CIU studies for omalizumab 150 mg and 300 mg, 
respectively, were: headache (12%, 6%), nasopharyngitis (9%, 7%), arthralgia (3%, 3%), viral 
upper respiratory infection (2%, 1%), nausea (1%, 3%), sinusitis (1%, 5%), upper respiratory 
tract infection (1%, 3%), and cough (1%, 2%). Injection site reactions of any severity occurred 
during the trials in more omalizumab treated patients;[2.7%] at 300 mg, [0.6%] at 150 mg) 
compared with 0.8% in  placebo-treated patients.  
 
Anaphylaxis has been reported to occur after administration of omalizumab in asthma clinical 
trials and in postmarketing spontaneous reports. The frequency of anaphylaxis was estimated 
to at least 0.2%. A case-control study showed that among XOLAIR users, patients with a history 
of anaphylaxis to foods, medications, or other causes were at increased risk of anaphylaxis 
associated with XOLAIR, compared to those with no prior history of anaphylaxis. Based on this, 
AAAAI guidelines support monitoring patients for 2 hours for the first 3 injections of xolair and 
the prescription of an epipen injector.  
 
Malignant neoplasms were observed in 20 of 4127 (0.5%) omalizumab treated patients 
compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents (≥12 
years of age) with asthma and other allergic disorders. The observed malignancies in XOLAIR-
treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, 
and parotid occurring more than once, and five other types occurring once each. A subsequent 
5-year observational study of 5007 XOLAIR-treated and 2829 non- XOLAIR -treated patients 
with moderate to severe persistent asthma and a positive skin test reaction or in vitro reactivity 
to a perennial aeroallergen found that the incidence rates of primary malignancies (per 1000 
patient years) were similar in both groups (12.3 vs 13.0, respectively) ( Package Insert).   
 
Risk of Study Procedures  
Phlebotomy: pain, bruising, infection, light-headedness and fainting.  The American Red Cross 
recommends that no more than 480 mL of blood be donated in a 2 month time period.  The 
maximum blood that would be drawn in a 2-month period in the primary outcome study is 436 
mL over 9 separate blood draws, whereas the total volume drawn is 515 over 90 days.  At no 


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time will Red Cross guidelines be exceeded.  Further, CBCs will be drawn at baseline for safety 
monitoring and at the end of week 12.  
Skin biopsy: Risks of skin punch biopsy include pain, swelling, bleeding, bruising, infection, and 
scarring at the site of the biopsy.  Allergic reactions to lidocaine are rare, but may cause hives, 
itching, asthma, hay fever, or a drop in blood pressure.  Significant bleeding from biopsy sites is 
rare.  Infection of a biopsy site is unusual, but may occur.  A scar the size of a pencil eraser will 
result at the biopsy site.  This scar will be slightly raised or depressed below the surface of the 
skin and will be a little lighter or darker than the rest of your skin. 
Risk of Concomitant Medications, Prophylactic Medications and Rescue 
Medications  
Antihistamines (concomitant medications allowed during study) may cause sedation, 
dizziness, coordination problems, and dried mucous membranes. 
 
Diphenhydramine (Rescue medication) may cause sedation. 
 
Epipen  (Rescue medicine). The most common side effects include increase in heart rate, 
stronger or irregular heartbeat, sweating, nausea and vomiting, difficulty breathing, paleness, 
dizziness, weakness or shakiness, headache, apprehension, nervousness or anxiety. These side 
effects usually go away quickly. 
Benefits of Intervention(s)  
The patients treated with omalizumab are expected to experience decreased urticarial 
symptoms. These benefits are not expected to be maintained after treatment discontinuation.  
The benefits may begin at any point during treatment. There are no known benefits of the study 
procedures in the general population or in subjects with CIU. 


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OBJECTIVES 
Primary Objective(s)  
This is a study of the kinetics of clinical symptom relief during treatment of patients with CIU 
with omalizumab. The purpose is to determine if the rate of clinical remission is concordant 
with the rate that IgE-dependent functions of basophil change. We propose as the primary 
outcome as the time for change in the functional response from baseline of basophil in vitro 
anti-IgE for histamine release (defined as a 2-fold rise at suboptimal concentrations of anti-IgE) 
relative to the time to reach MID of > 5 point change in either itch of hive. We expect subjects 
with baseline basophil CIU-NR (non-responder) phenotype to become Responders and baseline 
Responder phenotype to demonstrate a rise the in suboptimal anti-IgE response.  
 
Secondary Objective(s)  
1.Change in the weekly pruritus score from baseline to the 12th week in the treatment 
period. The pruritus score will be measured twice daily (a.m. and p.m.), on a scale of 0 
(none) to 3 (intense). The weekly pruritus score is the sum of average daily pruritus 
scores over the previous 7 days. 
 
2. Change in the weekly score for number of hives from baseline to the 12th week in the 
treatment period. The number of hives is measured twice daily (a.m. and p.m.), on a 
scale of 0 (none) to 3 (> 12 hives, see below). The weekly score of number of hives is the 
sum of the average daily scores over the previous 7 days. 
 
Scoring for Wheals 
0= None 
1= Mild 1-6 hives/12 hours 
2= Moderate 7-12 hives/12 hours 
3= Severe > 12 hives/12 hours 
 
Scoring for Itch 
0= None 
1= Mild 
2= Moderate 
3= Severe 
 
 
3. Change in the amount of rescue medication (diphenhydramine 25 mg) from baseline 
to the 12th week in the treatment period using the question on the rescue medication use 
in the patient diary. 
 
4. Change in SKINDEX29 quality of life survey instrument with 29 questions on a 5-
point Likert will be given at baseline and again at 90 days. 
 


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Exploratory Objective(s) 
1) Change in basophil surface IgE, FcεRI and Syk by flow cytometry- Day 0, 1, 3, 6, 10, 
20, 30 and 90 days 
 
2) Change in Dendritic cell surface IgE, FcεRI -Day 0, 1, 3, 6, 10, 20, 30 and 90 days 
 
3) Change in Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated histamine along with 
sensitivity measures- Day 0, 1, 3, 6, 10, 20, 30 and 90 days 
  
 
4) Serum free IgE measures -(stored serum) Day 0, 1, 3, 6, 10, 20, 30 and 90 days 
 
5) Characterization of presence of serum autoantibody presence ± Syk inhibitors -Day 0, 
1, 3, 6, 10, 20, 30 and 90 days 
 
6) Basophil enumeration by manual counting and blood histamine content - Day 0, 1, 3, 
6, 10, 20, 30 and 90 days. This will determine the presence or absence of basopenia and 
identify subjects for mRNA profiling studies.  
 
7) Basophil mRNA profiling baseline at 3 timepoints (baseline, meaningful clinical 
changes, and 30 days) in select subjects with sufficient basophil numbers 
 
8) Numbers of IgE +, FcεRI + cells in non-lesional skin biopsies at day 0, 6, 90 to monitor 
skin mast cells well as the MrgX2 receptor expression  
 
9) Change in circulating leukocyte population numbers that are targeted by omalizumab 
such as blood basophils, eosinophil and lymphocyte counts by automated analysis 
(week -3 and week 12).  
 
10) Measurement of urine prostaglandins and eicosanoids at Day -14,  0, 1, 3, 6, 10, 20, 30 
and 90. 
 


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STUDY DESIGN  
This is a Phase IV, single-center, open-label 12 week omalizumab treatment study of CIU 
subjects refractory to standard of care to examine to identify disease relevant IgE bearing cells 
that are altered concordant with the onset of clinical symptom relief .  CIU patients will 
receiving open-label treatment with omalizumab at the current FDA-approved dose of 300 
mg/month for 12 weeks. We favor this approach to gain the greatest participation from eligible 
subjects given the widespread knowledge of the efficacy of omalizumab in CIU. Results from 
the 3 Phase III studies in CIU provide evidence that a meaningful change in symptoms is 
apparent at 1-2 wks. The MID (Minimal Important Difference) is achieved by 70% of patients 
by 2 wks on multiple background drugs for hives. All subjects will have CIU for 3 months, and 
will be age 18 or older. All subjects will have a baseline UAS score of 2 or greater despite 
treatment with daily doses of non-sedating H1 antihistamines. The UAS is a composite score of 
pruritus (0-3) and hives (0-3) with a maximum value of 6. This study will include a 2-week run-
in. The study will enroll 30 patients. 
 
 
  Figure 1: Study Schema 
 
The study will enroll 30 patients and will consist of three phases. 
 
Screening (Day -21 to day -14) 


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During the screening period, each patient’s eligibility for the trial will be established. To 
be eligible at the screening visit (Week -3), patients: 
 
Must have a non-diary based daily urticaria activity score (UAS) score ≥ 2 established in the 
outpatient setting based on the patient’s condition over 12 hours prior to the visit; the UAS is a 
composite score of pruritus (0–3) and number of hives (0–3) with a maximum value of 6. This 
requirement may be met either at screening day, run-in visit (Day -14), or Day 0. 
 
Must have been on an approved dose of an H1 antihistamine for CIU such as loratadine 10 mg 
once a day or equivalent, for at least 7 days prior to the screening visit. Approved agents 
include loratadine 10 qd, desloratadine 5 mg qd, fexofenadine 180 mg qd, cetirizine 10 mg qd or 
levocetirizine 5 mg qd as once daily medications at the current FDA-approved dose. If 
necessary for symptom control, per international guidelines, patients who use up to 4-fold the 
standard daily dose will be allowed in the study. 
 
Must be willing to fill out a twice-daily patient-diary to establish the patient’s Urticaria Activity 
Score 7 (UAS7) score. The UAS is a composite diary- recorded score with numeric severity 
intensity ratings (0 = none to 3 = intense) for 1) the number of wheals (hives); and 2) the 
intensity of the pruritus (itch). The UAS7 is the sum of the daily average UAS scores (average of 
a.m. and p.m.) for 7 days. The maximum UAS7 value is 42.  
 
 
Run-in (Day -14  to Day 0)   
 
To be eligible to begin the run-in period (Day -14 to 0), patients: 
 
Must have a UAS7 score ≥ 16 established in the screening week or subsequent run-in period. 
 
Must remain on stable dose of a single H1 antihistamine at approved dose (not including 
antihistamine rescue medication) as established at the screening visit.  
 
During the run-in period, patients will establish their baseline symptom scores using the 
diary. Patients with a diary-based UAS7 symptom score ≥ 16 during the screening or 
run-in periods  will be eligible to enter the 12-week open label treatment period.  The 
baseline UAS7 score at time of drug treatment (Day 0) must be calculated using the 
diary scores for 7 days. The UAS7 score will be calculated on the last 7 days captured in 
the diary prior to the first drug treatment visit. Only in rare circumstances, (pending lab 
studies, in clinic UAS score < 2) will a longer screening period be permitted.  
 
Open Label Treatment Period (Day 0 to Week 12) 
At Day 0 of treatment, eligible patients will be give 300 mg of omalizumab SQ every 4 
weeks for a total of 12 weeks ( 3 injections) . Efficacy, safety, and pharmacodynamic (PD) 
data will be collected. The primary endpoint will be measured at the time of meaningful 
change in UAS7 expected to occur within 1-2 weeks of first dose of omalizumab. For the 
duration of the 12-week treatment period, patients must remain on stable doses of their 
pre-determined CIU H1 antihistamine treatment. All patients will be provided 
diphenhydramine (25 mg po TID) as rescue medication for pruritus relief on an as-


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needed basis (to a maximum of three doses in 24 hours). Patients who require treatments 
other than diphenhydramine (e.g., prednisone) to treat persistent/worsening disease 
will be discontinued from the study. All patients will be provided with an epipen as per 
AAAAI guidelines for omalizumab recipients.  
 
 
Study Endpoints 
Primary Endpoint(s)  
We propose as the primary outcome as the time for change in the functional response from 
baseline of basophil in vitro anti-IgE for histamine release (defined as a 2-fold rise at suboptimal 
concentrations of anti-IgE) relative to the time to reach MID of > 5 point change in either itch of 
hive. We expect subjects with baseline basophil CIU-NR ( non-responder) phenotype to become 
Responders and baseline Responder phenotype to demonstrate a rise the in suboptimal anti-IgE 
response.  
 
Secondary Endpoint(s)  
Change in the weekly pruritus score from baseline to the 12th week in the treatment period. The 
pruritus score will be measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 (intense). 
The weekly pruritus score is the sum of average daily pruritus scores over the previous 7 days. 
 
Change in the weekly score for number of hives from baseline to the 12th week in the treatment 
period. The number of hives is measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 
(> 12 hives, see Table 1). The weekly score of number of hives is the sum of the average daily 
scores over the previous 7 days. 
 
    Table 1. 
 
 
 
 
Change in the amount of rescue medication (diphenhydramine 25 mg) from baseline to the 12th 
week in the treatment period using the question on the rescue medication use in the patient 
diary. 


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 Change in SKINDEX29 quality of life survey instrument with 29 questions on a 5-point Likert 
will be given at baseline and again at 90 days ( Appendix 5). 
 
Exploratory Endpoint(s)  
1) Change in basophil surface IgE, FcεRI and Syk by flow cytometry from baseline at 1, 3, 6, 
10, 20, 30 and 90  
 
2) Change in Dendritic cell surface IgE, FcεRI, from baseline at Days 1, 3, 6, 10, 20, 30 and 90  
 
3) Change in Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated histamine along with 
sensitivity measures from baseline at 1, 3, 6, 10, 20, 30 and 90 days 
  
 
4) Change in serum free IgE measures from baseline at days 1, 3, 6, 10, 20, 30 and 90  
 
5) Characterization of presence of serum autoantibody presence ± Syk inhibitors at baseline 
and at days 1, 3, 6, 10, 20, 30 and 90  
 
6) Change in basophil enumeration by manual counting and blood histamine content 
from baseline at days 1, 3, 6, 10, 20, 30 and 90. This will determine the presence or 
absence of basopenia and identify subjects for mRNA profiling studies.  
 
7) Change in basophil mRNA profiling baseline at 3 timepoints (baseline, meaningful clinical 
changes, and 30 days) in select subjects with sufficient basophil numbers as identified at 
baseline measure.  
 
8) Change in numbers of IgE +, FcεRI + cells in non-lesional skin biopsies from baseline to 
days 6 and 90  to monitor skin mast cells well as the MrgX2 receptor expression  
 
9) Change in circulating leukocyte population numbers that are targeted by omalizumab 
such as blood basophils, eosinophil and lymphocyte counts by automated analysis 
(week -3 to week 12).  
 
10) Change in urine prostaglandins and eicosanoids at  Pre-treatment (Day, -21 -14,  0,) 1, 
3, 6, 10, 20, 30 and 90. 
 
Study Completion 
This study will be considered “completed” when the primary, secondary and/or exploratory 
objectives have been met.  This includes the analysis of all the data required to meet the chosen 
objectives.   


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SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Inclusion Criteria  
Male or female, age 18years or older 
 
Females must be surgically sterile or postmenopausal or using a highly effective form of birth 
control throughout the duration of the study such as an oral contraceptive, or double barrier 
method contraception condom with spermatocide or IUD.  Females in certain categories (not 
sexually active, vasectomized partner, tubal occlusion) will be admitted at the discretion of the 
investigator on a case-by-case basis. 
 
Females must have a negative urine pregnancy test at screening and other visits specified in this 
protocol unless documented to have a hysterectomy or post-menopausal. 
 
Clinical history of moderate to severe CIU at the time of screening, as defined by pruritus and 
hives for > 3 days in a 7-day period for > 6 consecutive weeks despite treatment with H1 
antihistamine. 
 
CIU diagnosis > 3 months (by history) 
 
No underlying etiology clearly defined for urticaria (main manifestation cannot be physical 
urticaria). 
 
Non-diary based UAS scores  ≥ 2 at either the screening visit (Week -1), at the run-in visit (Day 
1), or on Day 15. 
 
A diary-based UAS7 score ≥ 16 during the screening or run-in periods  despite stable doses of 
H1 antihistamine. 
 
Compliance with study procedures during run-in period (e.g., completion of the study diary). 
 
Exclusion Criteria 
1. Pregnant females, confirmed by a positive Human Chorionic Gonadotropin (HCG) test, or females 
with plans to become pregnant or breastfeed during the duration of the study.  
 
2.  Recent history of drug or alcohol abuse (within 3 years prior to screening visit). 
 
3. Inability or unwillingness of a participant to give written informed consent or comply with study 
protocol. 
 
4. Use of any investigational drugs within 30 days of screening.  
 


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14. Any clinically relevant abnormal findings in clinical chemistry, hematology, physical examination, 
pulse, blood pressure at baseline, which, in the opinion of the investigator, could put the patient at risk 
because of his/her participation in the study. 
 
15. Past or current medical problems or findings from physical examination or laboratory testing that are 
not listed above, which, in the opinion of the investigator, may pose additional risks from participation in 
the study, may interfere with the participant’s ability to comply with study requirements or may 
compromise the quality of the data obtained from the study. 
 
Participant Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
 
The participant elects to withdraw consent from all future study activities, including follow-up. 
Patient decision. The patient is at any time free to discontinue treatment, without prejudice to 
further treatment 
The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to 
reestablish contact with the participant have failed). 
The participant dies.  
The participant develops a medical condition or is initiated on new medication(s) not 
previously mentioned in the list of prohibited medications that, in the opinion of the 
investigator, may pose additional risks from participation in the study, may interfere with the 
5.  Active atopic dermatitis or other skin disease associated with pruritus during the time of the study, 
which require treatment with topical corticosteroids. 
 
6. Clinically relevant major systemic disease (making interpretation of the study results difficult) 
including a history of anaphylaxis.  
 
7. Inability to comply with study and follow-up procedures 
 
8. Patients may not take during treatment period or have been taking within the past one-month any of 
the following medications/treatments: regular (daily/every other day) hydroxychloroquine, 
sulfasalazine, dapsone, methotrexate, cyclosporin, IVIG, or other monoclonal antibody therapies. 
 
9. Patients may not take doxepin during screening, run-in, or treatment period or have been taking 
doxepin within the past 2 weeks regularly (daily/every other day) prior to screening.  
 
10. Patients may not use cutaneous corticosteroid (intranasal, inhaled, and ophthalmic steroids are 
permitted) during the screening, run-in, or treatment phases.  
 
11. Patients may not use oral or systemic steroids during the study or within 4 weeks prior to enrollment. 
 
12. Patients may not take H2 antihistamines and leukotriene receptor antagonists within 7 days before 
screening, during the screening, run-in, or treatment phases. The exception will be if they are already on 
these medications for the treatment of GERD, asthma or allergic rhinitis. 
 
13. Contraindications to diphenhydramine. 
 


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participant’s ability to comply with study requirements or may compromise the quality of the 
data obtained from the study. 
The participant meets any of the individual stopping rules as delineated in Section 8.  
Patient is non-compliant with study protocol in the judgment of the PI.  
Management of Participant Withdrawal  
Patients are at any time free to withdraw from study, without prejudice to further treatment 
(withdrawal of consent). Such patients will always be asked about the reason(s) and the 
presence of any adverse events. Adverse events will be followed up (See Sections 0 and 0); the 
patient should return patient diaries, questionnaires, and all study drugs. If possible, they will 
be seen and assessed by an investigator.  
  
For patients withdrawn due to incorrect inclusion, no further assessments will be performed 
except for the completion of the Follow-up Visit. This is done out of concern for the patients' 
safety.  
 
If a patient prematurely discontinues the study after drug treatment the patient will be asked to 
complete the final visit at the time of discontinuation. For patient withdrawn due to study 
specific discontinuation criteria, see Section 4.3.  
 
Withdrawn subjects will not be replaced. 
 


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INTERVENTION MATERIALS 
Investigational PRODUCT (s)/INTERVENTION (s)  
Omalizumab is a sterile, white, preservative free, lyophilized powder contained in a single use 
vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a 
subcutaneous (SC) injection. Each 202.5 mg vial of omalizumab also contains L-histidine (1.8 
mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 20 (0.5 mg) and sucrose 
(145.5 mg) and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 
1.4 mL SWFI, USP.  
Packaging and Labeling 
Omalizumab will be supplied by the manufacturer Novartis.  
Preparation, Administration, and Dosage 
Omalizumab will be prepared for administration according to the FDA approved package 
insert. A pharmacist at the research pharmacy located within the Johns Hopkins Asthma and 
Allergy Center will dispense the study drug and rescue medications to subjects. The drug will 
be administered by the research nurse typically in the upper arm region.  Subjects will be 
observed for 2 hours post each of the 3 omalizumab monthly injections and provided with an 
epipen. Subjects will be trained in the appropriate use of the epipen. 
 
Accountability of Investigational Product(s)/ Intervention(s) 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will 
maintain adequate records of the disposition of the intervention material(s), including the date 
and quantity of the drug received, to whom the drug was dispensed (participant-by-participant 
accounting), and a detailed accounting of any intervention material(s) accidentally or 
deliberately destroyed. 
 
The study site will maintain records for receipt, storage, use, and disposition.  A dispensing log 
will be kept current for each participant.  This log will contain the identification of each 
participant and the date and quantity of the intervention material(s) dispensed. 
 
All records regarding the disposition of the investigational product(s)/intervention material(s) 
will be available for inspection. All residual product(s) will be destroyed or retained for future 
in vitro studies.  
 
 
 


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Assessment of Compliance with Intervention Material(s) 
All study drug will be supplied on site at the study site. Monitoring of basophil IgE receptor 
levels will be performed as a measure of PD.  The pharmacy will keep records of doses 
dispensed and returned pills will be counted.  
 Discontinuation of Intervention Material(s) 
Refer to Section 0 and Section 0.  
 
 


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OTHER MEDICATIONS 
Concomitant Medications 
Concomitant medications may be used as follows: loratadine 10 qd, desloratadine 5 mg qd, 
fexofenadine 180 mg qd, cetirizine 10 mg qd or levocetirizine 5 mg qd as once daily medications 
at the current FDA-approved dose. Patients taking H2 blockers for diseases other than CIU (e.g. 
Gastroesophageal Reflux Disease) will be permitted to continue their use during the study. 
Continued use of leukotriene receptor antagonists will be allowed only if sole indication is for 
the treatment of asthma and/or allergic rhinitis. Inhaled asthma controllers, including 
corticosteroids, are also permitted during the study. These diseases must be recorded as part of 
the medical history collected during the screening period. All concomitant medication and 
changes in treatment will be recorded in appropriate section. 
Prophylactic Medications 
None 
Rescue Medications 
Diphenhydramine 25 mg will be provided as a rescue medication, which may be used up to 
three times a day as needed.  
Epipens are issued as a rescue medicine for the risk of anaphylaxis with omalizumab.  
  
Prohibited Medications 
Oral or cutaneous corticosteroids or other immunosuppressive medications (e.g. 
hydroxychloroquine, methotrexate, sulfasalazine, dapsone, cyclophosphamide) will be 
prohibited at enrollment but oral corticosteroids may be allowed as a rescue medication. In this 
case, the subjects would be discontinued from the study.  
 
The use of leukotriene receptor antagonists (e.g. montelukast) will not be allowed within 7 days 
of screening, during the screening, run-in, or treatment phases. The only exception will be the 
use of leukotriene receptor antagonists for asthma or allergic rhinitis (Section 0). Doxepin may 
not be taken during screening, run-in, treatment, or within the past 2 weeks regularly 
(daily/every other day) prior to screening.  


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STUDY VISITS AND PROCEDURES 
Enrollment and Randomization  
A dedicated clinical study coordinator will be responsible for advertising, screening and 
providing consents to the study subjects. This research study will be explained in lay terms to 
each potential research participant. The potential participant will sign an informed consent form 
before undergoing any screening study procedures.  Participants who are deemed eligible for 
the study (see Section 4.1, 4.2, and 4.3) will be enrolled and assigned a unique participant 
number.   
 
Screening Visit(s) 
Visit 1, (Week -3) 
Obtain informed consent document signed by subject and assign number. 
Review inclusion and exclusion checklist. 
Demographic information, medical and medication history including diagnosis of CIU for 3 
months. 
Urine pregnancy test for all females unless surgically sterile or postmenopausal. 
Comprehensive physical exam including vital signs, body weight and height, and skin exam. 
Complete In Clinic UAS: Must have a non-diary based daily urticaria activity score (UAS) score   
≥ 2 established in the outpatient setting based on the patient’s condition over 12 hours prior to 
the visit; the UAS is a composite score of pruritus (0–3) and number of hives (0–3) with a 
maximum value of 6.This requirement may be met either at screen, run-in visit (Day 1), or Day 
15. 
Must have been on an approved dose of an H1 antihistamine for CIU such as loratadine 10 mg 
once a day or equivalent, for at least 7 days prior to the screening visit. Approved agents 
include loratadine 10 mg qd, desloratadine 5 mg qd, fexofenadine 180 mg qd, cetirizine 10 mg 
qd or levocetirizine 5 mg qd as once daily medications at the current FDA-approved dose. If 
needed for symptom control, up to 4 fold standard dosing is allowed.  
Obtain Safety labs: Complete blood count (including platelet count) with differential 
glucose, BUN, bicarbonate, phosphorus, magnesium, creatinine, total and direct 
bilirubin, alkaline phosphatase, total protein, albumin, AST, (ALT), LDH, and calcium, 
store serum tube for baseline IgE measures and autoantibody testing (15 mL blood). 
Urine collection for measurement of urine prostaglandins and eicosanoids up to 10cc per 
collection. 
Must be willing to fill out a twice daily patient diary to establish the patient’s seven-day 
urticaria activity score (UAS7)  
Dispense one week diary with instructions (Appendix 2) 


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Assessment of adverse events during study visit 
Schedule next visit (in 1 week).  
Visit 2, (Day -14 ± 2 days): Start of Run-In Visit 
Assessment of adverse events that may have occurred since the previous visit 
Confirmation of inclusion/exclusion criteria  
Review of safety lab values and confirm that they are within normal range.  
Review UAS diary reporting.  To be eligible to begin the run-in period (Week -2 to 0), the 
patients: 
Must have a UAS7 score ≥ 16 established in the screening week with no missing entries. 
Must remain on stable dose of H1 antihistamine at  dose (not including antihistamine rescue 
medication) established at the screening visit.  
Complete In Clinic UAS.  
Brief physical exam (Vital Signs, Skin Exam, Cardiovascular Exam, Respiratory Exam). 
Draw blood for basophil enumeration, BHR, flow, and serum studies (32 ml) 
Whole blood for basophil flow assays  (4 mL green top tube)  
Tube for BHR, Blood histamine content, basophil enumeration to determine if patient meets 
criteria for mRNA profiling studies(> 1.5 x106 cells/100 cc)  (28 mL EDTA syringe) 
Urine collection for measurement of urine prostaglandins and eicosanoids  
Dispense 2 week UAS diary for patient symptom recording and rescue medicine Benadryl 
supplements. 
Schedule the next visit (in 2 weeks). 
 
Treatment Study Visit(s)   
Visit 3 (Day 0): First treatment visit 
Assessment of adverse events that may have occurred since the previous visit. 
Confirmation of inclusion/exclusion criteria. 
Complete In Clinic UAS.  
Urine pregnancy test for all females unless surgically sterile or postmenopausal. 
Review diary information to confirm compliance (90% filled) and adequate disease activity for 
drug treatment in the latter 7 days (Day-7 to Day-1) to meet entry criteria (UAS score > 16 
during screening or run-in periods). Record Benadryl supplement use.  
Focused physical exam of the head and neck, heart, lungs and skin including vital signs 
Complete Skindex survey. 
Draw blood for mechanistic outcomes (87 mL) 


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Serum sample for free IgE measure/autoantibody testing  (5 mL stored) 
Whole blood for basophil flow assays (4 mL green top tube)  
Tube for BHR and Blood histamine content, basophil enumeration (28 mL EDTA syringe) 
Blood sample for dendritic cell functional study ± basophil mRNA profiling (50 mls) only in 
subjects with basophils > 15,000 basophils/ml). 
Urine collection for measurement of urine prostaglandins and eicosanoids 
Perform non-lesional skin biopsy. Provide instructions for biopsy site care. 
Inject subject with omalizumab 300 mg. Observe for 2 hours for signs of anaphylaxis..  
Dispense epipen and educated patient on use.  Provide rescue medicine (25 mg 
diphenhydramine TID prn, 1 month supply).  
Remind patient to complete twice daily UAS diary for symptom recording.  
Schedule the next visit the next day. 
 
Visit 4 (Day 1):  Post 1st Treatment ,Week 0 
Assessment of adverse events that may have occurred since the previous visit. 
Complete In Clinic UAS.  
Review diary information to confirm compliance.  
 
4. Draw blood for mechanistic outcomes (32 mL) 
 
 
a. Whole blood for basophil flow assays  (4 mL green top tube)  
 
 
b. Tube for BHR, Blood histamine content, baso count  (28 mL EDTA syringe) 
 
5. Urine collection for measurement of urine prostaglandins and eicosanoids  
6. Schedule the next visit in 2±1 days 
 
Visit 5 (Day 3 ±1): Post 1st Treatment, Week 0 
 
1.   Assessment of adverse events that may have occurred since the previous visit 
2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date).  
4. Draw blood for mechanistic outcomes (32 mL) 
 
 
a.Whole blood for basophil flow assays  (4 mL green top tube)  
 
b.Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
 
5. Urine collection for measurement of urine prostaglandins and eicosanoids  
6. Schedule the next visit in 3 days ±1 
Visit 6 (Day 6 ±1): Post 1st Treatment, Week 1 
 
1.  Assessment of adverse events that may have occurred since the previous visit 


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2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date). 
Determine if UAS7 scores to date have declined by MID > 5 from baseline.  If so perform 
mid study non- lesional biopsy and basophil mRNA profiling (if appropriate subject).  
4. Focused physical exam of the head and neck, heart, lungs and skin including vital 
signs 
5. Draw blood for mechanistic outcomes (37 - 87 mL) 
 
a. Serum sample for free IgE measure/autoantibody testing  (4 mL stored) 
 
b. Whole blood for basophil flow assays  (5 mL green top tube)  
 
c. Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
d. If indicated -Blood sample for dendritic cell functional study ± basophil mRNA 
profiling (50 mls) only in subjects with basophils > 15,000 basophils/ml). Perform 
only one time during treatment period. 
6. If indicated by UAS7 decline, perform non-lesional skin biopsy. Provide instructions 
for biopsy site care. 
 
7. Urine collection for measurement of urine prostaglandins and eicosanoids  
8. Schedule the next visit in 4 days ±2 
Visit 7 (Day 10 ±2): Post 1st Treatment, Week 2 
 
1.  Assessment of adverse events that may have occurred since the previous visit 
2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date). 
Determine if UAS7 scores to date have declined by MID > 5 from baseline.  If so perform 
mid study non- lesional biopsy and basophil mRNA profiling (if appropriate subject).  
4. Focused physical exam of the head and neck, heart, lungs and skin including vital 
signs 
5. Draw blood for mechanistic outcomes (32 - 82 mL) 
 
a. Whole blood for basophil flow assays  (4 mL green top tube)  
 
c. Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
d. If indicated -Blood sample for dendritic cell functional study ± basophil mRNA 
profiling (50 mls) only in subjects with basophils > 15,000 basophils/ml). Perform 
only one time during treatment period. 
6. If indicated by UAS7 decline, perform non-lesional skin biopsy. Provide instructions 
for biopsy site care. 
 
7. Urine collection for measurement of urine prostaglandins and eicosanoids  
8. Schedule the next visit in 10 days ±2. 
Visit 8 (Day 20 ±2): Post 1st Treatment, Week 3 
 
1.  Assessment of adverse events that may have occurred since the previous visit 


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2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date). 
Determine if UAS7 scores to date have declined by MID > 5 from baseline.  If so perform 
mid study non- lesional biopsy and basophil mRNA profiling (if appropriate subject).  
4. Focused physical exam of the head and neck, heart, lungs and skin including vital 
signs 
5. Draw blood for mechanistic outcomes (32 - 82 mL) 
 
a. Whole blood for basophil flow assays  (4 mL green top tube)  
 
b. Tube for BHR and Blood histamine content (28mL EDTA syringe) 
c. If indicated -Blood sample for dendritic cell functional study ± basophil mRNA 
profiling (50 mls) only in subjects with basophils > 15,000 basophils/ml). Perform 
only one time during treatment period. 
6. If indicated by UAS7 decline, perform non-lesional skin biopsy. Provide instructions 
for biopsy site care. 
 
7. Urine collection for measurement of urine prostaglandins and eicosanoids  
 
8. Schedule the next visit in 10 days ±4 
Visit 9 (Day 30 ±2): Second Treatment Visit, Week 4 
 
1.  Assessment of adverse events that may have occurred since the previous visit 
2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date). 
Determine if UAS7 scores to date have declined by MID > 5 from baseline.  If so perform 
mid study non- lesional biopsy and basophil mRNA profiling (if appropriate subject). If 
MID has not been reached, perform non-lesional biopsy and basophil mRNA profiling 
(if appropriate subject)  
4. Focused physical exam of the head and neck, heart, lungs and skin including vital 
signs 
5. Draw blood for mechanistic outcomes (37 - 87 mL) 
 
a. Serum sample for free IgE measure/autoantibody testing  (5 mL stored) 
 
b. Whole blood for basophil flow assays  (4 mL green top tube)  
 
c. Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
d. If indicated -Blood sample for dendritic cell functional study ± basophil mRNA 
profiling (50 mls) only in subjects with basophils > 15,000 basophils/ml). Perform 
only one time during treatment period. 
6. If indicated by UAS7 decline or study visit, perform non-lesional skin biopsy. Provide 
instructions for biopsy site care. 
 
7. Urine collection for measurement of urine prostaglandins and eicosanoids  
8. Inject subject with omalizumab 300 mg. Observe for 2 hours for signs of anaphylaxis..  
9. Dispense rescue medicine (25 mg diphenhydramine TID prn, 1 month supply).  


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10.  Schedule the next visit in 30 days ±7 
 
Visit 10 (Day 60 ±7): Third Treatment Visit, Week 8 
 
1.  Assessment of adverse events that may have occurred since the previous visit 
2.  Complete In Clinic UAS.  
3. Review diary information to confirm compliance (90% filled, Day 0 to date).  
4. Focused physical exam of the head and neck, heart, lungs and skin including vital 
signs 
5. Draw blood for mechanistic outcomes (32 mL) 
 
a. Whole blood for basophil flow assays  (4 mL green top tube)  
 
b. Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
 
6. Urine collection for measurement of urine prostaglandins and eicosanoids  
7. Inject subject with omalizumab 300 mg. Observe for 2 hours for signs of anaphylaxis..  
8. Dispense rescue medicine (25 mg diphenhydramine TID prn, 1 month supply).  
 
9.  Schedule the next visit in 30 days ±7 
Visit 11 (Day 90 ±7): Final visit Week 12 
 
1.  Assessment of adverse events that may have occurred since the previous visit 
2.  Complete In Clinic UAS.  
3. Comprehensive physical exam including vital signs, body weight and height, and skin 
exam. 
4. Review diary information to confirm compliance (80% filled, Day 0 to date).  
5. Complete Skindex survey 
6. Draw blood for mechanistic outcomes (47 mL) and safety labs  
 
a. Serum sample for free IgE measure/autoantibody testing  (5 mL stored) 
 
b. Whole blood for basophil flow assays  (4 mL green top tube)  
 
c. Tube for BHR and Blood histamine content (28 mL EDTA syringe) 
d. Obtain Safety labs: Complete blood count (including platelet count) with 
differential  and CMP (10 mL blood).  
 
7. Urine collection for measurement of urine prostaglandins and eicosanoids  
 
8. Perform non-lesional skin biopsy. Provide instructions for biopsy site care. Arrange 
contact for follow-up call.  
9. Collect final diary for patient symptom recording.  
 
As needed visits 


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Subjects may come in at any time at the discretion of the investigator or the subject for follow 
up. 
 
Early discontinued patients will be required to report for safety follow-up visit within a month 
of study discontinuation. 
7.4 Visit Windows  
Study visits should take place within the time limits below: 
As detailed above, most visits have a ± 2 day window except as indicated for visits in the first 
week ±1, and study visits 9-11 ( ±4-7). 
 
 
 


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SAFETY PROCEDURES 
Stopping Rules 
Study Stopping Rules 
Study enrollment and ongoing study procedures will be suspended pending expedited review 
of all pertinent data by the institutional review board (IRB), and medical monitor if any one of 
the following occurs: 
A serious adverse event (Section 0) 
 
Individual Stopping Rules 
A study participant will be discharged from the study if he/she suffers:  
A serious adverse event. (Section 0) 
A severe, unanticipated, drug-related event (Section 0) 
Pregnancy (Section 0) 
 
Premature Discontinuation of Intervention(s) with continued study 
participation/follow-up 
Continued follow up if the intervention were discontinued for safety reasons would be based 
on the visit number in the protocol at the time of drug discontinuation and the possibility of 
evaluating outcome.  
 
Premature Termination Follow-up 
Participants who are prematurely terminated from the study will be followed to monitor safety 
for a minimum of 30 days or until resolution of the disqualifying event whichever is longer or 
until the Medical Monitor and the Principal Investigator determine that the follow-up is 
complete. 
 
Participant Replacement 
Participants who prematurely terminate from this study will not be replaced. 
 


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Adverse Events  
This section defines the types of adverse events and outlines the procedures for appropriately 
collecting, grading, recording, and reporting them.  Information in this section complies with 
ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting and ICH E6: Guideline for Good Clinical Practice, and applies the standards set forth in 
the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events version 3.0 
(Aug. 9, 2006).  The Investigators conducting this trial have reviewed these criteria and consider 
them appropriate for this subject population.  
 
Steps included in the protocol to enhance patient safety are as follows: Subjects will receive 
omalizumab in room 3B. 46 at JHAAC, which is equipped with an anaphylaxis treatment kit. 
The PI and study team have previously conducted several studies of CIU with omalizumab in 
this research space and are experienced in this administration and safety monitoring. In clinical 
care, omalizumab is approved since 2003 and has been given to > 100,000 pts using a similar 
practice of administration. The PI and/ or study nurse is present during the dosing observation 
period of 2 hours to manage anaphylaxis or symptoms suggestive of anaphylaxis if they occur. 
In this case, we would administer epinephrine via an epipen. All subjects are also dispensed 
epipens as well and trained on their proper use. We will treat subjects at the first signs of 
anaphylaxis as per AAAAI guidelines and practice parameters.  
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product. The XOLAIR(r) (omalizumab) Events of Special 
Interest are: 
- 
Anaphylaxis 
-       Drug-induced liver injury 
-       Suspected transmission of an infectious agent by the study drug 
  
 
Adverse Event Definition 
An adverse event is any occurrence or worsening of an undesirable or unintended sign, 
symptom, abnormal laboratory finding, or disease that is temporally associated with 
participation in this study whether considered related to the study or not. 
 
Any adverse event that occurs from the moment the subject has signed the consent form will be 
recorded and is reportable.  An adverse event will be followed until any of the following takes 
place:  a) it is resolved, b) participant is stable, c) a minimum of 30 days after participant is 
terminated from the study or d) the Medical Monitor and the Principal Investigator determine 
that follow-up is complete. 
 
Serious Adverse Event (SAE) Definitions 
An SAE is defined as “any adverse event occurring at any dose that suggests a significant 
hazard, contraindication, side effect, or precaution.” This includes but is not limited to any of 
the following events: 


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Death.  A death that occurs during the study or that comes to the attention of the investigator 
during the protocol-defined follow-up after the completion of study will be reported whether it 
is considered to be study-related or not.    
A life-threatening event.  A life-threatening event is any adverse experience that, in the view of 
the investigator, places the study participant at immediate risk of death from the reaction as it 
occurred. 
An inpatient hospitalization or prolongation of existing hospitalization. 
Persistent or significant disability. 
An event that required intervention to prevent permanent impairment or damage.  
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, it 
may jeopardize the participant and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
Congenital anomaly or birth defect. 
 
Regardless of the relationship of the adverse event to the study, the event will be reported as an 
SAE if it meets any of the above definitions. 
 
‘Expected’ verses ‘Unexpected’ Adverse Event Definition 
A suspected adverse reaction is considered “expected” when it is listed in the 
investigator brochure, the package insert or the protocol. An adverse event is considered 
“unexpected” when its nature or severity is not consistent with the information that is provided 
in the Package insert, and/or this protocol (Section 0). 
 
Management of Adverse Events 
Collecting Procedure 
Adverse events may be discovered through any of these methods: 
Observing the participant. 
Questioning the participant, with standardized questions at the beginning (except Visit 1) and 
the end of all study visits. 
Receiving an unsolicited complaint from the participant. 
An abnormal value or result from a clinical or laboratory evaluation (e.g., a radiograph, an 
ultrasound, or an electrocardiogram) can also indicate an adverse event.   
 


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Recording and Reporting Procedure 
Throughout the study the Principal Investigator will record all adverse events on appropriate 
adverse event case report forms regardless of their severity or relation to the study. 
 
 NOTIFYING THE MEDICAL MONITOR  
The Principal Investigator will ensure the timely dissemination of AE information to the 
Medical Monitor. 
 
NOTIFYING THE INSTITUTIONAL REVIEW BOARD  
The Principal Investigator will ensure the timely dissemination of AE information to the IRB in 
accordance with applicable regulations and guidelines. 
 
Grading and Attribution  
GRADING CRITERIA 
In addition to determining whether an adverse event fulfills criteria for a serious adverse event 
or not, the severity of adverse events experienced by study participants will be graded 
according to the criteria set forth in the National Cancer Institute’s Common Terminology Criteria 
for Adverse Events Version 3.0 (published Aug. 9, 2006).  This document (referred to herein as the 
NCI-CTCAE manual) provides a common language to describe levels of severity, to analyze 
and interpret data, and to articulate the clinical significance of all adverse events. 
 
Adverse events listed in the NCI-CTCAE will be graded on a scale from 1 to 5 according to the 
following standards in the NCI-CTCAE manual: 
 
Grade 1 = Mild adverse event. 
Grade 2 = Moderate adverse event. 
Grade 3 = Severe and undesirable adverse event.  
Grade 4 = Life-threatening or disabling adverse event. 
Grade 5 = Death. 
 
Adverse events not included in the NCI-CTCAE listing, which have relative specificity for this 
protocol will be recorded and graded 1 to 5 according to the grade definition provided below:  
 


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For anaphylaxis: 
Grade 1= Oral urticaria or erythema 
Grade 2= Flushing, urticaria, periorbital or facial angioedema; mild dyspnea, wheeze or 
upper respiratory symptoms; mild abdominal pain and/or emesis 
Grade 3= Marked dysphagia, hoarseness, and/or stridor; shortness of breath, wheezing 
& retractions; crampy abdominal pain, recurrent vomiting and/or diarrhea; and/or 
mild dizziness 
Grade 4= Cyanosis or SpO2 < 92% at any stage, hypotension, confusion, collapse, loss of 
consciousness; or incontinence 
Grade 5= Death 
Other adverse events not included in the NCI-CTCAE listing, will be recorded and graded 1 to 
5 according to the General Grade Definition provided in the Table below: 
 
Grade 1 
Mild 
Transient or mild discomforts (< 48 hours), no or minimal medical 
intervention/therapy required, hospitalization not necessary 
(non-prescription or single-use prescription therapy may be 
employed to relieve symptoms, e.g., aspirin for simple headache, 
acetaminophen for post-surgical pain). 
Grade 2 
Moderate 
Mild to moderate limitation in activity some assistance may be 
needed; 
no 
or 
minimal 
intervention/therapy 
required, 
hospitalization possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization possible. 
Grade 4 
Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical/therapy intervention required hospitalization or 
hospice care probable. 
Grade 5 
Death 
Death. 
  
 
DEFINITION OF ATTRIBUTION 
The relationship, or attribution, of an adverse event to the study will be determined by the 
Principal Investigator or designee by using the descriptors provided in the following table.  The 
Principal Investigator or designee will record the determination of attribution on the 
appropriate adverse event or serious adverse event form.  The relationship of an adverse event 


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to the investigational drug(s)/intervention(s)/procedure(s) or other study drug will be further 
determined. 
NCI-CTCAE attribution of adverse events 
Code 
Descriptor 
Definition 
UNRELATED CATEGORY  
1 
Unrelated 
The adverse event is clearly not related to study  
RELATED CATEGORIES  
2 
Unlikely 
The adverse event is doubtfully related to study  
3 
Possible 
The adverse event may be related to study  
4 
Probable 
The adverse event is likely related to study  
5 
Definite 
The adverse event is clearly related to study  
 
(For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE 
website:   http://ctep.cancer.gov/reporting/ctc.html) 
 
Management of Serious Adverse Events 
SAE Collecting Procedure 
Serious adverse events will be collected described for adverse events in Section 0. 
 
SAE Recording and Reporting Procedure 
Serious adverse events will be recorded on the serious adverse event case report form 
(Appendix 4) and will include a narrative of the event signed and dated by the Principal 
Investigator and the site Medical Monitor.  In addition, the FDA MedWatch 3500A form will be 
filled out. 
 
REPORTING PREGNANCY  
The Principal Investigator will counsel the participant and discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus.  Monitoring of the participant will continue 
until the conclusion of the pregnancy, and a follow-up adverse event case report form detailing 


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the outcome of the pregnancy will be submitted. Follow-up information detailing the outcome 
of the pregnancy should be reported to the Medical Monitor as it becomes available. Any 
premature termination of the pregnancy will be reported. Any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE. 
 
UNEXPECTED, NON-SERIOUS ADVERSE EVENTS  
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and study 
related will be recorded and reported to the site Medical Monitor under the serious adverse 
event reporting procedure outlined below in Sections 0, and 0. 
 
SAE REPORTING CRITERIA AND PROCEDURES 
The Principal Investigator will be notified by the staff no later than 24 hours after a staff 
member becomes aware of the SAE. 
The site Medical Monitor will be notified by the Principal Investigator no later than 24 hours 
after the Principal Investigator becomes aware of the SAE.   
Within another 24 hours, the site Medical Monitor will discuss with the Principal Investigator 
the impact of the SAE on the participant and on the study and will decide whether standard or 
expedited reporting will be applied.  A finalized, initial SAE case report form (Appendix 4) and 
a MedWatch 3500A form will be generated by the Principal Investigator.   
 
NOTIFYING THE MEDICAL MONITOR 
The Principal Investigator will ensure the timely dissemination of SAE information, including 
expedited reports, to the Medical Monitor.  
 
NOTIFYING THE INSTITUTIONAL REVIEW BOARD 
The Principal Investigator will ensure the timely dissemination of SAE information, including 
expedited reports, to the IRB in accordance with IRB regulations and guidelines. In addition, all 
SAEs will be reported to the study drug manufacturer, Novartis.  
 
 
 
 


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Protocol Deviations 
The practices below are consistent with Good Clinical Practice (GCP ICH E6) Sections: 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
Quality Assurance and Quality Control, section 5.1.1 
Noncompliance sections 5.20.1, and 5.20.2. 
 
Protocol Deviation Definition 
A protocol deviation is any noncompliance with the protocol, Good Clinical Practice (GCP), or 
the study’s Manual of Operations (MOP).  Noncompliance may be either on the part of the 
participant, the investigator, or the study staff.   
 
Management of Protocol Deviations 
DETECTING PROTOCOL DEVIATIONS 
Protocol deviations will be detected by direct questioning of participants and weekly review of 
CRFs to determine if visits take place in appropriate windows. 
 
REPORTING PROTOCOL DEVIATIONS 
Upon determination that a protocol deviation has occurred, the study staff will a) notify the 
Principal Investigator and b) and will begin completing the Protocol Deviation Form (Appendix 
).  The Principal Investigator will complete and sign the Protocol Deviation form and submit it 
to the site IRB, per IRB regulations.  


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SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN 
Sample Size and Power Calculations 
The sample size will be determined based on power calculations for the primary endpoint. The 
primary endpoint for the study utilizes the Urticaria Activity Score 7. This is a composite of a 
daily score of 0-3 for hives and 0-3 for itch with a maximal daily score of 6 and maximum 
weekly score of 42. Based on the Phase III study results with omalizumab in CIU, the baseline 
scores were UAS7=30 with a standard deviation of 7 in approximately 300 subjects completing 
run-in evaluation (25). Given that the minimally important difference based on this scoring 
system is 5 (55), we estimated the number of subjects needed for the present study. In that 
study, the 1-week test-retest correlation coefficient for UAS7 was 0.74. We have thus 
conservatively estimated the 4-week test-retest correlation to be 0.5. A sample size of 24 subject 
is adequate to detect a clinically relevant difference of 5 units of UAS7 with 80% power and 5% 
alpha error.  
 
We are guided in our design by the pooled efficacy reported in Phase III CIU studies, past 
studies of kinetics and function reported for basophil receptor changes, and our knowledge of 
two equally distributed functional basophil subsets.  
 
Based on pooled Phase III CIU trial results with omalizumab for 300 mg/monthly for 12 weeks 
(Maurer EAACI 2014), approximately 70% of CIU subjects have a 70% reduction in UAS7 and 
40% are fully asymptomatic (UAS7=0). The median time to achieve an MID response is 1 week 
for those on standard dose anti-histamine therapy (25, 27), and 2 weeks for patients maintaining 
multiple therapies (4-fold standard dose antihistamines, ± LTRA, ± H2 blockers)(26) as 
compared to a median of 4-5 weeks for those treated with placebo. Overall, 70% of treated 
subjects across all phase III studies achieved an MID for itch score at week 2.  
 
The worst-case scenario is that 30% percent of our omalizumab treated CIU subjects will not 
have a meaningful change in symptoms by 2 weeks.  If we enroll 30 subjects and have a 20% 
dropout, we would expect 17 of 24 to have a significant clinical response (roughly 50/50 
distribution for basophil subsets, CIU R and NR). Our plan is to look at multiple cellular 
parameters in treated patients and relate cellular changes to the timing of the MID for itch (>5 
points) or hives (> 5 points) with the primary outcome being the percentage achieving a 50% 
rise in basophil anti-IgE functions at the time of reaching a clinical MID. We have also 
considered the concerns of basopenia, which may interfere with meaningful assessments 
through the study or allow reasonable collection of basophils for mRNA studies. Our 
longitudinal study involving active CIU subjects (n=164, with repeated sampling of basophil 
measures) reveals that 12-15% of individuals had extreme basopenia (56). We also expect that 
omalizumab therapy will yield an increase in circulating blood basophil presence. We have 
documented a 40-50% increase in blood basophils in Phase III study participants after 12 weeks 
therapy with monthly 300 mg injections (Saini, 2014 AAAAI meeting). 
 
 


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Data Analysis 
Study Participant Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided 
for all enrolled participants.  Demographic data will include age, race, sex, body weight, and 
height; these data will be presented in the following manner: 
Continuous data (i.e., age, body weight, and height) will be summarized descriptively by mean, 
standard deviation, median, and range.   
Categorical data (i.e., sex and race) will be presented as enumerations and percentages. 
The Wilcoxon signed rank test will be used to before and after treatment if a non-Gaussian 
distributed of data is generated; otherwise, if the data are normally distributed, and paired t test 
will be used.  Wilcoxon singed rank tests will be used to compare continuous variables and 
Fisher's exact tests will be used to compare categorical variables.  The level of significance 
employed will be 0.05.  Relationships between the primary efficacy variable and various in vitro 
and in vivo variables in will be explored using the Pearson product-moment correlation 
coefficient or the Spearman rank correlation coefficient, as appropriate. 
 
Summary statistics will be reported for all secondary efficacy variables.  Continuous variables 
will be summarized by sample size, mean, median, standard deviation, minimum, and 
maximum.  Discrete variables will be summarized by frequencies and percentages.    
 
Primary Endpoint Analysis 
The primary endpoint analysis is treated patients and relate cellular changes to the timing of the 
MID for itch (>5 points) or hives (> 5 points) with the primary outcome being the percentage 
achieving a 50% rise in basophil anti-IgE functions at the time of reaching a clinical MID. 
 
Diary entries for itch and/or hive a.m./p.m. scores may be missing for some days. These 
missing scores will be imputed using the average of available corresponding scores in that 
week. 
 
Patients whose post-baseline diaries are completely missing will not be included in the analysis. 
 
Secondary Endpoint Analyses  
This study is not designed or powered to perform hypothesis testing on secondary endpoints. 
All secondary analyses will be treated as supportive. P-values will be presented for the 
secondary endpoints but will not be adjusted for multiplicity and should be interpreted with 
caution.  


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Change in the weekly pruritus score from baseline to the 12 th week in the treatment period.  
The pruritus score will be measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 
(intense). The weekly pruritus score is the sum of average daily pruritus scores over the 
previous 7 days.  
 
Change in the weekly score for number of hives from baseline to the 12th week in the treatment 
period.   
The number of hives is measured twice daily (a.m. and p.m.), on a scale of 0 (none) to 3 (>12). 
The weekly score of number of hives is the sum of the average daily scores over the previous 7 
days.  
 
Change in the amount of rescue medication (diphenhydramine 25 mg) from baseline to the 12th 
week in the treatment period using the question on the rescue medication use in the patient 
diary. 
 
4. Change in SKINDEX29 quality of life survey instrument with 29 questions on a 5-point Likert 
will be given at baseline and again at 90 days. 
 
Exploratory Endpoint Analyses  
Exploratory endpoints related to mechanisms of immune modulation and tolerance assessed 
prior to, during and after therapy, including those related to: 
 
1) Change in basophil surface IgE, FcεRI and Syk by flow cytometry from baseline at 1, 3, 6, 
10, 20, 30 and 90  
 
2) Change in Dendritic cell surface IgE, FcεRI,  and IgE receptor related functions from 
baseline at Days 1, 3, 6, 10, 20, 30 and 90  
 
3) Change in Basophil anti-IgE, anti FcεRI, C5a, FMLP mediated histamine along with 
sensitivity measures from baseline at 1, 3, 6, 10, 20, 30 and 90 days 
  
 
4) Change in serum free IgE measures from baseline at  days 1, 3, 6, 10, 20, 30 and 90  
 
5) Characterization of presence of serum autoantibody presence ± Syk inhibitors at baseline 
and at days 1, 3, 6, 10, 20, 30 and 90  
 
6) Change in basophil enumeration by manual counting and blood histamine content 
from baseline at days 1, 3, 6, 10, 20, 30 and 90. This will determine the presence or 
absence of basopenia and identify subjects for mRNA profiling studies.  
 
7) Change in basophil mRNA profiling baseline at 3 timepoints (baseline, meaningful clinical 
changes, and 30 days) in select subjects with sufficient basophil numbers as identified at 


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baseline measure.  
 
8) Change in numbers of IgE +, FcεRI + cells in non-lesional skin biopsies from baseline to 
days 6 and 90  to monitor skin mast cells well as the MrgX2 receptor expression  
 
9) Change in circulating leukocyte population numbers that are targeted by omalizumab 
such as blood basophils, eosinophil and lymphocyte counts by automated analysis 
(week -3 to week 12).  
 
10) Changes in urine prostaglandins and eicosanoids at baseline Day (-21, -14,  0) relative 
to post -treatment (1, 3, 6, 10, 20, 30 and 90). 
 
 
Safety Analysis  
Safety analyses will include AEs, SAEs, laboratory abnormalities, and physical examination 
abnormalities. All participants in the safety sample will be included in all safety analyses. 
Frequency of AEs will be tabulated by system organ class and preferred term, as well as by 
seriousness, severity, and treatment relatedness. Frequency of SAEs will be tabulated by system 
organ class and preferred term. For pertinent laboratory measurements, mean and mean change 
from baseline values will be presented by treatment group and visit. Frequency of physical 
examination abnormalities will be tabulated by treatment group.  
 
Pharmacodynamic Data Analyses 
Primary, secondary, and exploratory endpoints may be further analyzed based on  the 
pharmacodynamic parameters assayed using blood basophil surface IgE and FceRI change flow 
cytometry assay. This assay was successfully used in several past omalizumab studies. 
Medical History 
Medical history within the past 12 months—including the existence of current signs and 
symptoms—will be collected for each body system. 
 
Medication Use 
All medications taken by or administered to study participants beginning 30 days before 
enrollment and continuing throughout the study will be collected. All medications used will be 
coded according to the WHO drug dictionary. The number and percentage of participants 
receiving prior and concomitant medications/therapies will be presented overall and by 
medication class. 
 


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Study Completion 
The percent of participants who complete the study, losses to follow-up, times to lost to follow-
up, and reasons for discontinuation (e.g., adverse events) will be presented.   
 
Interim Analyses  
Given the small study size, no interim data analysis is planned. 
 
Deviations from Statistical Plan 
The principal features of the study design and of the plan for statistical analysis of the data are 
outlined in this protocol. Any changes in these principal features will require a protocol 
amendment.  


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 IDENTIFICATION AND ACCESS TO SOURCE DATA  
 
Identifying Source Data 
The investigator will keep accurate records to ensure that the conduct of the study is fully 
documented.  Data derived from source documents will be transferred to protocol-specific 
CRFs.  The results of all clinical and clinical laboratory evaluations will be maintained in the 
participant’s medical records and the data will be transferred to clinical CRFs, as applicable. 
 
   Updating Source Documentation 
Documents describing the safety profile of an investigational product(s)/intervention 
material(s), such as the investigator’s brochure and the package insert, will be amended as 
needed by the investigational product(s)/intervention material(s) manufacturer to ensure that 
the description of safety information adequately reflects any new clinical findings.  
 
The Principal Investigator will provide the site Medical Monitor, and the IRB with the most up-
to-date versions of the above documents as soon as the Principal Investigator becomes aware of 
any changes.  For purchased investigational product(s)/intervention material(s), the Principal 
Investigator will confirm that there are no changes to the package insert every 3 months.  In 
case of package insert changes, the Principal Investigator will notify the site Medical Monitor 
and the IRB.      
 
 
Permitting Access to Source Data 
The investigational site participating in this study will maintain the highest degree of 
confidentiality for the clinical and research information obtained from the participants in this 
clinical trial.  Medical and research records will be maintained at each site in the strictest 
confidence.  However, as a part of the quality assurance and legal responsibilities of an 
investigation, the investigational site will permit authorized representatives of the sponsor(s) 
and health authorities to examine (and when required by applicable law, to copy) clinical 
records for the purpose of quality assurance reviews, audits, and evaluations of the study safety 
and progress.  Unless required by the laws that permit copying of records, only the coded 
identity associated with documents or with other participant data may be copied (and all 
personally identifying information will be removed).  Authorized representatives as noted 
above are bound to maintain the strict confidentiality of medical and research information that 
is linked to identified individuals.   


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QUALITY CONTROL AND QUALITY ASSURANCE 
The Principal Investigator will keep accurate records to ensure that the conduct of the study is 
fully documented.  The investigator will ensure that all CRFs and participant study files are 
legible and complete for every participant. When the CRFs are complete, they will be reviewed 
by the Principal Investigator.  All discrepancies identified will be resolved with the Principal 
Investigator and the CRFs will be amended as needed.  
 


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ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
12.1  
Statement of Compliance 
This study was designed to ensure the protection of subjects according to the ethical principles 
of the Declaration of Helsinki and amendments concerning medical research in human subjects. 
This clinical study will be conducted using good clinical practice (GCP), as delineated in 
Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the 
criteria specified in this study protocol.  Before study initiation, the protocol, the informed 
consent documents will be reviewed and approved by IRB, as well as any other appropriate 
health authorities.  Any amendments to the protocol or to the consent materials will also be 
approved by the appropriate bodies listed above prior to implementation. 
 
12.2  
Informed Consent and Assent  
The informed consent form will provide information about the study to a prospective 
participant to allow for an informed decision about participation in the study.  All participants 
(or their legally acceptable representative) must read, sign, and date a consent form prior to 
study participation.   
 
The informed consent form will be revised whenever important new safety information is 
available, whenever the protocol is amended, and/or whenever any new information becomes 
available that may affect participation in the trial. 
 
A copy of the informed consent will be given to a prospective participant for review.  The 
Principal Investigator or an approved designee will discuss the consent with the prospective 
participant and answer questions.  The prospective participant will be told that being in the trial 
is voluntary and that he or she may withdraw from the study at any time, for any reason. 
 
12.3 
Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each 
participant will be assigned a sequential identification number and these numbers rather than 
names will be used to collect, store, and report participant information. 
 


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REFERENCES 
 
1. 
Greaves MW. Chronic urticaria. N Engl J Med. 1995;332(26):1767-72. PubMed PMID: 
7760895. 
2. 
Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol. 
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3. 
Saini SS. Chronic spontaneous urticaria: etiology and pathogenesis. Immunol Allergy 
Clin North Am. 2014;34(1):33-52. Epub 2013/11/23. doi: 10.1016/j.iac.2013.09.012. PubMed 
PMID: 24262688. 
4. 
Gaig P, Olona M, Munoz Lejarazu D, Caballero MT, Dominguez FJ, Echechipia S, Garcia 
Abujeta JL, Gonzalo MA, Lleonart R, Martinez Cocera C, Rodriguez A, Ferrer M. Epidemiology 
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PubMed PMID: 15552715. 
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Zuberbier T, Balke M, Worm M, Edenharter G, Maurer M. Epidemiology of urticaria: a 
representative cross-sectional population survey. Clin Exp Dermatol. 2010;35(8):869-73. Epub 
2010/05/12. doi: 10.1111/j.1365-2230.2010.03840.x. PubMed PMID: 20456386. 
6. 
Grattan CE, Humphreys F. Guidelines for evaluation and management of urticaria in 
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2133.2007.08283.x. PubMed PMID: 18021095. 
7. 
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-
Arnau AM, Grattan CE, Kapp A, Maurer M, Merk HF, Rogala B, Saini S, Sanchez-Borges M, 
Schmid-Grendelmeier P, Schunemann H, Staubach P, Vena GA, Wedi B. 
EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009;64(10):1427-
43. Epub 2009/09/24. doi: ALL2178 [pii] 
10.1111/j.1398-9995.2009.02178.x. PubMed PMID: 19772513. 
8. 
Chow SK. Management of chronic urticaria in Asia: 2010 AADV consensus guidelines. 
Asia Pacific allergy. 2012;2(2):149-60. Epub 2012/06/16. doi: 10.5415/apallergy.2012.2.2.149. 
PubMed PMID: 22701866; PubMed Central PMCID: PMC3345329. 
9. 
The diagnosis and management of urticaria: a practice parameter part I: acute 
urticaria/angioedema part II: chronic urticaria/angioedema. Joint Task Force on Practice 
Parameters. Ann Allergy Asthma Immunol. 2000;85(6 Pt 2):521-44. Epub 2001/02/24. PubMed 
PMID: 11190256. 
10. 
Cooper KD. Urticaria and angioedema: diagnosis and evaluation. J Am Acad Dermatol. 
1991;25(1 Pt 2):166-74. PubMed PMID: 1869691. 
11. 
Najib U, Bajwa ZH, Ostro MG, Sheikh J. A retrospective review of clinical presentation, 
thyroid autoimmunity, laboratory characteristics, and therapies used in patients with chronic 
idiopathic urticaria. Ann Allergy Asthma Immunol. 2009;103(6):496-501. Epub 2010/01/21. doi: 
10.1016/S1081-1206(10)60266-9. PubMed PMID: 20084843. 
12. 
Ferrer M. Epidemiology, healthcare, resources, use and clinical features of different 
types of urticaria. Alergologica 2005. J Investig Allergol Clin Immunol. 2009;19 Suppl 2:21-6. 
Epub 2009/06/18. PubMed PMID: 19530414. 
13. 
Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. Br J Dermatol. 
1981;104(4):369-81. Epub 1981/04/01. PubMed PMID: 7236502. 
14. 
Buss YA, Garrelfs UC, Sticherling M. Chronic urticaria--which clinical parameters are 
pathogenetically relevant? A retrospective investigation of 339 patients. J Dtsch Dermatol Ges. 


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2007;5(1):22-9. Epub 2007/01/19. doi: 10.1111/j.1610-0387.2007.06194.x. PubMed PMID: 
17229201. 
15. 
O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic 
urticaria on the quality of life. Br J Dermatol. 1997;136(2):197-201. PubMed PMID: 9068731. 
16. 
Kaplan AP, Horakova Z, Katz SI. Assessment of tissue fluid histamine levels in patients 
with urticaria. J Allergy Clin Immunol. 1978;61(6):350-4. PubMed PMID: 659726. 
17. 
Ito Y, Satoh T, Takayama K, Miyagishi C, Walls AF, Yokozeki H. Basophil recruitment 
and activation in inflammatory skin diseases. Allergy. 2011;66(8):1107-13. Epub 2011/03/05. 
doi: 10.1111/j.1398-9995.2011.02570.x. PubMed PMID: 21371044. 
18. 
Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. TH1/TH2 cytokines and inflammatory 
cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with 
the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol. 2002;109(4):694-
700. PubMed PMID: 11941321. 
19. 
Pienkowski MM, Adkinson NF, Jr., Plaut M, Norman PS, Lichtenstein LM. 
Prostaglandin D2 and histamine during the immediate and the late-phase components of 
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20. 
Atkins PC, Schwartz LB, Adkinson NF, von Allmen C, Valenzano M, Zweiman B. In 
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Allergy Clin Immunol. 1990;86(3 Pt 1):360-70. PubMed PMID: 1698845. 
21. 
Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and 
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6870316. 
22. 
Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. 
2009;39(6):777-87. Epub 2009/04/30. doi: CEA3256 [pii] 
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23. 
Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies 
against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl 
J Med. 1993;328(22):1599-604. PubMed PMID: 7683772. 
24. 
Brodell LA, Beck LA, Saini SS. Pathophysiology of chronic urticaria. Ann Allergy 
Asthma Immunol. 2008;100(4):291-7. PubMed PMID: 18450112. 
25. 
Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, Agarwal S, Doyle 
R, Canvin J, Kaplan A, Casale T. Omalizumab for the treatment of chronic idiopathic or 
spontaneous urticaria. N Engl J Med. 2013;368(10):924-35. Epub 2013/02/26. doi: 
10.1056/NEJMoa1215372. PubMed PMID: 23432142. 
26. 
Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, Veith J, Kamath N, 
Staubach P, Jakob T, Stirling RG, Kuna P, Berger W, Maurer M, Rosen K. Omalizumab in 
patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard 
combination therapy. J Allergy Clin Immunol. 2013;132(1):101-9. Epub 2013/07/03. doi: 
10.1016/j.jaci.2013.05.013. PubMed PMID: 23810097. 
27. 
Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Bulbul Baskan E, Bradley MS, Canvin J, 
Rahmaoui A, Georgiou P, Alpan O, Spector S, Rosen K. Efficacy and Safety of Omalizumab in 
Patients with Chronic Idiopathic/Spontaneous Urticaria who Remain Symptomatic on H1 
Antihistamines: A Randomized, Placebo-Controlled Study. J Invest Dermatol. 2015;135(3):925. 
Epub 2014/12/17. doi: 10.1038/jid.2014.512. PubMed PMID: 25501032. 
28. 
Saini SS. Basophil responsiveness in chronic urticaria. Curr Allergy Asthma Rep. 
2009;9(4):286-90. Epub 2009/08/07. PubMed PMID: 19656475. 


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Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol. 
2008;20(6):709-16. PubMed PMID: 18832031. 
30. 
Eckman JA, Hamilton RG, Gober LM, Sterba PM, Saini SS. Basophil phenotypes in 
chronic idiopathic urticaria in relation to disease activity and autoantibodies. J Invest Dermatol. 
2008;128(8):1956-63. Epub 2008/03/22. doi: 10.1038/jid.2008.55. PubMed PMID: 18356810. 
31. 
Kern F, Lichtenstein LM. Defective histamine release in chronic urticaria. J Clin Invest. 
1976;57(5):1369-77. PubMed PMID: 57121. 
32. 
Oliver E, Sterba, PM, Saini, SS Interval Shifts in Basophil Measures correlate with 
Disease Activity in Chronic Idiopathic Urticaria Allergy. 2015;In press. 
33. 
Vonakis BM, Vasagar K, Gibbons J, S. C. , Gober L, Sterba P, Chang H, Saini SS. Basophil 
FceRI histamine release parallels expression of Src-homology2-containing inositol phosphatases 
in chronic idiopathic urticaria. J Allergy Clin Immunol. 2007;119:441-8. 
34. 
Rorsman H. Basopenia in urticaria. Acta allergologica. 1961;16:185-215. Epub 
1961/01/01. PubMed PMID: 14493753. 
35. 
Grattan CE, Dawn G, Gibbs S, Francis DM. Blood basophil numbers in chronic ordinary 
urticaria and healthy controls: diurnal variation, influence of loratadine and prednisolone and 
relationship to disease activity. Clin Exp Allergy. 2003;33(3):337-41. PubMed PMID: 12614448. 
36. 
Caproni M, Volpi W, Macchia D, Giomi B, Manfredi M, Campi P, Cardinali C, D'Agata 
A, Fabbri P. Infiltrating cells and related cytokines in lesional skin of patients with chronic 
idiopathic urticaria and positive autologous serum skin test. Exp Dermatol. 2003;12(5):621-8. 
PubMed PMID: 14705803. 
37. 
Smith CH, Kepley C, Schwartz LB, Lee TH. Mast cell number and phenotype in chronic 
idiopathic urticaria. J Allergy Clin Immunol. 1995;96(3):360-4. PubMed PMID: 7560638. 
38. 
Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, Kuroda 
K, Nunomura S, Hayama K, Terui T, Ra C, Okayama Y. Expression of Mas-related gene X2 on 
mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin 
Immunol. 2014;134(3):622-33 e9. Epub 2014/06/24. doi: 10.1016/j.jaci.2014.05.004. PubMed 
PMID: 24954276. 
39. 
Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, Metcalfe DD. The 
alpha form of human tryptase is the predominant type present in blood at baseline in normal 
subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995;96(6):2702-10. 
PubMed PMID: 8675637. 
40. 
Ferrer M, Nunez-Cordoba JM, Luquin E, Grattan CE, De la Borbolla JM, Sanz ML, 
Schwartz LB. Serum total tryptase levels are increased in patients with active chronic urticaria. 
Clin Exp Allergy. 2010;Epub ahead of print. Epub 2010/08/20. doi: CEA3582 [pii] 
10.1111/j.1365-2222.2010.03582.x. PubMed PMID: 20718781. 
41. 
Jacques P, Lavoie A, Bedard PM, Brunet C, Hebert J. Chronic idiopathic urticaria: 
profiles of skin mast cell histamine release during active disease and remission. J Allergy Clin 
Immunol. 1992;89(6):1139-43. PubMed PMID: 1376735. 
42. 
Cohen RW, Rosenstreich DL. Discrimination between urticaria-prone and other allergic 
patients by intradermal skin testing with codeine. J Allergy Clin Immunol. 1986;77(6):802-7. 
PubMed PMID: 3711548. 
43. 
McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X. Identification of a 
mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2014. Epub 
2014/12/18. doi: 10.1038/nature14022. PubMed PMID: 25517090. 
44. 
Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, Church 
MK, Ensina LF, Gimenez-Arnau A, Godse K, Goncalo M, Grattan C, Hebert J, Hide M, Kaplan 
A, Kapp A, Abdul Latiff AH, Mathelier-Fusade P, Metz M, Nast A, Saini SS, Sanchez-Borges M, 


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Schmid-Grendelmeier P, Simons FE, Staubach P, Sussman G, Toubi E, Vena GA, Wedi B, Zhu 
XJ, Maurer M. The EAACI/GA LEN/EDF/WAO Guideline for the definition, classification, 
diagnosis, and management of urticaria: the 2013 revision and update. Allergy. 2014. Epub 
2014/05/03. doi: 10.1111/all.12313. PubMed PMID: 24785199. 
45. 
Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, Spector S, Maurer M. A 
randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients 
with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol. 
2011;128(3):567-73 e1. Epub 2011/07/19. doi: 10.1016/j.jaci.2011.06.010. PubMed PMID: 
21762974. 
46. 
Maurer M, Altrichter S, Bieber T, Biedermann T, Brautigam M, Seyfried S, Brehler R, 
Grabbe J, Hunzelmann N, Jakob T, Jung A, Kleine-Tebbe J, Mempel M, Meurer M, Reich K, 
Rueff F, Schakel K, Sengupta K, Sieder C, Simon JC, Wedi B, Zuberbier T, Mahler V, Staubach P. 
Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against 
thyroperoxidase. J Allergy Clin Immunol. 2011;128(1):202-9 e5. Epub 2011/06/04. doi: 
10.1016/j.jaci.2011.04.038. PubMed PMID: 21636116. 
47. 
Kaplan A, Ferrer M, Bernstein JA, Antonova E, Trzaskoma B, Raimundo K, Rosen K, 
Omachi TA, Khalil S, Zazzali JL. Timing and duration of omalizumab response in patients with 
chronic idiopathic/spontaneous urticaria. J Allergy Clin Immunol. 2016;137(2):474-81. Epub 
2015/10/21. doi: 10.1016/j.jaci.2015.08.023. PubMed PMID: 26483177. 
48. 
Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, Weldon D, 
Zuraw B, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, 
Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. The diagnosis and management of 
acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-7. Epub 
2014/04/29. doi: 10.1016/j.jaci.2014.02.036. PubMed PMID: 24766875. 
49. 
Potter PC, Kapp A, Maurer M, Guillet G, Jian AM, Hauptmann P, Finlay AY. 
Comparison of the efficacy of levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic 
urticaria patients. Allergy. 2009;64(4):596-604. Epub 2008/12/05. doi: ALL1893 [pii] 
10.1111/j.1398-9995.2008.01893.x. PubMed PMID: 19053988. 
50. 
Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based 
review, Part 2. Ann Allergy Asthma Immunol. 2008;100(6):517-26; quiz 26-8, 44. Epub 
2008/07/03. doi: 10.1016/S1081-1206(10)60047-6. PubMed PMID: 18592813. 
51. 
Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based 
review, part 1. Ann Allergy Asthma Immunol. 2008;100(5):403-12. 
52. 
Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced 
reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 
2004;114(3):527-30. Epub 2004/09/10. doi: 10.1016/j.jaci.2004.06.032 
S0091674904017348 [pii]. PubMed PMID: 15356552. 
53. 
Gober L, Sterba P, Eckman J, Saini S. Effect of Anti-IgE (Omalizumab) in Chronic 
Idiopathic Urticaria Patients  J Allergy Clin Immunol 2008;121:S147. 
54. 
Futata E, Azor M, Dos Santos J, Maruta C, Sotto M, Guedes F, Rivitti E, Duarte A, Sato 
M. Impaired IFN-alpha secretion by plasmacytoid dendritic cells induced by TLR9 activation in 
chronic idiopathic urticaria. Br J Dermatol. 2011;164(6):1271-9. Epub 2011/01/05. doi: 
10.1111/j.1365-2133.2010.10198.x. PubMed PMID: 21198536. 
55. 
Mathias SD, Crosby RD, Zazzali JL, Maurer M, Saini SS. Evaluating the minimally 
important difference of the urticaria activity score and other measures of disease activity in 
patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(1):20-4. 
Epub 2011/12/24. doi: 10.1016/j.anai.2011.09.008. PubMed PMID: 22192960. 


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56. 
Baker R, Vasagar K, Ohameje N, Gober L, Chen SC, Sterba PM, Saini SS. Basophil 
histamine release  activity and disease severity in chronic idiopathic urticaria. Ann Allergy 
Asthma Immunol. 2008;100:244-9. 
 
 


Appendices 
 
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Appendix 1. Schedule of Events 
 
 


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Scree
n 
 
Run
-in 
Treatment 
Day 
-21 
-14 
0 
1 
3 
6 
10 
20 
30 
60 
90 
Week 
-3 
-2 
0 
0 
0 
1 
2 
3 
4 
8 
12 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit Window (Days) 
 
± 2 
± 2 
0 
±1 
±1 
± 2 
± 2 
± 4 
±7 
±7 
General 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
Informed consent, 
screening 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical 
History 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (Blood 
pressure, Pulse) 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Weight, Height 
X 
 
 
 
 
 
 
 
 
 
 
Comprehensive 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
X 
Focused history and 
physical exam 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Physician In Clinic 
UAS Scoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication Use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test1 
X 
 
X 
 
 
 
 
 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medications 
 
 
 
 
 
 
 
 
 
 
 
Omalizumab  
 
 
X 
 
 
 
 
 
X 
X 
 
Primary Outcome 
Data 
 
 
 
 
 
 
 
 
 
 
 
Patient Recorded 
UAS7- Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Basophil HR-C5a, 
FMLP, anti-IgE, 
sensitivity, 
enumeration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Secondary Endpoint 
Data 
 
 
 
 
 
 
 
 
 
 
 
Skindex 
 
 
X 
 
 
 
 
 
 
 
X 


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Scree
n 
 
Run
-in 
Treatment 
Day 
-21 
-14 
0 
1 
3 
6 
10 
20 
30 
60 
90 
Week 
-3 
-2 
0 
0 
0 
1 
2 
3 
4 
8 
12 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Safety Outcome 
Measures 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
and platelets3 
X 
 
 
 
 
 
 
 
 
 
X 
Comprehensive 
Metabolic Panel4 
X 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
Measures 
 
 
 
 
 
 
 
 
 
 
 
Basophil Surface IgE 
FceRI Assay, Syk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory Outcome 
Measures 
 
 
 
 
 
 
 
 
 
 
 
Dendritic Cell studies-
Flow 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dendritic Cell function 
 
 
X 
 
 
X5, 6 
 
 
X 
 
 
Basophil mRNA profile  
 
 
X5 
 
 
X5, 6 
 
 
X5 
 
 
Total Blood Histamine 
Content 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-lesional skin 
biopsy 
 
 
X 
 
 
X6 
 
 
 
 
X 
Urine Prostaglandins 
and Eicosanoids 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Measures 
 
 
 
 
 
 
 
 
 
 
 
Serum studies- free 
IgE, autoantibodies7 
X7 
 
X7 
X7 
X7 
X 
X7 
X7 
X7 
X7 
X7 
 
UAS = urticaria activity score. 
1 All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy 
test at screening and prior to study drug administration. If the urine pregnancy test results are positive, dosing 
should be held and a serum pregnancy test performed by the central laboratory. Urine pregnancy tests will be 
performed at the site. 
2  Daily diary completed twice a day by the patient. Includes UAS7 (itch score, number of hives), largest size of 
hives, rescue medication (diphenhydramine) use, angioedema episodes, and number of calls to doctor or 
nurse.  
3  Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count 
(neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
4 Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total 
and direct bilirubin, total protein, albumin, ALT, AST.  
5 Basophil profiling will only occur in subjects with sufficient basophil number at baseline examination.  
6 Biopsy, DC function assays, and mRNA profiling (if indicated) will be timed to onset of MID symptom change. 


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7 Participants will have serum banked for free IgE measurements and autoantibody testing. Purple top stored at 
Visit 1. 
 


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Appendix 2: Patient Diary 
 
 
 
 
 


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Appendix 3: In Clinic UAS 
 
 
 


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Appendix 4: Serious Adverse Event Report Form 


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Serious Adverse Event (SAE) Report Form 
STUDY NAME 
Protocol Number:  
Site Number:  
Pt_ID:  
Visit Date: 
            /                   /                        . 
 d  d     m m m   y     y   y     y 
 
SAE onset date: 
          /                /                    . 
 
 
 
 
 
d d 
m m m 
y y y y 
SAE stop date:  
          /                /                    . 
 
 
 
 
 
d d 
m m m 
y y y y 
Location of serious adverse event: 
 
Was this an unexpected adverse event? 
 Yes 
 No 
Brief description of participants with no personal identifiers: 
Sex: 
 F 
 M Age:  
 
 
 
 
 
 
 
 
 
 
Diagnosis for study participation: 
 
 
 
 
 
 
 
 
Brief description of the nature of the serious adverse event (attach description if more 
space is needed):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category of the serious adverse event: 
 Date of death      /      /       . 
 
                     (dd/mmm/yyyy) 
 Life threatening 
 Hospitalization – initial or prolonged 
 Disability/incapacity 
 
 Congenital anomaly/birth defect 
 Required intervention to prevent 
permanent impairment 
 Other:  


Appendices 
CONFIDENTIAL 
Page 76 of 80 
Protocol [number] 
AZD1981 in CIU 
 
 
 
Intervention type: 
 Medication or nutritional supplement (specify): 
 
 Device (specify):  
 
 Surgery (specify): 
 
 Behavioral/lifestyle (specify): 
 
Relationship of event to intervention: 
 Unrelated (clearly not related to the intervention) 
 Possible (may be related to intervention) 
 Definite (clearly related to intervention) 
Was study intervention discontinued due to event? 
 Yes 
 No 
What medications or other steps were taken to treat the serious adverse event? 
 
 
 
 
 
 
 
List any relevant tests, laboratory data, and history, including preexisting medical conditions: 
 
 
 
 
 
 
 
Type of report: 
 Initial 
 Follow-up 
 Final 
Signature of Principal Investigator:  _______________________  Date:  _______________  
 
 
 
 
(Note: If this CRF is used as a source document, it must be signed and dated by study personnel.) 
Serious Adverse Event (SAE) Report Form 
nccam.nih.gov/...nih.../Serious_Adverse_Events_Form_08-15-12.docx 
 
 


Appendices 
CONFIDENTIAL 
Page 77 of 80 
Protocol [number] 
AZD1981 in CIU 
 
 
 
 
 
 
Appendix 5: Skindex questionnaire 
 


Appendices 
CONFIDENTIAL 
Page 78 of 80 
Protocol [number] 
AZD1981 in CIU 
 
 
 
 
 
 


Appendices 
CONFIDENTIAL 
Page 79 of 80 
Protocol [number] 
AZD1981 in CIU 
 
 
 


Appendices 
CONFIDENTIAL 
Page 80 of 80 
Protocol [number] 
AZD1981 in CIU 
 
 
 
Appendix 6: Protocol deviation forms 
 
 
 

ICF_001.pdf: 
Date: September 9, 2019  
Principal Investigator: Sarbjit S. Saini  
                                            Application No.: IRB00105590    NCT03111628 
Approved September 9, 2019  
  
Page 1 of 13 Combined 
Informed Consent/Authorization June 2015 Version 15  
If you are using Epic for this study, fax a copy  
  
of the signed consent form to 410-367-7382.  
  
  
  
  
   
 
  
Patient I.D. Plate  
  
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY  
AUTHORIZATION FORM  
 
Protocol Title:   
 
Role of IgE Bearing Cells in Chronic Idiopathic Urticaria   
 
Application No.:   
 
IRB00105590  National Clinical Trial Number: NCT03111628
Sponsor:  
  
  
 
National Institutes of Allergy & Infectious Disease (NIAID)  
Principal Investigator: Sarbjit S. Saini, M.D.  
5501 Hopkins Bayview Circle   
Baltimore, Maryland 21224   
Phone: 410-550-2129  
Fax: 410-550-2527   
  
  
 
1. 
What you should know about this study:    
• 
You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand.  
• 
You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.    
• 
During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate.  
• 
If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors.  
• 
When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The  
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.   
• 
Biospecimens will be collected in this study.  Biospecimens may include any of the following:  
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person.  
• 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.   


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• 
If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number.  
  
2. 
Why is this research being done?  
This research is being done to improve our understanding of what white blood cells are involved in the 
disease call Chronic Idiopathic Urticaria (CIU).   
  
In this study, we will use an U.S. Food and Drug Administration (FDA) approved therapy called 
omalizumab (Xolair) for patients with CIU who continue to have symptoms despite taking 
antihistamines.  
By using this therapy, we aim to better understand which cells are involved in creating hives lesions.   
  
Omalizumab (Xolair) is considered a standard care option for patients who are not fully controlled on an 
antihistamine.   
  
People aged 18 years or older, with chronic hives without a known cause for at least 3 months not 
controlled by an antihistamine may join this study.  
  
How many people will be in this study?   
About 30 people are expected to take part in this study at the Johns Hopkins Asthma and Allergy Clinic.  
  
3.  
What will happen if you join this study?  
If you agree to be in this study, we will ask you to do the following things:  
  
The study involves 11 visits over 15 weeks.  
  
First visit, Screening Visit (Day -21):  
At the first visit we will do the following:  
• 
Review this consent form and answer any questions you have.  
• 
History and physical exam: We will ask you questions about your medical history and perform a 
physical exam, which will include checking your vital signs (for example, heart rate, blood pressure, 
weight, and height), looking at your skin, and listening to your heart and lungs. At this initial 
screening visit, the study doctor will review the clinical care of your hives.  
• 
Blood Draw: This will be done by putting a needle into your vein, which is the standard method used 
to obtain blood for tests. At this visit, about 1 tablespoon of blood will be drawn. This blood will be 
sent to the lab for basic blood counts, electrolytes (salts in your blood) and liver and kidney tests.   
• 
Urine Test: We will do a pregnancy test on all women who are capable of having children. The 
results of this test must be negative to continue in this study.   
• 
Urine Collection: We will collect approximately 10 cc of urine from all participants to test for 
prostaglandins (inflammatory markers).  
• 
We will dispense a one week diary for recording your hive symptoms every day.   
  
Screening period:   
During the screening period (first 7 days), you will be asked to keep a diary of your daily symptoms 
(two entries per day). You will visit the study doctor’s office at the end of the screening period to 
discuss your symptoms of hives and to review your diary. Your daily symptom scores will be used to 


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determine if you are eligible to continue in the study. Accurate maintenance of the diary is important for 
the study and will be required in order to continue the study.   
  
Second visit, Run-in period (Day -14):   
At this second visit, we will review your diary and eligibility criteria to determine if you can continue in 
the study. You may be asked to leave the study based on your symptom diary, labs from the previous 
visit, or your response to antihistamine treatment.   
If you are able to continue to take part in the study, the following things will be done:  
• 
Focused History and physical exam: We will ask you about any adverse events and other 
medications you are taking. We will ask you questions about updates to your medical history and 
perform a brief physical exam, which will include checking your vital signs (for example, heart rate, 
blood pressure), looking at your skin, and listening to your heart and lungs.   
• 
Blood Draw: This will be done by putting a needle into your vein, which is the standard method used 
to obtain blood for tests. At this visit, about 2 tablespoons of blood will be drawn. This blood will be 
sent to the lab to perform studies on the cells we believe are involved in producing hives.  
• 
Urine Collection: We will collect approximately 10 cc of urine from all participants to test for 
prostaglandins (inflammatory markers).   
• 
Urine Test: We will do a pregnancy test on all women who are capable of having children.   
• 
Dispense Rescue Drug: We will dispense to you a two week supply of diphenhydramine (Benadryl).   
• 
Run-in period: During the run-in period (2 weeks), you will then be asked to keep an electronic diary 
of your daily hive symptoms (two entries per day) and record your use of as needed Benadryl. You 
will be asked maintain you daily anti-histamine throughout the rest of the study. Accurate 
maintenance of the diary is important for the study and will be required in order to continue the 
study. Based on your symptom diary, you may be asked to leave the study.   
  
Third Visit, First Treatment (Day 0):   
At the start of this visit we will review your run-in period symptoms. Based on your symptom diary, you 
may be asked to leave the study. Otherwise, you will proceed to the treatment phase of the study.  
  
This treatment with omalizumab (Xolair) requires two injections (150 mg each) of omalizumab (Xolair) 
one right after the other. You will have to remain at the study center for 2 hours after the injection.   
  
You will be given an epipen and information on how and when to use it.   
  
We will also draw 6 Tablespoons of blood and perform a skin biopsy (take a pencil eraser sized piece of 
skin). We will also collect approximately 10 cc of urine.  
  
During the treatment period (12 weeks), you will be asked to keep an electronic diary of your daily hive 
symptoms (two entries per day) and record your use of as needed Benadryl.   
  
You will be asked to come for frequent visits in the next month to test how your symptoms and blood 
cells may be changed by the drug.   
  
You will fill out a survey on your hives (Skindex).   
  
Fourth and Fifth Visits (Day 1 and Day 3):   


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You will return to the center 1 day and 3 days after the first drug injection for blood sampling for lab 
study. On each of these visits, 2 tablespoons of blood will be drawn. We will also collect approximately 
10 cc of urine. In addition, we will review your symptoms of hives recorded in your diary and ask you 
about current symptoms.  
  
Sixth Visit (Day 6):   
On the 6th day after the first drug injection, you will visit the center for review of the diary, a blood 
sample (2 to 6 tablespoons, depending on your symptoms), and another skin biopsy. The timing of this 
skin biopsy and larger blood sample (6 tablespoons) will depend on your symptoms. We will also collect 
approximately 10 cc of urine.  
  
It is important to maintain an accurate symptom diary for the treatment phase of the study and it will be 
required in order to continue in the study.  
  
Seventh and Eighth Visit (Day 10 and 20):    
You will return to the center on the 10th and 20th day after the first drug injection. We will perform 
blood sampling (2 Tablespoons) and review of the diary. The second skin biopsy  and larger blood 
sample (6 Tablespoons) can occur on visits 7 or 8 if not completed at visit 6 based on your hive 
symptoms. We will also collect approximately 10 cc of urine.  
  
Ninth Visit, Second Drug treatment (Day 30):   
About 1 month after the first drug injection, you will visit the center for a second drug treatment. This 
treatment with omalizumab (Xolair) requires two injections of omalizumab (Xolair). You will have to 
remain at the study center for 2 hours after the injection.   
  
We will draw 6 Tablespoons of blood and perform the second skin biopsy if not done at an earlier visit. 
We will also collect approximately 10 cc of urine.   
  
We will also review your diary. It is important to maintain an accurate symptom diary for the treatment 
phase of the study and it will be required in order to continue in the study.   
  
We will supply you with more Benadryl if needed.  
  
Tenth Visit, Third Drug treatment (Day 60):   
About 1 month after the second drug injection, you will visit the center for a third and final drug 
treatment. This treatment with omalizumab (Xolair) requires two injections of omalizumab (Xolair). 
You will have to remain at the study center for 2 hours after the injection.   
  
We will also draw 2 Tablespoons of blood, collect approximately 10 cc of urine and review your diary. 
It is important to maintain an accurate symptom diary for the treatment phase of the study and it will be 
required in order to continue in the study. We will supply you with more Benadryl if needed.  
  
Eleventh Visit, Final Visit (Day 90):   
About 1 month after the third drug injection, you will visit the center for the final visit. This visit will 
involve a physical exam, urine sample (10 cc), skin biopsy and blood sample (3 Tablespoons). We will 
collect your diary.  You will fill out a survey on your hives ( Skindex). We will inform you of the results 
of the tests for basic blood counts, electrolytes (salts in your blood) and liver and kidney tests.  


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Future Contact   
We would like your permission to contact you about other studies that you may be eligible for in the 
future.   
  
Please check box and sign to indicate your choice below:   
  
YES  ________________________   
Signature of Participant   
  
NO  __________________   
Signature of Participant   
  
Request to collect and store biospecimens for future research    
As part of this research study, we would like to ask you to let us store your biospecimens and health 
information for future research on CIU and other allergic diseases.  
  
The study doctor can provide you with additional information if you have questions. Also, further 
information about our use of your biospecimens can be found in this consent document under the 
heading What happens to Data and Biospecimens that are collected in the study?.  
  
Will you allow us to store the biospecimens we collect for this study for use in future research?  
 
YES     ________________________    
  
  
  
 
Signature of Participant  
  
  
  
  
  
  
 
NO      __________________   
  
  
  
Signature of Participant  
  
  
How long will you be in the study?  
You will be in this study for 15 weeks total.   
  
4.  
What are the risks or discomforts of the study?  
  
Omalizumab (Xolair)  
In CIU patients, the most commonly observed adverse reactions from 3 CIU studies for omalizumab 
(Xolair) at 300 mg, were: headache  6%), nasopharyngitis (inflammation of the throat and nasal 
passages) (7%), arthralgia (joint pain) ( 3%), viral upper respiratory infection (1%), nausea ( 3%), 
sinusitis (5%), upper respiratory tract infection ( 3%), cough ( 2%), urinary tract infection ( 2%), fungal 
infections (2%), anxiety (2%) and swelling of the hands and feet (2%). Injection site reactions of any 
severity occurred during the trials in more omalizumab (Xolair) treated patients; [2.7%] at 300 mg, 
compared with 0.8% in placebo-treated patients.   
  


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Since omalizumab (Xolair) has been approved, there have been reports of hair loss as well as some 
patients having a severe drop in blood platelets, the cells in the blood that help stop bleeding.  Because 
the number of these cases is small, it is not possible to determine whether these events were associated 
with omalizumab (Xolair).  
  
The most serious side effects seen in other studies are anaphylaxis and cancer.  Anaphylaxis is a severe 
allergic reaction that could result in death.  Signs and symptoms of anaphylaxis may include hives, 
swelling of the throat or tongue, trouble breathing, low blood pressure, lightheadedness, and loss of 
consciousness. Anaphylaxis has been reported to occur after administration of omalizumab (Xolair) in 
asthma clinical trials and in postmarketing spontaneous reports. Anaphylaxis has been reported to occur 
after administration of omalizumab (Xolair) in clinical studies (1 out of every 1000 subjects, 0.1%) and 
in post-marketing experience (at least 2 out of every 1000 subjects 0.2%).  Reactions have occurred after 
the clinic observation period post-injection, so you need to be aware of the signs and symptoms of 
anaphylaxis and contact your study doctor immediately. A severe allergic reaction would require 
immediate medical treatment and could result in permanent disability or death. A study showed that 
among omalizumab (Xolair) users, patients with a history of anaphylaxis to foods, medications, or other 
causes were at increased risk of anaphylaxis associated with omalizumab (Xolair). Based on this, The 
American Academy of Allergy, Asthma & Immunology (AAAAI) guidelines support monitoring 
patients for 2 hours for the first 3 injections of Xolair and the prescription of an epipen injector.   
  
You must remain in the clinic after your injection(s) as part of routine monitoring. You will be dispensed 
an epi-pen to use in case you have signs or symptoms of anaphylaxis.  You will be instructed on how 
and when to use the epi-pen.  You should carry this with you during the study.  If you need to use the 
epi-pen, you will be instructed to contact 911 for further medical care, and notify the study doctor after 
you have received emergency care.  
   
Other severe reactions that have been seen with omalizumab (Xolair) with less than 1% occurrence are:  
chest tightness and stroke like symptoms.  
  
A small number of cancer cases have been reported in research studies of omalizumab (Xolair).  More 
subjects who received omalizumab (Xolair) (5 out of every 1000 subjects 0.5%) reported cancer than 
those subjects who received placebo or other control treatment (2 out of every 1000 subjects 0.2%).  The 
types of cancer observed in omalizumab (Xolair)-treated subjects were a variety of types, with breast, 
non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types 
occurring once each.  While the total number of affected subjects is too small to demonstrate that 
omalizumab (Xolair) causes cancer, the possibility of a relationship between omalizumab (Xolair) and 
the development of cancer cannot be ruled out.  
  
The FDA review of the 5-year safety study in September 2014 found no difference in the rates of cancer 
between those patients being treated with omalizumab (Xolair) and those who were not being treated 
with omalizumab (Xolair). However, due to limitations in the 5-year study, we cannot rule out a 
potential risk of cancer with omalizumab (Xolair).  
   
FDA review of a 5-year safety study found a slightly higher rate of heart and brain blood vessel 
problems occurred in patients being treated with omalizumab (Xolair) compared to those patients not 
treated with omalizumab (Xolair). The heart and brain blood vessel problems included mini-strokes 
known as transient ischemic attacks or TIAs; heart attacks; sudden, unexpected chest pain; high blood 


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pressure in the arteries of the lungs called 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, we are unable to definitively confirm or determine the exact 
increased level of these risks with omalizumab (Xolair).  
  
Omalizumab (Xolair) contains a small amount of a specific sugar (sucrose).  The amount of sucrose in a 
vial of omalizumab (Xolair) is 145 mg, and one dose of omalizumab (Xolair) will be composed of up to 
2 vials.  Subjects with certain disorders related to how their bodies handle sugar (diabetes mellitus, 
glucose-galactose malabsorption syndrome, fructose intolerance, or sucrose-isomaltase deficiency) 
should discuss the specific impact of this small amount of sugar and the associated risks with the study 
doctor.  
  
Fever, Arthralgia, and Rash:  Some subjects taking omalizumab (Xolair) have experienced signs and 
symptoms including arthritis (joint inflammation), arthralgia (joint pain), rash, fever and 
lymphadenopathy (swollen/enlarged lymph nodes) starting 1 to 5 days after receiving an omalizumab 
(Xolair) injection.  These signs and symptoms are similar to those seen in subjects with a condition 
called serum sickness, which is an immune reaction to certain types of medications.  The study doctor 
will stop omalizumab (Xolair) if you develop these signs and symptoms.  
  
If you experience dizziness, fatigue, syncope (fainting) or somnolence (drowsiness), you should not 
drive or use machines.  
  
  
As is true for participation in any research study, there may be unknown and potentially serious or 
lifethreatening side effects that could occur with omalizumab (Xolair). There may be side effects and 
discomforts that are not yet known.  
  
Benadryl (Diphenhydramine):   
Diphenhydramine (Rescue medication) may cause sedation.  
  
Epipen:   
The most common side effects include increase in heart rate, stronger or irregular heartbeat, sweating, 
nausea and vomiting, difficulty breathing, paleness, dizziness, weakness or shakiness, headache, 
apprehension, nervousness or anxiety. These side effects usually go away quickly.  
  
Blood Drawing Risks:   
During this study, blood will be drawn from a vein to perform tests that allow your doctors to see how 
you are doing.  Drawing blood may cause pain where the needle is inserted, and there is a small risk of 
bruising and/or infection at the place where the needle is inserted.  Some people experience dizziness, 
upset stomach, or fainting when their blood is drawn.  
  
Skin biopsy risks:   
Risks of skin punch biopsy include pain, swelling, bleeding, bruising, infection, and scarring at the site 
of the biopsy.  Allergic reactions to lidocaine are rare, but may cause hives, itching, asthma, hay fever, 
or a drop in blood pressure.  Significant bleeding from biopsy sites is rare.  Infection of a biopsy site is 
unusual, but may occur.  A scar the size of a pencil eraser will result at the biopsy site.  This scar will be 


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slightly raised or depressed below the surface of the skin and will be a little lighter or darker than the 
rest of your skin.  
  
Confidentiality: There is the risk that information about you may become known to people outside this 
study.  
  
5.  
Are there risks related to pregnancy?  
  
Reproductive Risks  
The effects of omalizumab (Xolair) on a fetus or embryo are unknown and may be harmful; therefore, 
you should not become pregnant or father a child while in this study.    
  
Women must be sterile, postmenopausal, or using a highly effective form of birth control throughout the 
study.   
  
To participate in this study, you must agree to use an effective method of birth control to prevent 
pregnancy.  Woman capable of having children must use one or more of the following acceptable 
methods of contraception:  surgical sterilization, hormonal contraception, and/or double-barrier methods.  
Check with your study doctor about the methods of birth control to use and how long to use them.  
  
Women capable of having children will be required to take a pregnancy test prior to study entry and at 
each visit prior to dosing of omalizumab (Xolair).  The result of the test must be negative for you to 
continue to take part in the study.   
  
  
  
If you are pregnant, you cannot be in this study because of possible harm to the fetus.  If at any time 
during the study you suspect that you have become pregnant, please notify the study doctor immediately.    
  
You should not nurse (breastfeed) a baby while on this study because omalizumab (Xolair) may enter 
breast milk and the potential of harming your baby is unknown at this time.  
  
This research may hurt an embryo or fetus in ways we do not currently know.   
  
6. 
Are there benefits to being in the study?  
There may or may not be a direct benefit to you from being in this study. However, your participation in 
the study may benefit society by helping us learn more about better ways to treat hives in the future.  
  
7. 
What are your options if you do not want to be in the study?  
If you decide not to join this study, other options are available. You do not have to join this study to get 
treatment. Other options include:  
• 
Getting no treatment  
• 
Getting standard treatment for your condition without being in a study (including getting 
omalizumab (Xolair)).  
• 
Getting a different experimental treatment/taking part in another study.  
  


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You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected.  
  
8. 
Will it cost you anything to be in this study?  
No.  
  
9. 
Will you be paid if you join this study?  
• 
You will be paid $40 dollars for the 8 study visits that do not require skin biopsies (for a total of 
$320).   
• 
You will be paid $75 for each of the 3 visits that involve skin biopsies (for a total of $225).     
• 
This means that if you complete all study visits, you will be paid a maximum of $545 for taking part 
in the study.   
  
You will be provided with a parking voucher at each visit.   
  
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us.  
  
10. 
Can you leave the study early?  
• 
You can agree to be in the study now and change your mind later.  
• 
If you wish to stop, please tell us right away.  
• 
Leaving this study early will not stop you from getting regular medical care.   
  
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.   
  
11. 
Why might we take you out of the study early?  
You may be taken out of the study if:  
• 
Staying in the study would be harmful.  
• 
You need treatment not allowed in the study.  
• 
You fail to follow instructions.  
• 
You become pregnant.  
• 
The study is cancelled.  
• 
There may be other reasons to take you out of the study that we do not know at this time.   
  
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities.  
  
12. 
How will your privacy be protected?   
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule.  
  


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The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records ([which may include 
information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental health 
treatment).  
  
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.     
  
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study. If you are in a cancer study that receives federal 
funding, the National Cancer Institute (NCI) now requires that we report identifiable information (such 
as, zip code) about your participation.  You may contact the NCI if you have questions about how this 
information is used.   
  
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study.  
  
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be 
redisclosed.  
  
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal  
Investigator’s name, address, phone and fax information are on page one of this consent form.   
  
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization.  
  
13. 
What treatment costs will be paid if you are injured in this study?   
Johns Hopkins and the federal government do not have programs to pay you if you are hurt or have other 
bad results from being in the study.  However, medical care at Johns Hopkins is open to you as it is to all 
sick or injured people.  
  
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you.  
  
By signing this form you will not give up any rights you have to seek compensation for injury.   
  


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14. 
What is a Certificate of Confidentiality?  
Your study information is protected by a Certificate of Confidentiality. This Certificate allows us, in 
some cases, to refuse to give out your information even if requested using legal means.  
  
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting research data in 
the medical record or sharing research data for this study or future research. Disclosures that you make 
yourself are also not protected.  
  
15. 
What does a conflict of interest mean to you as a participant in this study?   
A researcher has a financial or other interest in this study.    
  
In some situations, the results of this study may lead to a financial gain for the researcher and/or Johns 
Hopkins.  This financial interest has been reviewed in keeping with Johns Hopkins’ policies.  It has been 
approved with certain conditions, which are intended to guard against bias and to protect participants.  
  
If you have any questions about this financial interest, please talk to Dr. Eric Oliver, 410-550-2007. This 
person is a member of the study team, but does not have a financial interest related to the study. You 
may also call the Office of Policy Coordination (410-361-8667) for more information. The Office of 
Policy Coordination reviews financial interests of investigators and/or Johns Hopkins.  
  
16. 
What other things should you know about this research study?  
a. What is the Institutional Review Board (IRB) and how does it protect you?  The Johns Hopkins 
Medicine IRB is made up of:  
• 
Doctors  
• 
Nurses  
• 
Ethicists  
• 
Non-scientists  
• 
and people from the local community.   
  
  
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research.  
  
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.    
  
b. What do you do if you have questions about the study?     
Call the principal investigator, Dr. Saini at 410-550-2129. If you wish, you may contact the principal 
investigator by letter or by fax.  The address and fax number are on page one of this consent form. If 


Date: September 9, 2019  
Principal Investigator: Sarbjit S. Saini  
                                            Application No.: IRB00105590    NCT03111628 
Approved September 9, 2019  
  
Page 12 of 13 
Combined Informed Consent/Authorization June 2015 Version 15  
you cannot reach the principal investigator or wish to talk to someone else, call the IRB office at 
410-955-3008.    
  
c. What should you do if you are injured or ill as a result of being in this study?   
If you think you are injured or ill because of this study, call Dr. Saini at 410-550-2129 during regular 
office hours.   
  
If you have an urgent medical problem related to your taking part in this study, call Dr. Sarbjit 
Saini at 410-550-2129 during regular office hours and at 410-978-3706 after hours and on weekends.   
  
d. What happens to Data and Biospecimens that are collected in the study?   
Johns Hopkins and our research partners work to understand and cure diseases.  The biospecimens 
and/or data you provide are important to this effort.  
  
  
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.   
  
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.     
  
  
  
  
  
  
17. 
What does your signature on this consent form mean?   
Your signature on this form means that: You understand the information given to you in this form; you accept the 
provisions in the form and you agree to join the study. You will not give up any legal rights by signing this 
consent form.   
  
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM  
  
  
________________________________________________________________________________________________________________________  
Signature of Participant                                                                           (Print Name)                                                  
  
Date/Time   
  
  
________________________________________________________________________________________________________________________  
Signature of Person Obtaining Consent                                                  (Print Name)                                                
  
Date/Time  
  
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN  
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED).   
  
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS.  
  
  
 


Date: September 9, 2019  
Principal Investigator: Sarbjit S. Saini  
                                            Application No.: IRB00105590    NCT03111628 
Approved September 9, 2019  
  
Page 13 of 13 
Combined Informed Consent/Authorization June 2015 Version 15  
  
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT  
  
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study.  
  
________________________________________________________________________________________________________________________  
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                      
  
Date/Time    
  
  
  
________________________________________________________________________________________________________________________  
Signature of Participant                                                    (Print Name)                                                                     Date/Time        
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN  
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED).   
  
  
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS.