Conditions: Asthma
Keywords: mild asthma young adults rhinovirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
Population surveys have shown a positive correlation between increased levels of total serum immunoglobulin E (IgE) and bronchial hyperreactivity. However, it is also clear that exacerbations of asthma are frequently triggered by viral respiratory tract infections, especially those caused by human rhinovirus (RV), also known as the "common cold" virus. This protocol explores the relationship between rhinovirus and allergen/IgE provoked inflammation. Experimental challenges with human (RV) result in more persistent upper respiratory tract symptom scores in asthmatics than in controls. Asthmatics with high levels of IgE also show greater sensitivity to methacholine and higher levels of expired nitric oxide (eNO) than those with low levels of IgE. These data suggest that patients with asthma and high levels of IgE are more likely to have pre-existing inflammation of the airways before virus challenge. This study is being done to determine whether anti-IgE therapy (with omalizumab) will lead to a significant decline in inflammatory biomarkers prior to virus inoculation, and thus reduce the severity of clinical manifestations after an experimental human RV challenge.

Detailed description:
The study is a randomized, double-blind placebo controlled study involving a group of 42 mild asthmatics. Subjects will be randomized 1:1 to omalizumab (a humanized monoclonal anti-IgE antibody) or placebo for 8 weeks and then inoculated with rhinovirus (strain-16 produced under GMP conditions and approved for this research by the FDA). Clinical and laboratory (mechanistic) data will be evaluated for 8 weeks before and for 4 weeks after the virus challenge.

The study is being done to test the hypothesis that the reduction of total free IgE in asthmatics treated with omalizumab for 8 weeks prior to and during an experimental RV challenge will lead to a significant decline in lower respiratory tract (chest) symptoms recorded by subjects during the first four days of infection following the challenge compared to lower respiratory tract symptoms recorded during the same period by asthmatic subjects who are treated with placebo.

The primary endpoint will be based on the comparison of cumulative lower respiratory tract symptoms scores (CLRTS) in the asthmatic subjects treated with omalizumab compared to those treated with placebo over the first 4 days of acute infection. Diary cards will be scored daily for cough, shortness of breath, chest discomfort and wheezing using a modification of the Jackson criteria. To participate in this study, subjects must live within 90 minutes by car from the University of Virginia.

Note: This protocol has been reviewed and is being monitored for safety by the NIH/NIAID Safety Monitoring Committee and by he IRB at the University of Virginia (IRB-HSR# 14427).

Arms:
arm 1: Subjects with mild asthma will be treated with omalizumab for 8 weeks before and for 3 weeks after an experimental challenge with rhinovirus. Omalizumab will be given subcutaneously every 2 to 4 weeks according to the manufacturer's recommendations. arm 2: Subjects with mild asthma will be treated with placebo medication for 8 weeks before and for 3 weeks after an experimental challenge with rhinovirus. The placebo mediation will consist of the same diluent used for suspending the omalizumab without omalizumab added.

Interventions: intervention 1: omalizumab intervention 2: Rhinovirus (strain 16)
Intervention descriptions: intervention 1: This medication has been approved for clinical use to treat patients with moderate to severe asthma by the FDA in 2003 and for use in this study (BB-IND# 10510) intervention 2: This strain of pooled rhinovirus has been approved for use in experimental challenges (BB-IND# 15162) and for use in this study (BB-IND# 10510) by the FDA.

Protocol document:
Prot_SAP_000.pdf: 
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PROTOCOL NIH/NIAID: U01 AI 100799 – 04 
IRB PROTOCOL IDENTIFYING NUMBER 
IRB HSR # 14427 
An Evaluation of Treatment with Omalizumab to Improve the 
Asthmatic Response to an Experimental Infection with 
Rhinovirus 
 
VERSION 13.0 (August 1, 2016) 
 
Omalizumab/Rhinovirus IND: BB-IND #10510 
IND Sponsor: Peter Heymann, M.D., University of Virginia 
This clinical study is funded by the National Institute of Allergy and Infectious Diseases (NIAID) and is provided 
with Omalizumab and placebo by Novartis Pharmaceuticals. 
 
 
 
 
 
 


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PRINCIPAL INVESTIGATORS 
Thomas Platts-Mills, MD, PhD, FRS 
Department of Medicine 
P.O. Box 801355 
University of Virginia  
Charlottesville, VA 22908 
Tel# 434-924-2209 
Fax# 434-924-5779 
Email: tap2z@virginia.edu 
 
 
Peter Heymann, MD 
Department of Pediatrics 
P.O. Box 800386 
University of Virginia 
Charlottesville,  VA  22908 
Tel#  434-982-3654 
Fax#  434-924-5778 
E-mail: pwh5a@virginia.edu 
 
 
 
 
 
 
 
 
 
CO-INVESTIGATOR(S) (if applicable) 
 
Ronald  Turner, PhD Professor of Pediatrics  
Associate Dean for Clinical Research  
Department of Pediatrics  
University of Virginia School of Medicine  
P.O. Box 800386  
Barringer Building, Room 4441  
Hospital Drive  
Charlottesville, VA 22908  
Phone:  434-243-9864  
Fax:  434-982-4246 
Email: rbt2n@virginia.edu   
 
Anne-Marie Irani, MD 
Professor of Pediatrics and Medicine 
Head, Division of Pediatric Allergy & Immunology  
Virginia Commonwealth University 
Medical College of Virginia 
Tel# 804-828-9620 
Fax# 804-828-1751 
E-mail : airani@vcu.edux 
 
BIOSTATISTICIAN 
James T. Patrie MS 
Senior  Biostatistician  
Division of Biostatistics and Epidemiology  
Department of Public Health Sciences  
University of Virginia Health Sciences  
Charlottesville, VA 22908 
Phone: 434-924-8576 
Fax: 434-243-5787  
email jp4h@virginia.edu 
 
 
 
 
NIAID MEDICAL OFFICER 
 Lisa M Wheatley MD MPHDivision of Allergy, 
Immunology and Transplantation 
National Institute of Allergy and Infectious Diseases 
 5601 Fishers Lane 6B56Rockville, MD 20892Phone: 240-
627-3573lisa.wheatley@nih.gov 
 
  
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential investigators, consultant
study staff and applicable independent ethics committees or institutional review boards.  The contents of this document s
not be disclosed to others without written authorization from AADCRC and NIAID, unless it is necessary to obtain 
informed consent from potential study subjects. 


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INVESTIGATOR SIGNATURE PAGE 
Protocol U01-UVA-02  
 
Version/Date:  
VERSION 13.0 (August 1, 2016) 
 
IND Number  
Omalizumab – BB-IND #10510 
 
  Principal Investigator:  
Peter Heymann, MD   
Short Title:  Omalizumab to Improve Asthmatic Response to RV-16 Infection 
IND Sponsor: Peter Heymann, MD 
INSTRUCTIONS:  The Principal Investigator will print, sign, and date at the indicated location 
below.  A copy should be kept in the investigator’s records and the original signature page sent to 
the NIAID.   
After signature, please return the original of this form by surface mail to:  
 
Project Manager: Steven Sigelman, BSN 
DAIT/ NIAID/ AAABB 
5601 Fishers Lane 6B57 
Rockville, MD 20892 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312 , and the 
International Conference on Harmonization (ICH) document “Guidance for Industry:  E6 Good 
Clinical Practice:  Consolidated Guidance” dated April 1996 (this should be reference #1 in Section 13) 
and the spirit of the Declaration of Helsinki,  Further, I will conduct the study in keeping with local, 
legal, and regulatory requirements.   
 
As the Principal Investigator, I agree to conduct AADCRC-UVA-02:  An Evaluation of Treatment with 
Omalizumab to Improve the Asthmatic Response to an Experimental Infection with Rhinovirus.  I agree to 
carry out the study by the criteria written in the protocol and understand that no changes can be 
made to this protocol without written permission by the NIAID, the local IRB and the FDA. 
 
 
 
__________________________________________ 
Principal Investigator (Print) 
 
 
 
 
___________________________________________                                      _____________________ 
Principal Investigator (Signature)                                                                              Date 
 
 


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Synopsis  
Title 
An Evaluation of Treatment with Omalizumab to Improve the Asthmatic 
Response to an Experimental Infection with Rhinovirus 
Short Title 
 Omalizumab to Improve Asthmatic Response to RV 16 Infection 
Rationale 
Population surveys have shown a positive correlation between increased 
levels of total serum IgE and bronchial hyperreactivity and it is also clear 
that exacerbations of asthma are frequently triggered by viral respiratory 
tract infections, especially human RV. This protocol explores the 
relationship between rhinovirus and allergen/IgE. Experimental 
challenges with human (RV) result in significantly higher upper 
respiratory tract symptom scores in asthmatics than in controls. 
Asthmatics with high levels of IgE showed greater sensitivity to 
methacholine and higher levels of eNO than those with low levels of IgE. 
These data suggest that patients with asthma and high levels of IgE are 
more likely to have pre-existing inflammation of the airways before virus 
challenge. This study is being done to determine whether anti-IgE 
antibody will lead to a significant decline in inflammatory biomarkers 
prior to virus inoculation, and thus reduce the severity of clinical 
manifestations after experimental human RV challenge. 
Clinical Phase 
Phase II 
Mechanistic Study 
×Yes           □No 
IND Sponsor 
Peter Heymann, MD 
Principal Investigators  
Peter Heymann, MD and Thomas Platts-Mills, MD, PhD, FRS 
Participating Site(s) 
University of Virginia (Charlottesville,  VA)   
 
Accrual Objective 
42 total subjects:  21  with Omalizumab and RV challenge, 21 with placebo 
and RV challenge 
Study Objective 
To test the hypothesis that the reduction of total free IgE in asthmatics 
treated with omalizumab for 8 weeks prior to and during an experimental 
RV challenge will lead to a significant decline in lower respiratory tract 
(chest) symptoms recorded by subjects during the first four days of 
infection following the challenge compared to lower respiratory tract 
symptoms recorded during the same period by asthmatic subjects treated 
with placebo.  


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Study Design 
Randomized,  double-blind placebo controlled study in a group of  42 
mild asthmatics.  Subjects will be randomized 1:1 to omalizumab (a 
humanized monoclonal anti-IgE antibody) or placebo for 8 weeks and 
then   inoculated with GMP RV 16 with a subsequent clinical and 
laboratory (mechanistic) follow up for 4 weeks.  
Study Duration 
45 months   
Primary Endpoint 
The primary endpoint will be based on the comparison of cumulative 
lower respiratory tract symptoms scores (CLRTS)  in  the asthmatic 
subjects treated with omalizumab compared to those treated with placebo 
over the first 4 days of acute infection. The lower respiratory tract 
symptoms evaluated will include shortness of breath, chest discomfort, 
and wheezing.  
Secondary Endpoints 
Secondary endpoints will include a comparison of CLTRS scores  in the 
asthmatic and non-asthmatic subjects over the first 4 days of the acute 
infection, and will include symptoms of shortness of breath, chest 
discomfort, wheezing, as well as cough. Secondary outcomes will also 
include a comparison of changes from baseline in 1) methacholine 
sensitivity (PC20), 2)  expired nitric oxide (eNO), 3) impulse oscillometry, 
4) immune cell analyses including frequency of circulating eosinophils 
and RV and allergen specific regulatory and effector T-cells, 5) 
concentrations of nasal wash mediators and cytokines, 6) weights of nasal 
mucous and secretions collected during the first 4 days of the infection, 
and 7)cumulative upper respiratory tract symptoms scores (CURTS) 
detected during peak cold symptoms over the first 4 day s of the infection 
among subjects enrolled in the omalizumab and placebo treated groups. 
Diary cards will be scored daily for runny nose, sneezing, nasal 
congestion, sore throat, headache, chills/fever, fatigue, itchy eyes, watery 
eyes and red eyes using a modification of the Jackson criteria as 
previously described (16). An additional secondary endpoint will be rate 
of subjects whose FEV1 drops by more than 20% from their baseline value 
at the time of enrollment. We will also compare changes in the same 
parameters and in the CLTRS scores between the treatment groups from 
baseline, using the same statistical methods described for the primary 
endpoint, over the first 7 and 21 days of the infection, in parallel with 
results from the validated ACT questionnaire, to detect differences 
stimulated by RV, and we will compare changes in markers of 
inflammation and bronchial hyperreactivity between the omalizumab and 
placebo groups during the 8 weeks of drug administration before RV 
challenge in order to evaluate the effect of these changes on the response 
to RV. 
Inclusion Criteria 
• Subject must be able to understand and provide written informed 
consent 
• Age 18 to < 40 years of age, any gender, any racial/ethnic origin 


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• Physician-diagnosed asthma 
• ACT score > 19 
• Short-acting beta-agonist use < daily in last 4 weeks 
• FEV1 > 70%, or FEV1/FVC ratio > 75% for subjects with FVC values 
between 80 and 87% predicted whose FEV1 values fall below 70%.  
• Positive Methacholine challenge test (i.e. at least 20% fall in FEV1 at a 
Methacholine concentration of ≤16 mg/ml) at screening protocol 
before enrollment (20).  
• Total serum IgE level ≥ 125 IU/ml documented during screening 
protocol. 
• Positive test for allergen specific IgE antibody by prick skin testing 
documented during screening protocol. to allergens associated with 
current allergen exposure at the time of the RV challenge: e.g., dust 
mite, Alternaria, and/or ragweed for subjects challenged with RV in 
the fall, or positive tests to tree and/or grass allergens for those 
challenged with RV in the spring. In keeping with the study design 
goals of inoculating subjects during periods of allergen exposure, 
sensitization to other allergens (e.g., cat or dog) will also qualify for 
enrollment if subjects are currently exposed to these allergens at home. 
Participant must be willing to comply with study procedures and 
requirements. Participant must be considered eligible for participation 
based on results of screening procedures conducted by  protocol number 
20100686 at VCU and IRB# 12656 at UVA). Refer to Appendix 4.  
Exclusion Criteria 
• 
Inability or unwillingness of a participant or subject’s legal 
representative to give written informed consent and HIPPA 
authorization  
• 
Positive test for serum neutralizing antibody to RV-16 at screening 
within 6 weeks (i.e., subjects with a neutralizing antibody titer > 
1:4 will be excluded).  
• 
To avoid RV-16 inoculations in subjects with more restrictive lung 
volumes, those whose FVC is < 80% predicted will also be 
excluded.  
• 
Total IgE levels measured at screening protocol that are too 
elevated based on a subjects weight, to meet the recommendations 
proposed by Novartis for treatment with Omalizumab (21).  
• 
Chronic heart disease, lung diseases other than asthma, or other 
chronic illnesses, including primary and/or secondary 
immunodeficiency.  
• 
Hospitalization or treatment in the ER for asthma (unless the 
treatment involved the use of a bronchodilator only)  during the 
last three years. 
• 
Subjects who have had one or more night time awakenings caused 
by asthma symptoms and/or who have needed their SABA 
(albuterol) inhaler for asthma symptoms > 4 days during the week 
before enrollment, or during the week before the inoculation with 
RV-16.  
• 
Intubation or management in the intensive care unit for an asthma 


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exacerbation 
• 
An upper or lower respiratory tract infection within six weeks 
prior to enrollment 
• 
Previous nasal or sinus surgery within the last 12 months. 
• 
Who have a 5 pack/year history of smoking, or any smoking 
within the last 6 months.    
• 
Female subjects who are, or who plan to become, pregnant during 
the study, or who are nursing a baby. Additionally, to be included 
in this study, a woman of child-bearing potential must have a 
negative urine pregnancy test at screening, during the run, and 
prior to viral inoculation and agree to use an  effective method of 
birth control such as, but not limited to, birth control pills, 
contraceptive foam, diaphragm, IUD, abstinence, or condoms. 
• 
Subjects who have used  omalizumab within 6 months prior to 
enrollment, or inhaled corticosteroids,inhaled ipratropium 
bromide, an inhaled long acting beta agonist, inhaled cromolyn or 
nedocromil or systemic leukotriene modifiers for their asthma on a 
daily basis within 4 weeks prior to enrollment or subjects using 
nasal corticosteroids on a daily basis within 4 weeks prior to 
enrollment. Subjects who are currently receiving beta-adrenergic 
blocking agents. 
• 
Subjects who are currently receiving allergen immunotherapy (IT),  
or who have received allergen IT  within the last 3 years. 
• 
Hemoglobin <11.5 g/dL for non-African American subjects or 
hemoglobin < 11.0 g/dL for African American subjects detected 
during screening within 6 weeks of enrollment. 
• 
Absolute neutrophil count (ANC) < 1500 cells/mm3 (or 1.5 K/uL) 
detected during screening within 6 weeks of enrollment or Day -2. 
Investigational 
Product(s)/Intervention(s)  
This study will use 2 interventions: 
1. All subjects will receive Rhinovirus 16 challenge 
2. Half of the subjects will receive omalizumab and the other half placebo 
instead of Omalizumab 
Study Procedures 
The following procedures will be performed according to the schedules in  
Appendix 5 
• 
Medical and allergy history 
• 
 Limited physical exam   
• 
Urine pregnancy test/Urine LTE4 
• 
Nasal wash 
• 
Monitoring of nasal mucous and secretion weights during the 
first 4 days of the infection 
• 
Skin testing, including tests for Alternaria, dust mite, and 
ragweed, grass and tree pollen allergens 
• 
Spirometry 


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• 
Exhaled Nitric Oxide 
• 
CBC/differential 
• 
Serum IgE levels (total and allergen specific) 
• 
T-cells blood test 
• 
RV 16 antibody  titres by neutralization assay 
• 
Methacholine challenge 
• 
Impulse oscillometry 
• 
RV 16 inoculation 
• 
Completion of diary cards 
• 
Added to this study will be a nasal specimen obtained by using an ASI 
Rhino-Pro® nasal mucosal curette to do a light scraping along the 
inferior turbinate of each nostril to collect epithelial cells at 3 time points 
during the study. 
• 
A small piece of gauze  will be applied to the inferior turbinate of each 
nostril at 3 different time points during the study to sample nasal lining 
fluid to measure albumin, mediators and cytokines.  
Statistical considerations 
Using Monte Carlo simulation to estimate statistical power, 42 asthmatic 
subjects will be enrolled. For 8 weeks prior  to inoculation with RV-16 and 
during the infection, 21 subjects will be randomized to a treatment group 
receiving Omalizumab and 21 subjects will be randomized to a group 
receiving placebo. Accounting for a 20% drop out rate, 17 subjects in each 
treatment arm are expected to complete the study which. Based on the 
power calculations, this will be sufficient to detect a 2.4 unit difference in 
the CLTRS score during the first 4 days after RV inoculation between the 
2 treatment groups. The power of the test was determined to be 0.83. 
Statistical analyses of the data will use methods published in our previous 
experimental challenges of asthmatic and non-asthmatic subjects 
challenged with RV-16 (16). 


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Table of Contents 
1. 
BACKGROUND AND RATIONALE ................................................................ 16 
1.1 
BACKGROUND .................................................................................................................. 16 
1.2 
RATIONALE FOR SELECTION OF STUDY POPULATION ...................................... 18 
1.3 
INVESTIGATIONAL PRODUCT(S)/INTERVENTION(S) .......................................... 20 
1.4 
RATIONALE FOR SELECTION OF INVESTIGATIONAL 
PRODUCT(S)/INTERVENTION(S) AND REGIMEN .................................................. 24 
1.5 
CLINICAL EXPERIENCE .................................................................................................. 26 
1.6 
RISKS .................................................................................................................................... 27 
1.6.1 
Risks of study procedures………………………………………………………………..32 
2.  OBJECTIVES…………………………………………………………………………...34 
2.1 
PRIMARY OBJECTIVE(S) .................................................................................................. 34 
2.2 
SECONDARY OBJECTIVE(S)……………………………………………………………34 
2.3 
EXPLORATORY OBJECTIVE(S) ....................................................................................... 36 
3. 
STUDY DESIGN .................................................................................................... 37 
3.1 
STUDY ENDPOINTS ......................................................................................................... 38 
3.1.1 
Primary Endpoint(s)  .......................................................................................................... 38 
3.1.2 
Secondary Endpoint(s) ....................................................................................................... 39 
3.2 
STUDY COMPLETION ...................................................................................................... 41 
4. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ............................ 42 
4.1 
INCLUSION CRITERIA  .................................................................................................... 42 
4.2 
EXCLUSION CRITERIA .................................................................................................... 43 
4.3 
PARTICIPANT WITHDRAWAL CRITERIA .................................................................. 45 


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5. 
INVESTIGATIONAL PRODUCT(S)/INTERVENTION MATERIAL(S), 
OTHER STUDY PRODUCTS (CONTROLS/PLACEBOS) ............................ 47 
5.1 
INVESTIGATIONAL PRODUCT(S)/INTERVENTION(S) .......................................... 47 
5.2 
PREPARATION, ADMINISTRATION, AND DOSAGE ............................................... 47 
5.3 
ACCOUNTABILITY OF     INVESTIGATIONAL PRODUCT(S) AND 
INTERVENTION(S)………………………………………………………………………51  
5.4    MODIFICATION OR DISCONTINUATION OF INVESTIGATIONAL 
PRODUCT (s) / INTERVENTION MATERIALS (S)……………………..   51 
5.4.1 
Modification of Investigational Product(s)/Intervention(s) ......................................... 51 
5.4.2 
Premature Discontinuation of Investigational Product(s)/Intervention(s) ................ 52 
6. 
OTHER MEDICATIONS ............................................................................................. 53 
6.1 
CONCOMITANT MEDICATIONS .................................................................................. 53 
6.2 
PROPHYLACTIC MEDICATIONS .................................................................................. 53 
6.3 
RESCUE MEDICATIONS .................................................................................................. 53 
6.4   
PROHIBITED MEDICATIONS………………………………………………………….53 
7. 
STUDY VISITS AND PROCEDURES ............................................................... 54 
7.1 
ENROLLMENT AND RANDOMIZATION ................................................................... 54 
7.2 
SCREENING AND STUDY VISIT(S) ............................................................................... 54 
7.3 
VISIT WINDOWS ............................................................................................................... 63 
7.4 
STUDY PROCEDURES ...................................................................................................... 63 
7.5 
STUDY ARM ASSIGNMENT PROCEDURES ................................................................ 70 
7.5.1 
Blinding and Randomization ............................................................................................ 70 
7.5.2 
Securing Blinding and Randomization Information ...................................................... 71 
7.5.3 
Requirements for Unblinding ........................................................................................... 71 


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7.5.4 
Documenting and Unblinding .......................................................................................... 72 
7.6 
Mechanistic studies………………………………………………………………………..72 
8. 
SAFETY PROCEDURES ....................................................................................... 74 
8.1 
STOPPING RULES ............................................................................................................. 74 
8.1.1 
Study Stopping Rules ......................................................................................................... 74 
8.1.2 
Individual Stopping Rules ................................................................................................. 75 
8.1.3 
Early Discontinuation of Investigational Product(s)/Intervention(s) with continued 
study participation/follow-up .......................................................................................... 76 
8.1.4 
Follow-up after early study termination ......................................................................... 76 
8.1.5 
Participant Replacement .................................................................................................... 77 
8.2 
ADVERSE EVENTS ............................................................................................................ 77 
8.2.1 
Definitions ............................................................................................................................ 77 
8.2.1.1 Adverse Events and Suspected Adverse Reactions ......................................... 77 
8.2.1.2 Adverse Events Associated with Study Procedures ............................................... 78 
8.2.1.3 Serious Adverse Event (SAE) ................................................................................................ 82 
8.2.1.4 Unexpected Adverse Event .................................................................................................... 83 
8.2.1.5 Safety  Monitoring Committee .............................................................................................. 84 
8.2.2 
Collecting, Recording and Managing Adverse Events .................................................. 84 
8.2.2.1 Identifying Adverse Events ................................................................................................... 84 
8.2.2.2 Recording AEs ................................................................................................................... 85 
8.2.2.3 Recording SAEs ..................................................................................................................... 88 
8.2.2.4 Managing Adverse Events .................................................................................................... 88 
8.2.3 Grading and Attribution ........................................................................................................ 89 


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8.2.3.1 Grading criteria ...................................................................................................................... 89 
8.2.3.2 Definition of attribution: ........................................................................................................ 90 
8.2.4. SAE Reporting and Procedures ................................................................................................ 91 
8.2.4.1. Notifying the NIAID Medical Officer  .................................................................................. 91 
8.2.4.2 Unexpected, Non-Serious Adverse Events ............................................................................. 92 
8.2.4.3. Notifying the FDA ................................................................................................................. 92 
8.2.4.4. Notifying the  SMC  .............................................................................................................. 93 
8.2.4.5. Notifying the Institutional Review Board ............................................................................. 93 
8.2.4.6 Reporting Pregnancy .............................................................................................................. 93 
8.2.5 
Non Serious Adverse Events Reporting .......................................................................... 94 
8.2.5.1 Notifying the  SMC ............................................................................................................... 94 
8.2.5.2 Notifying the Institutional Review Board ............................................................................. 95 
8.2.5.3 Notifying the FDA ................................................................................................................. 95 
8.3 
PROTOCOL DEVIATIONS (PROTOCOL VIOLATION) ............................................. 95 
8.3.1 
Protocol Deviation Definition ........................................................................................... 95 
8.3.2 
Reporting Protocol Deviations .......................................................................................... 98 
9. 
SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN .................... 99 
9.1 
SAMPLE SIZE AND POWER CALCULATIONS .......................................................... 99 
9.1.1 
General considerations ....................................................................................................... 99 
9 
9.1.3 Study Participant Baseline Characteristics and Demographics...................................... 105 
9.1.4 Study Endpoints .................................................................................................................... 105 
9.1.5 Study Completion ................................................................................................................. 105 


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9.2 
INTERIM ANALYSES ...................................................................................................... 105 
9.3 
DEVIATIONS FROM STATISTICAL PLAN................................................................. 105 
10. 
IDENTIFICATION AND ACCESS TO SOURCE DATA ............................. 106 
10.1 
IDENTIFYING SOURCE DATA………………………………………… …….106 
10.2 
UPDATING SOURCE DOCUMENTATION ................................................................ 106 
10.3 
PERMITTING ACCESS TO SOURCE DATA ............................................................... 107 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................ 108 
12. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE ........................................................................................ 109 
12.1  
STATEMENT OF COMPLIANCE .................................................................................. 109 
12.2  
INFORMED CONSENT AND ASSENT ........................................................................ 109 
12.3 
PRIVACY AND CONFIDENTIALITY ........................................................................... 110 
13. 
PUBLICATIONS ........................................................................................................ 115 
14. 
REFERENCES ....................................................................................................... 116 
List of Appendices  
Appendix 1.  Diary Card- Lower respiratory symptoms……………………………………..122                                            
 Appendix 2.  Diary Card- Upper  respiratory symptoms……………………………………123 
Appendix 3.  Asthma Control Test (ACT) questionnaire…………………………………….124 
Appendix 4.  Outline of Screening Visits to Determine Eligibility………………………….125 
Appendix 5.  Schedule of Events……………………………………………………………….126 
Appendix 6.  Treatment Guidelines for Asthma Symptom Exacerbations……………………129  
 


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15. Addendum: Added Protocol for “Evaluating the Asthmatic 
Response to an Experimental Infection with Rhinovirus in the Atopic 
Host                                                                      124-142Glossary of 
Abbreviations/Definitions  
 
AADCRC 
Asthma and Allergic Diseases Cooperative Research Center 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CLRTS 
Cumulative lower respiratory tract symptoms  
 
CTCAE 
Common Terminology Criteria for Adverse Events 
(CURTS) 
Cumulative  upper  respiratory tract symptoms  
DAIT 
Division of Allergy, Immunology, and Transplantation 
cGCP 
current Good Clinical Practice 
ICH 
International Conference on Harmonization 
 
 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
PI 
Principal Investigator 
RV 
Rhinovirus 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee  
SUSARs  
 A Serious, Unexpected Suspected Adverse Reaction 


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1. 
BACKGROUND AND RATIONALE 
1.1 
Background   
The investigations described in this proposal are designed to examine alterations in the 
immune response to rhinovirus (RV) in the atopic host and to provide insight into 
mechanisms which contribute to exacerbations of asthma caused by this virus. All 
subjects enrolled will have physician diagnosed asthma and positive methacholine 
challenge tests characteristic for asthmatic individuals. No subjects will be excluded 
because of race, gender, or ethnic background.  During screening the atopic status of 
each subject will be defined with assessments of total IgE in serum and allergen specific 
IgE sensitization by prick skin testing to eleven aero-allergens which represent common 
allergen exposures in Virginia and the Mid-Atlantic States. Although many studies of 
asthmatic subjects define atopy as a positive test for IgE to one or more common 
aeroallergens, we have observed that the asthmatics with total IgE levels > 125 IU/ml 
enrolled in our RV challenge studies frequently have sensitization to several  
aeroallergens and the large majority have IgE antibody to dust mite (16). We feel that it 
will continue to be important to characterize the atopic status of subjects enrolled this 
study by assessing and reporting their total IgE levels and allergen specific 
sensitizations.     
 
Based on previous studies, pre-treatment with omalizumab will reduce the levels of 
serum-free total IgE in subjects to very low levels (i.e. reductions to <5% of baseline 
values) (1a). By binding to Fc epsilon, omalizumab modifies the expression of allergic 
symptoms by preventing the binding of IgE to IgE-receptor bearing cells (mast cells and 
basophils). Omalizumab has also been shown to reduce blood eosinophil counts and 
expired nitric oxide (eNO) levels during treatment (2). In keeping with this, we predict 
that treatment with omalizumab in our study will lead to a significant decline in 


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inflammatory biomarkers in the airway prior to RV inoculation and, thus, reduce the 
risks for an adverse response to RV during the infection. In clinical trials, omalizumab 
has already been shown to have steroid-sparing effects in asthmatic children and adults 
(3, 4). Moreover, treatment with this medication has reduced the frequency of asthma 
exacerbations leading to hospitalization and ER visits, which previous studies have 
shown are frequently associated with RV infections (5-10).  
   
In this investigation, we will use experimental RV challenges to provide a time-
sequence analysis of the response to RV following viral inoculation in asthmatic 
subjects. The strain of RV that will be used is a pool of RV (strain 16) that will be 
provided by Dr. Ronald Turner’s laboratory at the University of Virginia (UVA). Dr. 
Turner, is a co-investigator in this study, and has collaborated with Johnson & Johnson 
Pharmaceutical Research and Development to produce this pool of RV under GMP 
conditions. This pool has been safety tested and has been approved for experimental 
challenge studies by the FDA (BB-IND #15162; IND holder, Dr. Ronald Turner). In 
addition, this pool of RV has undergone extensive clinical trials during Dr. Turner’s 
evaluation of the new RV-16 pool using the experimental RV challenge model to 
evaluate subjects at the University of Virginia (see section 1.5 Clinical Experience). 
Using the Jackson criteria for scoring cold symptoms (11, 12), infection rate and total 
symptom scores are comparable to our previous experience with other rhinovirus 
challenge pools (both RV-16 used in our initial rhinovirus challenges and RV-39 
challenges conducted by Dr. Turner) with the exception of a higher than expected 
number of subjects who developed cold symptoms in the infected volunteers. The 
severity of cold symptoms, however, were similar to the severity of symptom recorded 
by asthmatics and control subjects in previous studies by Dr. Turner and other 
investigators at UVA using RV 16 prior to the requirement that the RV pools used for 
inoculation must be produced under GMP conditions (13-15). In addition, the majority 


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of published data from experimental rhinovirus challenges in asthmatic individuals, 
including our own, and including subjects with moderately severe asthma, have used 
RV-16 which would help us compare our results to these previous studies now that a 
GMP produced pool of RV-16 is available (e.g., 16, 34, 39).  
 
This study is being done to determine whether anti-IgE antibody will be effective in 
reducing the adverse effects of viral infections in patients with mild asthma. This study 
will determine whether anti-IgE can modify the inflammatory effects of viral infections.  
Moreover, the clinical implications of the results (if they support the hypothesis) are 
that efforts to reduce allergic inflammation may improve the tolerance of allergic 
asthmatics to the adverse effects of a viral infection. As in our previous studies of RV, 
we will make all test results (along with interpretation of their significance) available to 
patients.  Thus, we hope that patients will learn about the effects of the common cold on 
their asthma and how to minimize symptoms when they have an infection. The 
experimental RV challenge model will be used to test the hypothesis that treating 
asthmatics with omalizumab (a humanized monoclonal anti-IgE antibody) for 8 weeks 
prior to virus inoculation and during the infection will lead to a significant decline in 
upper and lower respiratory tract symptom scores, inflammatory biomarkers, and 
changes in lung function (e.g. methacholine sensitivity) compared to the results of these 
assessments in asthmatics treated with placebo prior to RV inoculation and during the 
infection. 
1.2 
Rationale for Selection of Study Population  
The experimental RV challenge model will be used to test the hypothesis that treating 
asthmatics with omalizumab (a humanized monoclonal anti-IgE antibody) for 8 weeks 
prior to virus inoculation and during the infection will decrease the risk for an 
asthmatic response to RV during the infection. 


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In our previous experimental challenge studies, and those of others, lower respiratory 
tract symptoms (mild wheeze, cough, dyspnea and/or chest tightness) have been 
reported in subjects with mild asthma (16, 17). Our previous studies have also shown 
that moderate to severe asthma exacerbations caused by naturally occurring infections 
with RV occur predominantly in children, and are much less common in asthmatic 
adults, especially those with mild asthma (17). As a result, we, as well as other 
investigators, have done our challenges by evaluating allergic adults (mostly college 
students) with mild asthma. In our studies, we can detect significant differences in 
lower respiratory tract symptoms, methacholine sensitivity, and markers of airway 
inflammation if we screen our subjects for atopy (total IgE levels > 125 IU/ml) and do 
our challenges during periods of increased allergen exposure (e.g. in the spring or fall 
months in Virginia) without risks for causing an asthma exacerbation requiring hospital 
care (16). In this regard, one of the important exclusion criteria for participation in our 
challenges is that we will not enroll subjects who have required treatment in the 
hospital or ER during the previous 3 years. Because RV infections occur frequently, we 
are confident that subjects who participate in this study will have tolerated natural RV 
infections over the last 3 years without experiencing a significant asthma exacerbation.  
 
To date, we have inoculated 45 mild asthmatic adults with RV (strains 16 or 39). Only 
one of these subjects, who was inoculated with RV-39, experienced audible wheezing 
and a reduction in FEV1 during peak cold symptoms. Her symptoms responded to a 
short (5 day) course of oral steroids. She and the other 44 subjects did not experience 
symptoms requiring a visit to the ER or hospital. We have also completed a surveillance 
study of 16 adults with mild asthma, using the same inclusion and exclusion criteria 
proposed for this study to monitor the effects of administering omalizumab 
Omalizumab on natural RV colds. The treatment (i.e. 8 subjects treated with 


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omalizumab and 8 treated with placebo) covered a period of 3 months. No subjects 
withdrew from this study and there were no adverse events. Ten of the 16 subjects 
(62%) had nasal washes which tested positive for RV by RT-PCR at least once during 
clinic visits scheduled every other week. No subject experienced significant chest 
symptoms or reductions in lung function triggered by these natural infections. 
However, we cannot rule out the possibility that the subjects may have been 
seropositive to some the strains of RV detected in this surveillance study (18). For this 
reason, the experimental challenge study described below is a much better study 
design, because subjects will either be sero-negative, or have low titers (< 1:4) of 
neutralizing antibody to the strain of RV (i.e. RV-16) used for inoculation.    
 
1.3 
Investigational Product(s)/Intervention(s)  
A.  Omalizumab  
Omalizumab (Xolair®) was approved by the FDA on June 20, 2003 for the treatment 
of adults and adolescents (age 12 and up) with moderate to severe asthma who have 
a positive skin test or in vitro reactivity to perennial aeroallergen and whose 
symptoms are inadequately controlled with inhaled corticosteroids.  Omalizumab is 
a recombinant DNA-derived humanized IgG1k monoclonal antibody that 
selectively binds to human immunoglobulin E (IgE).  Omalizumab is produced by a 
Chinese hamster ovary cell suspension culture in a nutrient medium containing the 
antibiotic gentamicin.  Note that gentamicin is NOT detectable in the final product. 
Omalizumab is a sterile, white preservative-free lyophilized powder contained in a 
single-use vial that is reconstituted with sterile water for injection and is 
administered subcutaneously.  
 
B.  Placebo drug (produced by the same manufacturer: Novartis Pharmaceuticals):  


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The product described in this module is the placebo to Xolair 150 mg Powder for 
solution for injection. The placebo is the same mixture of inactive excipients, in quality 
and quantity, as those used for the drug product, except that the drug substance, 
omalizumab, is not added. 
 
C.  Rhinovirus (strain 16)  
Rhinovirus (strain 16) will be used for inoculation in the RV challenge. The strain of RV 
that will be used is a pool of RV (strain 16) provided by Dr. Ronald Turner’s laboratory 
at the University of Virginia.  This pool has been extensively safety tested and has been 
approved for experimental challenge studies by the FDA (IND# 15162).  
 
The dose of RV used is in this study (300 - 500 TCID50 ) is similar to that used in our 
previous challenges (16). This inoculum is likely to be higher than the dose of RV 
associated with a natural infection, although information regarding how much of an RV 
inoculum is sufficient to produce a cold is not known.  The total dose of RV-16 used in 
this study is expected to result in a response in the lower airway that is sufficient to 
differentiate the asthmatic responses to RV-16 between the subjects who are treated 
with omalizumab prior to and during the infection and those who are treated with 
placebo, and at the same time will be safe in the study population of mild asthmatics 
proposed in this study. This is based on our previous investigations of 16 mild 
asthmatics and 9 controls challenged with a total dose of 100-150 TCID50 of rhinovirus 
16 where we used a modification of the Jackson criteria to score daily upper respiratory 
tract symptoms and lower respiratory tract symptoms (16). Upper and lower 
respiratory scores  were summarized for each individual by computing cumulative 
scores over study days 0 to 4 and over study days 0 to 21.  The study showed that in 
both asthmatic patient groups (i.e., those with high IgE and those with low IgE), the 
lower respiratory tract symptoms scores were significantly increased (P < .001) 


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compared with control patients by day 21 (high IgE = 13.5 [6.2 to 29.3]; low IgE = 8.5 
[3.2 to 22.3]; control patients = 0.7 [0.3 to 1.5]). Additionally, by day 4, the CLRTS scores 
for the asthmatic patients with high IgE were greater (mean [CI]: 4.2 [1.4 to 12.5]) than 
for the asthmatic patients with low IgE (1.0 [0.4 to 2.5, P = .05) and control patients (0.4 
[0.2 to 1.2] P = .0003 (low IgE group versus control patients , P = .2) which is the 
rationale for enrolling asthmatic subjects with total IgE levels > 125 IU/ml in our 
planned study with omalizumab. During the infection, all but 3 of the asthmatic 
subjects reported mild lower respiratory tract symptoms of cough, wheeze, shortness of 
breath, or chest discomfort and none of the asthmatic patients had symptoms requiring 
intervention with anti-inflammatory medications (i.e., inhaled or oral steroids).   
 
Also on the basis of the modified Jackson criteria, the development of peak upper 
respiratory symptoms in asthmatic patients was in many cases delayed: for example, 8 
of 9 control patients (89%) had peak symptoms during the first 4 days compared with 8 
of 16 asthmatic patients (50%, P = .05)  . Also the delayed development of peak 
symptoms observed for the asthmatic patients was more pronounced in the low IgE 
group: i.e., 4 of 6 (67%) with high IgE levels had peak symptoms during the first 4 days 
compared with 4 of 10 (40%) of those with low IgE levels. (See Figure 1 below) During 
the 21days of monitoring, asthmatic patients had cumulative symptom scores that were 
increased and prolonged compared with scores in control patients. The difference 
between scores for the high IgE group and control patients was significant (P < .02); the 
difference between scores for the low IgE group and control patients was not 
significant. 
 
 
 
 


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Figure 1. Upper respiratory tract symptom scores. *  
 
* Based on the modified Jackson criteria (16) the symptoms recorded daily by asthmatic and controls included sore throat, sneezing, 
rhinorrhea, and nasal congestion. Vertical line represents standard error bars. 
 
A previous study by other investigators has been conducted using doses of 1280-12800 
TCID50 of rhinovirus 16 in 8 subjects with allergic asthma (39). In this study, subject-
related symptom score was tabulation of 13 cold symptoms with highest possible score 
of 39 and the highest peak symptom score reported among study subjects was 15. 
Another study of experimental rhinovirus infection with used doses of 5,000 - 10,000 
TCID50 of RV 16 on 2 subsequent days and this resulted in bronchial infection 
demonstrated by in situ hybridization for RV16 on bronchial biopsy samples. Chest 
scores were higher in asthmatics than in non-asthmatics, however chest scores did not 
seem to correlate with a strong in situ hybridization signal (40). 


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1.4 
Rationale for Selection of Investigational 
Product(s)/Intervention(s) and Regimen  
Population surveys have shown a positive correlation between increased levels of total 
serum IgE and bronchial hyper-reactivity and it is also clear that exacerbations of 
asthma are frequently triggered by viral respiratory tract infections, especially human 
RV. Moreover, studies have demonstrated an enhancement of bronchial hyper 
reactivity during and following colds in atopic individuals. In preliminary studies using 
the experimental human RV challenge model at UVA, 16 young adults with asthma and 
9 non-allergic subjects without asthma were inoculated with human RV (strain 16). The 
results showed that the upper respiratory tract symptom scores for the asthmatics were 
significantly increased compared to controls. Six of the 16 asthmatics also had 
substantially elevated levels of total serum IgE (371-820 IU/mL) and these patients 
showed greater sensitivity to methacholine and had significantly higher levels of eNO 
throughout the study. High levels of IgE in the asthmatics were also associated with 
increased level of eosinophilic cationic protein (ECP) in nasal washes and total blood 
eosinophil counts, but lower levels of nasal sICAM-1, the epithelial cell receptor for 
human RV. Because the cell surface expression of ICAM-1 is stimulated by INF-gamma 
(together with IL-1 and TNF-alpha), the observation of lower levels of sICAM-1 in the 
high IgE asthmatics raises the hypothesis that increased allergic (Th2) eosinophilic 
inflammation prior to human RV inoculation may impair the development of INF-
gamma production from Th1/Tc1 lymphocytes and hinder viral clearance. These data 
suggests that patients with asthma and high levels of IgE are more likely to have pre-
existing inflammation of the airways, including augmented eosinophil response before 
virus inoculation and during the infection. The strain of RV that will be used is a pool of 
RV (strain 16) has been extensively safety tested and has been approved for 
experimental challenge studies by the FDA (IND# 15162). 


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Currently, omalizumab would not be a cost-effective medication for individuals with 
mild asthma. However, there is no reason to believe that mild asthmatics would not 
derive benefit from this medication, nor is there reason to suspect that they would have 
a greater risk for adverse events associated with omalizumab treatment.  As noted 
above, we have already treated 16 subjects with mild asthma in a surveillance study for 
3 months without any adverse events (IRB-HSR # 10408). This drug has also been 
shown to improve symptoms in individuals with allergic rhinitis (24-27).   
 
Since June, 2003, omalizumab has been available to treat children and adults (over age 
12 years) with moderate to severe asthma. Omalizumab is an expensive medication, but 
is cost-effective in those with moderate to severe disease. Although we will be using 
omalizumab in adults with mild asthma, there are several published studies 
demonstarting efficacy and safety in subjects with allergic rhinitis as noted above (24-
27).  
 
In this study, we will use experimental human RV challenges to provide a time-
sequence analysis of the response to RV following viral inoculation in mild asthmatic 
subjects. We predict that treatment with omalizumab will lead to a significant decline in 
inflammatory biomarkers (section 7.6) prior to inoculation, and thus reduce the risk for 
an adverse response to RV during the infection. Knowing which biomarkers decline 
and which do not during the administration of omalizumab should provide new 
mechanistic insights. 
 
This medication has been shown to decrease the incidence of asthma exacerbations in 
children and adults, who are atopic along with reductions in the use of oral and inhaled 
corticosteroids as well as exacerbations leading to hospitalizations and ER visits (3-10). 
As a result, there is significant cost saving benefits to asthmatics with moderate to 


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severe disease whose risks for hospital care is increased.  In our study Omalizumab will 
be given to subjects with mild asthma. The FDA has only approved the use of 
Omalizumab in subjects with moderate to severe asthma.  The FDA has previously 
reviewed this study (IND # 10510) and concluded (as of October 20, 2009) that the 
clinical trial may be initiated using a GMP produced pool of RV-39 that was available 
and used for our challenges at the time.  More recently, RV-16 was produced under 
GMP conditions and the FDA has approved the use of RV-16 for experimental 
inoculations (IND# 15162) which should allow us to use both RV-16 and Omalizumab 
as proposed for this study after final review by the NIH and the FDA.  
1.5 Clinical Experience 
The safety and efficacy of omalizumab has been evaluated and the results reported in 
three randomized, double-blind, placebo-controlled, multicenter trials. (3-7).  
The human RV type 16 was produced in human fetal lung fibroblasts -MRC-5 cells- 
under GMP conditions in collaboration with Johnson & Johnson, Inc. and has been used 
for experimental challenges and evaluated for safety and efficacy in clinical studies 
involving human volunteers during the fall (2011). Fifty-one non-asthmatic volunteers 
(mean age 25 years) were enrolled and inoculated with the new pool of RV-16 (29 with a 
1000 TCID50 dose and 22 with a smaller 100 TCID50 dose to learn whether the larger 
dose would increase the infection rate and severity of symptoms.  The primary purpose 
of this clinical trial was to assure that the new challenge pool was comparable to 
previous pools with regard to infection rate and symptom production.  Forty-eight 
(94%) of the 51 evaluable subjects were infected, and 85% of the 48 infected volunteers 
developed a symptomatic illness.  The results revealed no difference between the two 
doses used in infection rate or illness.  The infection rate and total symptom scores were 
comparable to our previous experience with other rhinovirus challenge pools with the 
exception of a higher than expected rate of illness (i.e. development of cold symptoms) 


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of the volunteers developed in the infected volunteers using the new RV-16 pool. One 
subject developed a respiratory illness 17 days after RV-inoculation.. After her acute 
post-challenge cold symptoms had resolved, she developed a respiratory illness 17 days 
after RV-16 inoculation that was diagnosed as bronchitis by her primary care physician 
who treated her with azithromycin starting 24 days after RV inoculation. She was seen 
29 days after inoculation by Dr. Turner. At that time her symptoms were resolving. No 
other significant virus related respiratory adverse events were reported among the 
subjects in this trial.   Taken together, this new pool has been approved for experimental 
challenge studies by the FDA (IND# 15162; IND holder Dr. Turner) and has advantages 
for use in future challenge studies to assess pathogenesis or treatment and is the same 
strain used in our original published study of experimental rhinovirus challenges in 
asthmatic subjects (16), and has been the strain used by the majority of other 
investigators who have published results using the experimental RV challenge model to 
evaluate the response to rhinovirus in asthmatic subjects.  
1.6 Risks 
Omalizumab:  
A recent review of the literature and the manufacturer’s prescribing/product 
information report (PLI) focused on post-marketing reports leading to an analysis of the 
safety and the risk of immune-system effects, hypersensitivity reactions, malignant 
neoplasia, parasitic infections, serum sickness and thrombocytopenia (28,29). The 
outcome of this analysis, based on an estimated exposure of 57,300 patients, who 
received treatment between June, 2003 and December, 2006, confirmed a small risk for 
anaphylactic symptoms (0.2 %), but no deaths occurred (or have ever been reported) 
and there were no increased risks for other symptoms or reactions in this analysis. More 
recently (October 30, 2015) the manufacturers of omalizumab (Xolair®) reported that 
asthmatics with a history of anaphylaxis to foods, medications, or other causes had a 


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higher risk of anaphylaxis with omalizumab injections compared to those without a 
history of anaphylaxis. However, the overall risk is still 0.2% and lower (0.1%) in 
clinical studies. This information will be reviewed in the consent process and all 
subjects enrolled will be given an Epi-Pen, along with demonstrations how and when to 
use it. In keeping with AAAAI recommendations and standard practice in the 
University of Virginia allergy clinics, subjects will also be observed for 2 hours after the 
first 3 injections of omalizumab or placebo  and for 30 minutes after receiving 
subsequent injections. Each subject will be receiving 3 or 6  injections of study drug 
during the investigation depending on body weight and baseline serum total IgE levels.  
A more recent, 5-year safety study found that a slightly higher rate of heart and brain blood 
vessel problems occurred in 5007 patients treated with Xolair® compared to 2829 patients not 
treated with Xolair® . These heart and brain blood vessel problems include chest pain, heart 
attack, blood clots in the lungs or legs, temporary symptoms of weakness on one side of the 
body, slurred speech, and change in vision. There were no increases in the rates of stroke or 
death from heart disease in the patients treated with Xolair® compared to patients not treated 
with Xolair®.  It is not known whether the slightly higher rate of heart and brain blood vessel 
problems is caused by Xolair®.  This study included adults with an average age of 45. There 
were more patients who had severe asthma in the group treated with Xolair® than there were in 
patients who were not treated with Xolair®.  It is possible that other medications used to treat 
severe asthma raised stroke and heart disease risks and not the Xolair®, but there is no way to 
know that for sure. 
 
Placebo drug (produced by the same manufacturer: Novartis Pharmaceuticals):  
The product described in this module is the placebo to Xolair 150 mg Powder for 
solution for injection. The placebo is the same mixture of inactive excipients, in quality 
and quantity, as those used for the drug product, except that the drug substance, 
omalizumab, is not added. 
 


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Rhinovirus (strain 16) 
Approximately 2000 volunteers have been challenged in studies conducted by Dr. 
Turner, Dr. Heymann, and their colleagues over the last 30 years and no serious 
complications attributable to the viral infection have been detected. The clinical 
syndrome associated with experimental infection is well-described.  Challenge of 
volunteers with 100 TCID50 produces infection in 90 to95% of susceptible volunteers.  
Symptoms first appear within 24 hours after inoculation and peak at 48-72 hours after 
challenge.  The clinical syndrome is comparable to that reported in natural colds (35, 36) 
although in one study with identical definitions for duration the median duration of 
illness was 3.5 days in volunteers with experimental colds and 5.5 days in volunteers 
with natural colds (37).  Approximately one-third of RV infections, whether natural or 
experimental, are asymptomatic.  Virus shedding in infected volunteers follows a 
pattern similar to that of the symptoms.  Virus concentrations in nasal lavage fluid, 
based on titers in culture, generally peak 2-3 days after challenge and then rapidly 
decrease.  Virus can be recovered by culture in 20% of subjects on day 18 after 
challenge, but no virus shedding is detected by day 20 (38).  To the best of our 
knowledge, human RV-16 has not been withdrawn from investigation or marketing in 
any country for any reason related to safety or effectiveness. In our studies, we have 
observed neutropenia in most of the 29 asthmatic subjects and also 16 controls 
following inoculation with RV-16 in our experimental challenges, which we believe is in 
keeping with the recruitment of neutrophils into the airways stimulated by RV. 
However, except for the possibility of bronchitis, which occurs infrequently in 
experimental infections, no subject has developed clinically significant bacterial 
infections in our studies, including bacterial sinusitis. Additionally, no subject in our 
studies with RV-16 has developed ANC’s less than 1000 cells/mm3.   


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The results from experimental challenges in asthmatics with RV-16 and RV-39 at the University 
of Virginia indicate that RV challenges can be done safely in mild asthmatics who are not using 
anti-inflammatory medications. This has also been the experience of others using the RV 
challenge model elsewhere.  In the first study of asthmatics enrolled in challenge studies at the 
University of Virginia using RV-39, one of 19 subjects needed intervention with inhaled steroids 
during peak cold symptoms (14). One college student enrolled in our studies needed a short 
course of oral steroids when challenged with RV-39 produced under GMP conditions. This 
student was one out of 23 asthmatic subjects who were inoculated with this pool in our 
experimental challenges. Additionally, 3 of the last 12 asthmatic subjects challenged with this 
pool of RV-39 more recently used albuterol more frequently for chest symptoms during peak 
symptoms, but they experienced no significant declines in their FEV1 values monitored at home 
or observed in our clinical research center.  No subject enrolled in any of our studies who have 
been challenged with either RV-16 or 39, or in studies published by others using RV-16 that we 
are aware of, has experienced an exacerbation requiring hospitalization or treatment in the ER. 
In our previous published study with RV-16 prior to the virus being manufactured under GMP 
conditions, 13 of the 16 subjects with mild asthma reported mild symptoms of cough, wheeze, 
or chest discomfort during the infection, but none required intervention with anti-inflammatory 
medications such as inhaled or oral corticosteroids (16). We are interested to use this new pool 
because the majority of published data from experimental challenges with RV have been done 
using RV-16 which is helpful in comparing our results (e.g., 34, 39). 
Recently, in a European study, challenges with RV-16 were well-tolerated by subjects with 
moderately severe asthma who were treated with inhaled corticosteroids (Adura P, Reed E, 
MacIntyre J, et al. Experimental rhinovirus-16 challenge in moderate asthma. 2010 ATS 
Conference abstract presentation (#5516))(41).  However, all asthmatic subjects in that study 
were using inhaled steroids at the time of inoculation which would interfere with our goals of 
judging the effects of omalizumab on lower respiratory tract symptoms and bio-markers of 
inflammation. 
All subjects in the proposed study will be inoculated with RV-16 and monitored daily for 4 days 
following inoculation in a hotel. Daily monitoring will include upper and lower respiratory 


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symptoms scores, and FEV1 measurements (using a hand held FEV1 monitor given to each 
subject) which will be recorded twice daily (morning and evening) on diary cards. Subjects will 
also be recording the number of puffs of albuterol used daily from metered dose inhalers with 
puff counters (which will also be checked daily by the study nurse coordinator).  In addition, 
monitoring each morning will include a physical examination focused on the respiratory tract 
(performed and recorded by a physician), along with spirometry and measurements of expired 
nitric oxide (FeNO).  This monitoring will be done to enhance our ability to detect changes 
during the acute infection and to ensure safety. Both the DoubleTree and Holiday Inn hotels in 
Charlottesville have had an on-going relationship with our research team. The hotels are 
located within 5 miles of the main medical campus. Each subject will have their own room and 
a member of our research team will stay in an adjacent room for 24 hours daily for 4 days 
during the entire hotel stay. The research team member will be a licensed physician or nurse 
and will be readily available should any problems occur. Thus far, no significant problems or 
serious adverse events have occurred for any of the asthmatics inoculated with either RV-16 or 
RV-39. 
To date, there is no evidence from extensive clinical trials with omalizumab, or since its use 
beginning in 2003 after FDA approval, that there have been any serious complications that 
might suggest that omalizumab might potentiate the effects of RV.  Although there have been 
no studies to specifically examine our stated hypothesis, we are confident that many of the 
patients who have received omalizumab for their asthma have experienced naturally-occurring 
RV infections without serious consequences. As for any adverse long-term safety effects of an 
experimental RV-16 infection, the cold symptoms observed have been generally similar to, but a 
bit shorter in duration than a natural RV infection (see above). Because most adults will 
experience at least one or two viral induced colds a year,  it would be very difficult to 
differentiate any adverse effects of an RV-16 experimental infection from the effects of a 
subsequent natural respiratory tract infection in an effort to evaluate any safety problems long-
term.  
 


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1.6.1 Risk of Study Procedures  
• Inoculation: it is expected that challenge with GMP RV-16 will cause a common cold 
comparable to that reported in natural colds although of a shorter duration than 
natural colds  
Nasal lavage: it may be associated with some discomfort due to < 10 second breath hold 
and the feeling of fluid in the nares. A rare potential complication is acute bacterial 
sinusitis (sinus infection)Light nasal scraping: After the nasal wash an additional nasal 
specimen will be obtained by using a ASI Rhino-Pro® nasal mucosal curette plastic 
device to do a light scrapping along the inferior turbinate of each nostril to collect 
epithelial cells. This will be done using a headlight and a disposable nasal speculum to 
spread the nares (Bionix) to enhance visibility of the turbinates. The nasal scrapings 
may be associated with discomfort during the procedure and sometimes sneezing. 
Minor problems with nose bleeding are infrequent because we are just scraping surface 
cells called epithelial cells. The nasal scrapings are being done to investigate how genes 
expressed by the lining cells in the nose (called epithelial cells) respond to changes in 
the environment, specifically in this study in response to exposure to the common cold 
virus (rhinovirus) or to environmental allergens. Importantly, the results from these 
scrapings will not be used to identify a participants genetic background or risk factors, 
and can't be used for genetic profiling. 
 
 
• Nasal lining fluid: An additional nasal specimen will be obtained by applying a 
small piece (1 X 1 cm) of sterile gauze (Surgicel®), routinely used by ENT surgeons 
at UVA during surgical procedures to provide hemostasis,  to inferior turbinate for 4 


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to 5 minutes in each nostril to collect a sample of epithelial cell lining fluid (about 0.2 
ml).   
• Monitoring nasal mucous weights and secretions during the 1st four days after virus 
inoculation: There are no risks involved. 
• Injection: the use of sterile technique will make infection at the site where 
Omalizumab injections are given extremely unlikely, but infection at injection site is 
a rare potential AE. 
• Blood draw: drawing blood causes transient discomfort and may cause fainting.  
Ecchymosis (bruising) at the blood draw site may occur but can be prevented or 
lessened by applying pressure to the draw site for several minutes.  The use of 
sterile technique will make infection at the site where blood will be drawn extremely 
unlikely. 
• Lung function tests,  exhaled nitric oxide testing and methacholine challenge: 
The risk of lung function tests and eNO testing is the discomfort of exhaling 
forcefully.  The inhalation of aerosols may be associated with mild shortness of 
breath, cough, chest tightness, wheezing, chest soreness or headache. Many patients 
do not have any symptoms at all. Symptoms (if they occur) are mild, last only a few 
minutes, and disappear following the inhalation of a bronchodilator medication, 
which will be administered as needed.  
• Impulse oscillometry: Mild light-headedness and coughing, shortness of breath, 
and/or chest tightness,  occurs infrequently and is easily reversed with inhaled 
albuterol. 
• Skin testing: it is expected to result primarily in discomfort, wheal and flare 
responses and pruritus. Approximately 2-3 in 10,000 skin prick tests results in 
allergic symptoms away from the site of the skin testing, such as sneezing, 
rhinorrhea, or rash. Very rarely, an individual who experiences this type of reaction 
may develop life-threatening symptoms such as anaphylaxis. 


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2. 
OBJECTIVES 
2.1 
Primary Objective(s)  
To test the hypothesis that the reduction of total free IgE in asthmatics treated with 
omalizumab for 8 weeks prior to and during an experimental RV challenge will lead to 
a significant decline in lower respiratory tract (chest) symptoms [i.e., cumulative lower 
respiratory symptoms (CLRTS)] recorded by subjects during the first four days of 
infection following RV challenge compared to lower respiratory tract symptoms 
recorded during the same time period by asthmatics treated with placebo.  The CLRTS 
scores will be recorded by subjects on diary cards twice daily throughout the study (see 
example of diary card in Appendix 1: Lower Respiratory Tract Symptoms). For the 
primary outcome, the evaluation of lower respiratory tract symptoms, which will be 
derived from the diary cards, will include shortness of breath, chest discomfort, and 
wheezing.   
 
2.2 
Secondary  Objective(s) 
Secondary endpoints will include a comparison of CLTRS scores  in the asthmatic and 
non-asthmatic subjects over the first 4 days of acute infection, and will include 
symptoms of shortness of breath, chest discomfort, wheezing, and cough. Secondary 
endpoints will also include a comparison of changes from baseline in:  
• methacholine sensitivity (PC20),  
• expired nitric oxide (eNO),  
• impulse oscillometry,  
• the frequency of circulating RV and allergen specific regulatory and effector T-cells, 
•  concentrations of nasal wash mediators and cytokines,  


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• cumulative upper respiratory tract symptom (CURTS) scores. See example of diary 
card for subjects to record their CURTS scores twice daily throughout the study in 
Appendix 2).  
 
The changes from baseline for these endpoints will be compared to the results for these 
assessments measured during peak cold symptoms over the first 4 day s of the infection 
among subjects enrolled in the omalizumab and placebo treated groups.  
Diary cards will be scored daily for runny nose, sneezing, nasal congestion, sore throat, 
headache, chills/fever, fatigue, itchy eyes, watery eyes and red eyes using a 
modification of the Jackson criteria as previously described (16).  
 
Using the same statistical methods described for the primary endpoint, we will also 
compare changes in the CURTS and CLTRS scores between the treatment groups from 
baseline over the first 7 and 21 days of the infection to detect differences stimulated by 
RV, and we will compare other the parameters monitored during the infection as listed 
above over these same time points.   Additionally, using our measurements focused on 
daily symptoms and the same parameters monitored during clinic visits as listed above, 
we will examine differences between the omalizumab and placebo groups during the 8 
weeks of drug administration before RV inoculation.  
 
Currently, there is no validated scoring system for monitoring asthma symptoms on a 
daily basis as planned for our study. As a result, in parallel with our daily assessments 
of lower respiratory tract symptoms, we will also be administering the validated 
Asthma Control Questionnaire (ACT) [included Appendix #3] to enhance our 
evaluation of lower respiratory tract symptoms before and after the infection. These 
questionnaires only take minutes to fill out and will be given directly to the study 
nurse.   By itself, the ACT questionnaire, which monitors symptoms over a one month 


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period (or other questionnaires which evaluate symptoms over a one week period), 
would not satisfy the goals of monitoring symptoms daily for this investigation and 
would not be sensitive to our evaluation over the first 4 days of the infection.  The ACT 
questionnaire, as noted below in Section 7.2, will be completed by subjects in clinic:  
• When subjects are enrolled 8 weeks before the RV challenge,  
• At the clinic visit 4 weeks before the challenge, On the day of RV inoculation in 
the hotel  
• One week after they complete the study (i.e. 28 days after RV inoculation at the 
final visit) when subjects will come to clinic to receive their payment for 
participation. 
 
Another secondary endpoint will be rate of subjects whose FEV1 drops by more than 
20% from their baseline value at the time of enrollment. 
2.3 
Exploratory Objective(s) 
This study will also evaluate whether establishing an IgE blockade with omalizumab 
will have an effect on symptoms (i.e., CURTS and CLRTS scores), lung function, 
biomarkers of inflammation, and allergen and rhinovirus specific lymphocytes in the 
circulation, in order to improve our understanding for the mechanisms of rhinovirus 
induced flares of asthma. .  
Thus, by establishing an IgE blockade, the administration of omalizumab may be a 
novel method for deciphering the mechanisms of RV induced changes in the lower 
airway and may help determine which Th2 associated pathways will be directly 
affected by the reduction in serum IgE.  We also expect to see significant differences in 
the frequencies of CD4+ and CD8+ regulatory T-cell subsets present in the circulation of 
subjects from the omalizumab and placebo treated groups during the infection. Of 
interest is whether we will be able to detect differences in cytokines and chemokines 


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generated in direct response to RV (e.g. IL-8, IP-10, IL1beta,  IL-12, INF-γ, and IFN-α2) 
between subjects enrolled in these two groups.  Based on preliminary data generated in 
collaboration with Drs. Woodfolk, Borish, and Braciale, we expect to see significant 
differences in the frequencies of CD4+ and CD8+effector and regulatory T-cell subsets 
present in the circulation of subjects from the omalizumab and placebo treated groups 
during the infection. 
The nasal scrapings are being done to investigate how genes expressed by the lining 
cells in the nose (called epithelial cells) respond to changes in the environment, 
specifically in this study in response to exposure to the common cold virus (rhinovirus) 
or environmental allergens. The changes in gene expression will be monitored by RNA 
sequencing and epigenetic testing. 
 
3.   STUDY DESIGN  
 
A total of 42 subjects will be enrolled in this randomized, double-blind, placebo-
controlled study over  a period of 33 months (February, 2013 through November, 2015).  
The 42 subjects will be randomized in a 1:1 ratio within each season to receive either 
Omalizumab or placebo for a total of 8 weeks.  At the end of 8 weeks, participants will 
receive four inoculations over a 15 minute period of RV strain 16 in the evening when 
they enter the hotel and are then required to stay in a hotel over the next four days for 
close monitoring and observation. A final dose of the study drug (omalizumab or 
placebo) will be administered 2 weeks after inoculation.   Subjects will be monitored 
daily for 21 days post RV 16 inoculation and for an additional week to complete the 
ACT questionnaire on day 28.  Thus, each subject will also be seen for their final follow-
up visit  at 28 days for completion of the ACT questionnaire, a validated questionnaire 
which reviews their recall for symptoms over the previous month (i.e., since RV 
inoculation) and when they will also receive their payment for their participation.  


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Study Design
Investigator initiated, double-blind placebo controlled, 1:1 randomization omalizumab : placebo
N=42,  (21 subjects treated with omalizumab and 21 with placebo) enrolled over 33 months 
starting in the Spring of 2013
Eligible subjects 
* 
Inoculation 
with GMP 
RV 16 
(300-500 TCID50)
Clinical and 
mechanistic 
follow-up for 3 
weeks; the ACT 
questionnaire 
will be 
completed at 4 
weeks.
8-week omalizumab 
8-week placebo
* Enrollment will begin either in the Fall (end of 
August), or the Spring (mid to end of February).  
Randomization of subjects will occur at enrollment.
RV  viral challenge 
 
Rhinovirus challenges will be conducted annually in the spring or the fall. To reduce 
the chance of seasonal imbalance (i.e., spring vs fall seasons) in the treatment 
assignments, we will generate two randomization lists.  One list will be utilized for the 
spring rhinovirus challenges, while the remaining list will be utilized for the fall 
rhinovirus challenges.  Each randomization list will be generated using a block 
randomization scheme in which the block sizes will all be an even number (e.g., 2,4,6,8), 
but variable in size and each block will have an equal number of assignments to the 
group treated with Omalizumab (Group 1) and group treated with placebo (Group 2). 
James Patrie, M.S. a Senior Biostatistician in the Department of Public Health Sciences at 
UVA will be providing the randomization. The block sizes used in generating the 
randomization will not be divulged to any members of the research team involved in 
the enrollment, monitoring, and evaluation of subjects. Amy Adams, Pharm.D., a 
coordinator of investigational drug studies at the University of Virginia, will be 
receiving the drug and placebo from Novartis, Inc. and will be supplying the drug to us 
in a blinded fashion according to the randomization plan.  


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3.1Study Endpoints 
3.1.1 Primary Endpoint(s)  
The primary endpoint will be based on the comparison of cumulative lower respiratory 
tract symptoms scores (CLRTS) recorded daily by the asthmatic subjects treated with 
omalizumab compared to the CLRTS  scores among subjects  treated with placebo over 
the first 4 days  following RV inoculation.  Lower respiratory tract symptoms to be 
included in this analysis are shortness of breath, chest discomfort and wheezing. These 
symptoms will be recorded twice daily by the asthmatic subjects as previously 
described (16).  Each symptom will be scored on a severity scale of 0 to 3 (i.e. 0 = 
symptoms not present; 1 = mild, but clearly present; 2 = moderate and uncomfortable; 
and 3 = severe, interfering with sleep or activity as shown on diary cards included in 
Appendix 3. Thus, the maximum total score recorded by a subject on any one day for 
these three parameters is 18 (16).    
 
3.1.2 Secondary Endpoint(s)  
Secondary endpoints will include a comparison of CLTRS scores  in the asthmatic and 
non-asthmatic subjects over the first 4 days of acute infection, and will include 
symptoms of shortness of breath, chest discomfort, wheezing, as well as cough. 
Secondary endpoints will also include a comparison of changes from baseline in: 
• methacholine sensitivity (PC20),  
• expired nitric oxide (eNO),   
• impulse oscillometry,  
• the frequency of circulating RV and allergen specific regulatory and effector T-cells, 
•  concentrations of nasal wash mediators and cytokines,  


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• cumulative upper and lower respiratory tract symptoms scores (CURTS and 
(CLRTS) detected during peak cold symptoms over the first 4 day s of the infection 
among subjects enrolled in the omalizumab and placebo treated groups.   
The upper respiratory tract symptoms monitored will include the following symptoms 
recorded twice daily by each subject on their diary cards: : runny nose, sneezing, nasal 
congestion, sore throat, headache, chills/fever, fatigue, itchy eyes, watery eyes and red 
eyes using a modification of the Jackson criteria as previously described (16).   
 
Additionally, using the same statistical methods described for the primary endpoint, we 
will compare changes in the symptom scores between the treatment groups from 
baseline over the first 7 and the 21 days of monitoring during the infection to detect 
differences stimulated by RV.  We will also compare changes in biomarkers of 
inflammation and bronchial hyper-reactivity between the omalizumab and placebo 
treatment groups during the 8 weeks of drug administration before RV challenge to 
evaluate the influence of the study drug on these mechanistic parameters and 
symptoms in both treatment groups. To do this, we will be evaluating the levels of well 
accepted inflammatory biomarkers in subjects with asthma (i.e. expired nitric oxide 
[FeNO] and blood eosinophil counts), which have been shown to decrease during the 
administration of omalizumab (2,6). These markers of inflammation will be measured 
together with assessments of methacholine sensitivity (to judge bronchial hyper-
reactivity) and impulse oscillometry (to judge airway resistance), so that we can 
evaluate the effects of study drug (omalizumab vs placebo) on the levels of 
inflammation and sensitive measures of lung function prior to and during the infection. 
For each subject, we will be measuring FeNO levels (ppb) and absolute blood 
eosinophil counts (cells/mm3) at each clinic visit and daily during the hotel stay as well 
as PC20 (mg/ml) for methacholine, impulse oscillometry, and lymphocyte analyses at 4 
time points, beginning at enrollment (8 weeks before the RV challenge), on the day of 


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inoculation (day 0), during peak cold symptoms (day 4), and at (day 21). The statistical 
plan, focused on comparing changes in these parameters from baseline between the 
treatment groups at each time point is described in Section 9. 
 
The Asthma Control Questionnaire (ACT) [included Appendix #3] will be administered 
and evaluated to enhance our assessment of lower respiratory tract symptoms before 
and after the infection. The ACT questionnaire, as noted below in Section 7.2, will be 
completed by subjects in clinic:  
• When subjects are enrolled 8 weeks before the RV challenge,  
• At the clinic visit 4 weeks before the challenge,  
• On the day of RV inoculation in the hotel  
• One week after they complete the study (i.e. 28 days after RV inoculation at visit 
the final visit) when subjects will come to clinic to receive their payment for 
participation. 
 
In addition, another secondary endpoint will be rate of subjects whose FEV1 drops by 
more than 20% from their baseline value at the time of enrollment. 
 
 
3.2 Study Completion 
This study will be considered “completed” when all participants have completed the 
study and data required to meet the chosen objectives are analyzed.   
 
After the study is completed, the Principal Investigator or Data Center will compile a 
final study report as per ICH E6 and 21CFR312. The study report will be submitted to 
the local IRB, NIAID, SMC and the FDA. 


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4 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
4.1 
Inclusion Criteria  
Subjects who meet all of the following criteria at screening will be eligible for 
enrollment as a study participant. Subjects must also be able to understand and provide 
written informed consent 
• Age 18 to < 40 years of age, any gender, any racial/ethnic origin 
• Physician-diagnosed asthma 
• ACT score > 19 at enrollment before the administration of study drug 
• Short-acting beta-agonist use < daily in last 4 weeks 
• FEV1 > 70%, or FEV1/FVC ratio > 75% for subjects with FVC values between 80 and 
87% predicted whose FEV1 values fall below 70%. 
• Positive Methacholine challenge test (i.e. at least 20% fall in FEV1 at a Methacholine 
concentration of ≤ 16 mg/ml) at screening protocol before enrollment (20).  
• Total serum IgE level ≥ 125 IU/ml documented during screening protocol. 
• Positive test for allergen specific IgE antibody by prick skin testing documented 
during screening protocol to allergens associated with current allergen exposure at 
the time of the RV challenge (e.g., dust mite, Alternaria, and/or ragweed for subjects 
challenged with RV in the fall, or positive tests to tree and/or grass allergens for 
those challenged with RV in the spring). In keeping with the study design goals of 
inoculating subjects during periods of allergen exposure, sensitization to other 
allergens (e.g., cat or dog) will also qualify for enrollment if subjects are currently 
exposed to these allergens at home. 
• Participant must be willing to comply with study procedures and requirements 


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• Participant must be considered eligible for participation based on results of screening 
procedures conducted by protocol number 20100686 at VCU and IRB# 12656 at 
UVA). Refer to Appendix 4. 
 
4.2 
Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment:  
• Inability or unwillingness of a participant or subject’s legal representative to give 
written informed consent and HIPPA authorization  
• Positive test for serum neutralizing antibody to RV-16. Subjects with a 
neutralizing antibody titer > 1:4 will be excluded at screening within 6 weeks of 
enrollment.  
•   To avoid RV-16 inoculations in subjects with more restrictive lung volumes, those 
whose FVC is < 80% predictive will also be excluded.  
 
• Total IgE levels measured at screening protocol that are too elevated based on a 
subjects weight, to meet the recommendations proposed by Novartis for 
treatment with Omalizumab (21).  
• 
Chronic heart disease, lung diseases other than asthma, or other chronic illnesses 
including primary and/or secondary immunodeficiency.  
• 
Hospitalization or treatment in the ER (unless the treatment involved the use of a 
bronchodilator only)  for asthma during the last three years. 
• 
Subjects who have had one or more night time awakenings caused by asthma 
symptoms and/or who have needed their SABA (albuterol) inhaler for asthma 
symptoms > 4 days during the week before enrollment, or during the week before 
the inoculation with RV-16.  
• 
Intubation or management in the intensive care unit for an asthma exacerbation 


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• 
An upper  or lower respiratory tract infection within six weeks prior to 
enrollment 
• 
Previous nasal or sinus surgery within the last 12 months. 
• Who have a 5 pack/year history of smoking, or any smoking within the last 6 
months.   
• 
Female subjects who are or who plan to become pregnant during the study, or 
who are nursing a baby. Additionally, to be included in this study, a woman of 
child-bearing potential must have a negative urine pregnancy test at screening, 
during the run, and prior to viral inoculation and agree to use an effective 
method of birth control such as, but not limited to, birth control pills, 
contraceptive foam, diaphragm, IUD, abstinence, or condoms during the entire 
duration of the study (through Day 28 after RV 16 inoculation). 
• Subjects who have used omalizumab within 6 months prior to enrollment,or 
have been using inhaled corticosteroids, inhaled cromolyn or nedocromil, a long 
acting beta agonist, inhaled ipratropium bromide, or systemic leukotriene 
modifiers for their asthma on a daily basis within 4 weeks prior to enrollment, or 
subjects using nasal corticosteroids on a daily basis within 4 weeks prior to 
enrollment.  
• Subjects who are currently receiving beta-adrenergic blocking agents. 
•  Subjects who are currently receiving allergen immunotherapy (IT),  or who have 
received allergen IT within the last 3 years.. 
• Hemoglobin <11.5 g/dL for non-African American subjects or hemoglobin < 11.0 
g/dL for African American subjects detected during screening within 6 weeks of 
enrollment.  
• Absolute neutrophil count (ANC) < 1500 cells/mm3 (or 1.5 K/uL) detected 
during screening within 6 weeks of enrollment or Day -2. 
 


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4.3 
Participant Withdrawal Criteria 
Participants may be terminated early from the study for the following reasons: 
a.   The participant elects to withdraw consent from all future study activities, including 
follow-up. 
b.   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). 
c.   The participant dies.  
d.   The participant develops a medical condition or is started on new medication(s) 
that, 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 that may impact the quality of the data obtained from the study. 
e.   The participant meets any of the individual stopping rules as delineated in section 8. 
f. A severe asthma exacerbation that requires treatment in the emergency room, 
hospitalization, or the use of systemic steroids, at any time during the study. 
g. Severe anaphylaxis secondary to Omalizumab dosing 
h. Poor control or persistent activation of secondary atopic disease.  
i. Non-adherence to dosing protocol and or study procedures. 
j. Pregnancy 
k. If a subject misses an Omalizumab dose, the dosing schedule will be resumed as soon 
as possible.  If a dose is missed > _1__ time the subject will be discontinued from dosing 
due to significant non-adherence. At each visit when Omalizumab is administered, 
subjects will be reminded about the importance of receiving all injections of this 
medication. 
 


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5 
INVESTIGATIONAL PRODUCT(S)/INTERVENTION MATERIAL(S), 
OTHER STUDY PRODUCTS (CONTROLS/PLACEBOS)  
5.1 
Investigational Product(s)/Intervention(s)  
Omalizumab (Xolair®) 
The study drug omalizumab and placebo will be provided at no cost by Novartis 
Pharmaceuticals. 
   
Placebo drug (produced by the same manufacturer: Novartis Pharmaceuticals):  
The product described in this module is the placebo to Xolair 150 mg Powder for 
solution for injection. The placebo is the same mixture of inactive excipients, in quality 
and quantity, as those used for the drug product, except that the drug substance, 
omalizumab, is not added. 
 
Rhinovirus (strain 16) 
The strain of RV that will be used is a pool of RV (strain 16) that will be provided by Dr. 
Ronald Turner’s laboratory at the University of Virginia (UVA). Dr. Turner, who is a co-
investigator in this study, has collaborated with Johnson & Johnson, Inc. to produce this 
pool of RV under GMP conditions.  This new pool was deemed by the FDA to be safe to 
use for the research experimental challenges to be conducted in this study. 
Please refer to sections 1.3 and 5.2 for more complete information on RV 16. 
5.2 
Preparation, Administration, and Dosage 
Before the experimental challenge with RV (strain 16), each subject will be treated for 8 
weeks with subcutaneous injections of either omalizumab (Group 1) or placebo (Group 
2) prior to the experimental RV challenge. The 42 asthmatic subjects enrolled in this 


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study will be randomized 1:1.  All subjects and study team members will be blinded as 
to which treatment group the subjects are randomized to. 
 
 
 
  
Omalizumab (Xolair®) 
Injections of either omalizumab -150 to 375 mg- or placebo will be given monthly, or 
bi-monthly, depending on the subject’s weight and total IgE level using the prescribing 
guidelines provided by the manufacturer (27).  
The dose (mg) and dosing frequency will be determined by serum total IgE level 
(IU/mL), measured before the start of treatment, and body weight (kg). See the dose 
determination charts below (Table 1 and Table 2) for appropriate dose assignment. 
Doses less than or equal to 300 mg will be given every 4 weeks. 
 


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 Doses will be adjusted for significant changes in body weight during the study (See 
Table 1 and Table 2). 
Preparation and administration of Omalizumab will be conducted according to 
manufacturer. Each vial of omalizumab from the manufacturer contains 150 mg of drug 
and will be reconstituted with 1.4 ml of sterile water for injection. The injection may 
take 5-10 seconds to administer because the solution is slightly viscous. Each vial 
delivers 1.2 mL (150 mg) of Omalizumab. We will not administer more than 150 mg per 
injection site. We will divide doses of more than150 mg among two or more injection 
sites. (Table 3). 
 
 


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Inoculation with RV-16 Procedures:   
A nasal wash will be performed prior to inoculation in order to obtain baseline 
assessments including tests for RV, cell counts, and inflammatory biomarkers.For virus 
inoculation, each patient will be inoculated with 0.25 ml of RV type 16 in each nostril 
after obtaining the pre-virus inoculation nasal wash. The RV-16 virus solution used for 
inoculation will be diluted in HANK’s balanced salt solution and will be pre-tittered to 
contain 300-500 TCID50/ml. (tissue culture infectious dose 50/ml.).  Thus, 75 – 125 
TCID50/0.25 ml will be instilled into each nostril during the initial inoculation. Five to 
10 minutes after the initial inoculation, another inoculum (using the same amount of 
RV) will be administered.  
 
Non investigational drugs that will be available at the clinical site include: EpiPen,  
Methacholine and Albuterol.  EpiPen, oral steroids, and albuterol will also be available 
with the physicians and study nurses in the hotel over the entire 4 day period after RV-
16 inoculation.  
 


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5.3 
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 investigational 
product(s)/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 investigational product(s)/intervention material(s) 
accidentally or deliberately destroyed. 
 
Records for receipt, storage, use, and disposition will be maintained by the study site.  
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 investigational 
product(s)/intervention material(s) dispensed. 
 
All records regarding the disposition of the investigational product(s)/intervention 
material(s) will be available for inspection by the site monitor, and NIAID. At the end of 
the study, drug accountability will be done and all unused drug will be returned to 
Novartis. 
5.4 Modification or Discontinuation of Investigational 
Product(s)/Intervention Material(s) 
5.4.1 Modification of Investigational Product(s)/Intervention(s) 
N/A 


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5.4.2 
Premature Discontinuation of Investigational 
Product(s)/Intervention(s) 
Study stopping rules and individual stopping rules are described in sections 8.1.1 and 
8.1.2, respectively. Participant withdrawal criteria are described in section 4.3 
If a subject withdraws from the study at anytime during the 8 week pre-treatment 
period, they will come to clinic within one week of their withdrawal and turn in their 
diary cards. They will also be asked about any adverse events and will be paid 
according to a pro-rated scale which is described in the consent form.  If the subject 
withdraws following virus inoculation, the same plan for follow-up will apply and 
subjects will be asked to return on day 28 to receive their payment, complete the ACT 
questionnaire, and a blood sample will be obtained (5ml) to check for serum 
neutralizing antibody (i.e. sero-conversion) to RV-16.  


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6 
OTHER MEDICATIONS 
6.1 
Concomitant Medications 
N/A 
6.2 
Prophylactic Medications 
N/A  
6.3 
Rescue Medications 
Following the injection, subjects will stay in the clinic for 2 hours after receiving the first 
3  injections and for 30 minutes after  subsequent injections An EpiPen unit will be 
given to each subject and they will be instructed how to treat any allergic symptoms 
observed after the Omalizumab or the placebo is given. Other rescue medications 
available at the study site and the hotel (for use after administration of omalizumab and 
rhinovirus challenge, respectively) are described in section 5.2. 
 
6.4   Prohibited Medications 
Include inhaled corticosteroids, leukotriene modifiers, inhaled cromolyn sodium, 
inhaled nedocromil sodium, long acting beta agonists, and ipratropium bromide. Nasal 
corticosteroids are also part of the exclusion criteria because using these medications 
can confound the interpretation of the effects of omalizumab on asthmatic symptoms in 
atopic subjects. Use of antihistamines is discouraged at all times during the study and 
prohibited on the day of and for the 4 days following inoculation with RV-16.Beta-
adrenergic blocker agents are also prohibited medications.  
 


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7 
STUDY VISITS AND PROCEDURES 
7.1 
Enrollment and Randomization 
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 will be enrolled and assigned a 
unique participant number. 
 
Subjects will be contacted by telephone or e-mail if they have met the inclusion and 
exclusion criteria for this study determined after they have successfully completed the 
screening visits described in the screening study protocol (UVA IRB# 12656) and briefly 
described below. 
 
It is anticipated that study participants will be enrolled from UVA, Virginia 
Commonwealth University, James Madison University, Liberty University, University 
of Richmond, Mary Baldwin College, Washington and Lee, and other universities 
located within 90 minutes by car from the UVA campus.  Participants will be recruited 
through the use of posters/flyers, newspaper ads, internet and referrals from other 
health care professionals. No participants will be selected from the laboratories of Dr 
Heymann,Dr Turner, or other key investigators.  
7.2 
Screening and study Visit(s) 
All visits will take place at the UVA Asthma and Allergic Disease Center in 
Charlottesville.  The hotel stay post RV-16 challenge will take place at either the 
Holiday Inn (1901 Emmet Street North) or the DoubleTree Hotel (900 Hilton Heights 
Road) in Charlottesville, VA  22901.  Procedure done during the visits will take up to 90 
minutes.  Additionally, during the visits  when the injections of omalizumab or placebo 


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are given, subjects will be observed for 2 hours after the first 3 injections and for 30 
minutes after subsequent injections to provide treatment in the event of an episode 
(uncommon) of anaphylaxis. 
 
Subjects meeting entry criteria include those selected from a previous screening 
study  summarized in Appendix 4. Unless otherwise stated, physiological values 
obtained from the screening protocol are valid for eight months. 
Subjects who are eligible and who decide to participate will undergo the following 
Study Visits   (See Appendix 5: Schedule of Events for an outline of the study 
schedule): 
 
Study Visit 1 (- 8 Weeks);  Note: To establish baseline values at enrollment, 
participants will be seen in the morning (between 7 AM and noon) at Elson Student 
Health Center, or at the Clincal Research Unit (CRU) located on the 1st floor of the 
Medical Center Barringer Wing at UVA, or at the Clinical Research Center (CRC) 
located on the 3rd floor of the new UVA Children’s Hospital Outpatient Building (Battle 
Building). All locations are approximately 10 minutes walking distance from our 
laboratory and the Asthma and Allergic Diseases Center[Note: All 3 locations will be 
used based on availability and convenience for our subjects and our staff who will be 
doing all of the assessments.] The following assessments will be completed at the 
enrollment visit (Visit 1): 
Potential subjects will sign the consent form at this visit prior to any additional 
study procedures.  Subjects will then be randomized.  The following procedures 
will take place at this visit: 
o Urine Pregnancy Test for all women of childbearing potential. 
o Nasal Wash 
o Nasal scraping using the ASI Rhino-Pro®  


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o Spirometry  
o Exhaled Nitric Oxide (eNO) 
o Methacholine challenge 
o Impulse oscillometry 
o 8 mls of blood will be collected for differential cell counts (CBC with 
differential), assessments of total and allergy specific IgE antibody, and 
for serum antibody titers (serology) to RV- 16. 
o 155 mls of blood (~ 5 ounces) will be collected (during the same 
venipuncture done to collect the 8 ml for blood counts) to interrogate the 
status of RV and allergen specific T cells in response to the infection in 
both groups and for basophil and dendritic cell experiments. 
o Subjects will be instructed on the use of the diary cards which will be 
used to record upper and lower respiratory tract symptom scores twice 
daily, as well as how to use the ATS approved Microlife Electronic PEF 
and FEV1 monitor and the number of puffs of albuterol required for 
resolution of symptoms.  
o Subjects will be instructed on the use of the EpiPen and given an EpiPen 
to use in case of emergency. Subjects will also be given an albuterol 
inhaler (MDI) with a puff counter to use as a rescue medicine as needed. 
Subjects will use this inhaler instead of their own albuterol MDI. 
o Baseline assessment of past medical history over the last month to use in 
our assessment of adverse events. 
o A limited physical examination will be performed including weight (Kg) 
o Subjects will be randomized 
o Subjects will receive their first dose of study drug (omalizumab vs. 
placebo).  Please refer to section 5.2  (Preparation, Administration and 
Dosage ) 


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o Subjects will fill out the ACT questionnaire. 
 
 
Omalizumab and placebo will be provided for this research by Novartis 
Pharmaceuticals.  After enrollment, 4 follow-up visits every other week (i.e., 6, 4, and 2 
weeks and just before the RV challenge) will be scheduled to monitor the effects of the 
study drug on allergic inflammation lung function. 
 
Between Visit 1 and 2: 
• Subjects will complete the diary card information on a twice daily basis. 
 
Study Visit 2 (- 6 Weeks) 
o At - 6 weeks, subjects receiving study drug injections every 2 weeks will 
come into the clinic for an injection of study drug (omalizumab vs. 
placebo) and a urine Pregnancy Test for all women of childbearing 
potential.  
• Assessment for Adverse Events and review of diary cards if subject is scheduled 
for study drug injection. 
 
Study Visit 3 (- 4 weeks) 
 
The following study procedures will be performed: 
• Urine Pregnancy Test for all women of childbearing potential 
• Nasal Wash 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
• 8 mls of blood will be collected for differential cell counts (CBC with differential). 
• Limited physical examination 
• Subjects will receive a dose of study drug (omalizumab vs. placebo).   


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• Review of the daily diary cards and assessment of Adverse Events 
• Subjects will fill out the ACT questionnaire.  
 
Between Visit 3 and 4: 
• Subjects will complete the diary card information on a twice daily basis. 
 
Study Visit 4 (- 2 weeks) 
The following study procedures will be performed: 
• Urine Pregnancy Test for all women of childbearing potential 
• Nasal Wash 
• Nasal scraping using the ASI Rhino-Pro® 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
• 8 mls of blood will be collected for differential cell counts (CBC with 
differential). 
• Limited physical exam 
• Subjects who will be receiving their study drug injections every 2 weeks will 
receive a dose of study drug (omalizumab vs. placebo) 
• Review of the daily diary cards and assessment for adverse events  
 
Between Visit 4 and Day of Admission to the hotel for evaluation and RV-16 
inoculation (Day 0)  
• Subjects will complete the diary card information on a twice daily basis. 
 
Study Visit 5 (within 2 days before virus inoculation; i.e., either 2 days or 1 day 
before, or on the day of admission to the hotel and virus inoculation):  
To establish baseline values just prior to inoculation with RV-16, subjects will be seen in 
the morning (between 7 AM and noon) at the Elson Student Health Respiratory 


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Research Unit, the Battle Building CRC, or the CRU at UVA for the following 
assessments: 
 
•  Urine LTE4 for all subjects. [Note: LTE4 is a cysteinyl leukotriene which 
can be measured in urine. This biomarker of inflammation will be checked 
at this visit and during peak cold symptoms (day #4 after virus 
inoculation).] 
• Nasal Wash 
• Nasal lining fluid 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
• Urine pregnancy test 
• Methacholine challenge 
• Impulse oscillometry 
• 8 mls of blood will be collected for differential cell counts (CBC with 
differential) and for serum neutralizing antibody titers to RV- 16. 
• 155 mls of blood will be collected for T-cell, basophil, and dendritic cell 
studies.  
• Limited physical exam 
• Subjects will receive a dose of study drug (omalizumab vs. placebo).   
• Review  of the daily diary cards and assessment for Adverse Events. 
 
Admission to the hotel:  (Day 0) Inoculation Day  
On Day 0 (after 8 weeks of study drug treatment) subjects will check into a local hotel 
(Holiday Inn Hotel in Charlottesville).  They will stay in this hotel for the next 4 days 
and will not be allowed to leave their rooms.  Each subject will have their own room 
that they cannot leave until the day of discharge (Day 4). A member of the study team 


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(physician or nurse) will be staying in an adjacent room (day and night) throughout the 
hotel stay. Each subject will be admitted to the hotel in the evening (between 5 and 7 
PM) of Day 0 and the following procedures will be done: 
 
• Urine Pregnancy Test for all women of childbearing potential  
• Collect and review completed diary card and issue new diary cards 
• Limited physical exam and temperature (PO) 
• Complete the Asthma Control Test 
• Expired nitric oxide  
• Nasal wash 
• Spirometry 
• Inoculation of subjects with RV-16 
• Each subject will be given boxes of tissues and ZIP lock freezer bags to 
put all used tissues into after nose blowing to monitor mucous/secretion 
weights during the hotel stay.  
 
Hotel Stay (Days 1-4 in the morning before noon) 
On hotel stay days 1 – 4 the following procedures will be performed: 
• Nasal Wash 
• Nasal scraping using the ASI Rhino-Pro® on day 2 only. 
• Nasal lining fluid on day 4 only. 
• Spirometry [Note: The spirometry scheduled on Day 4 may be done in the 
hotel, or later in the morning in the Battle Building CRC before the 
methacholine test.] 
• Exhaled Nitric Oxide (eNO) 
• 8 mls of blood will be collected for complete blood count and differential 
cell counts (CBC with differential) on days 2 and 4 only in the morning. 
• Evaluation by research staff every morning with limited physical exam 
and temperature (PO) 
• Review  of the daily diary cards and assessment for adverse events 


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• Prior to discharge from the hotel in the morning and additional 110 ml of 
blood will be obtained (during the same venipuncture done to collect the 8 
ml for blood counts) for the assessments of circulating T-cells, basophils, 
and dendritic cells. Another urine sample will be checked in the morning 
on day 4 from all subjects for LTE4 measurements.  
 
• Shortly after leaving the hotel (within 24 hours), subjects will return to the 
Elson Student Health Respiratory Research Unit, the Battle Building CRC, or 
CRUat UVA for a urine pregnancy test, methacholine test and impulse 
oscillometry to detect changes during peak cold symptoms. 
 
Between discharge from the hotel and Visit 6 (Day +7, i.e., one week after 
inoculation): 
• Subjects will continue to complete the diary card on a twice daily basis. 
 
Study Visit 6 (Follow-Up Visit on Post-Inoculation Day 7) 
On post-inoculation days 7 the following procedures will be performed: 
• Nasal Wash 
• Nasal scraping using the ASI Rhino-Pro® 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
•  8 mls of blood will be collected for differential cell counts (CBC with 
differential) and an additional 60 ml of blood will be obtained for T-cell 
and dentritic cell studies. 
• Impulse oscillometry 
• Evaluation by research staff with limited physical exam. 
• Review  of the daily diary cards and assessment for adverse events  
 


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Between visit 6 and 7:  
• Subjects will complete the diary card information on a twice daily basis. 
 
Study Visit 7 (Follow Up Visit on Post-Inoculation Day 14) 
• Nasal Wash 
• Nasal lining fluid obtained before the nasal wash 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
• 8 mls of blood will be collected for differential cell counts (CBC with 
differential)  
• Evaluation by research staff with limited physical exam 
• Subjects will receive a dose of study drug (omalizumab vs. placebo) if receiving 
study drug every 2 weeks  
• Review  of the daily diary cards and assessment for adverse events  
   
Between Visit 7and 8: 
• Subjects will complete the diary card information on a twice daily basis. 
 
Study Visit 8:  Evaluation Visit (Post-Inoculation Day 21) 
• Nasal Wash 
• Nasal scraping using the ASI Rhino-Pro® done after the nasal wash 
• Spirometry 
• Exhaled Nitric Oxide (eNO) 
• Methacholine challenge 
• Impulse oscillometry 
• Evaluation by research staff with limited physical exam 
• Urine for pregnancy screen for women of childbearing potential 


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• 8 mls of blood will be collected for differential cell  counts (CBC with 
differential) and serum neutralizing antibody (sero-conversion) to RV-16. 
During the same venipuncture, an additional 110 ml of blood will be 
obtained for T-cell, basophil, and dendritic cell studies. 
• Review  of the daily diary cards and assessment for adverse events 
 
Study Visit 9:  Twenty-eight days after RV inoculation, subjects will return to receive 
their payment (check) for completing the study and to complete the ACT questionnaire 
and to report any adverse events.  
 
Note: The total blood volume obtained during the study (i.e., 342 ml during the 8 weeks 
before RV inoculation and 336 ml during the infection over 3 weeks) is 678 ml over a 
period of 11 weeks and falls within the limits approved by our IRB. 
7.3  Visit Windows  
Study visits should take place within the time limits below: 
Visits 1 (8 weeks before the virus challenge), 6 (7 days after the virus challenge), 8 (21 
days after the virus challenge), and 9 (28 days after the virus challenge) will occur 
within a 24 hours window prior to or 48 hours following the planned visit scheduled 
according to the protocol. As noted above, Visit 5 can be scheduled 2 days before, 1 day 
before, or on the day of the virus inoculation. To accommodate subjects with difficult 
school or work schedules, Visits 2 (6 weeks before the challenge), 3 (4 weeks before the 
virus challenge), 4 (2 weeks before the virus challenge), and 7 (14 days after the virus 
challenge) will also occur within a 24 hour window prior to or 48 hours after the 
planned visit scheduled according to the protocol. 
 


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7.4 
Study Procedures 
Specifications and Guidelines 
1. Pregnancy Tests:  Fifteen to 30 mls of urine will be collected from all women of 
childbearing potential at -8, weeks, -4 weeks, -2weeks, Day 0 and 21. As in our 
previous studies (e.g. IRB-HSR #’s 12673) we will be doing these tests at study 
visits using the Answer, Early Result Pregnancy Test; Scantibodies Laboratory, 
Inc. Santee, CA). 
2. Hotel Stay:  Post inoculation with RV-16 all subjects will stay in a local hotel. 
(Holiday Inn Hotel on Rt. 29 North in Charlottesville Virginia) where several 
studies of RV challenges involving asthmatic and non-asthmatic subjects have 
already been done by UVA investigators (Drs. Heymann and Turner). Subjects 
will not be allowed to leave their rooms and are instructed to call for room 
service.  Each subject will be evaluated and samples will be collected on the day 
of virus inoculation and daily over the first four days during peak cold 
symptoms. Physicians and nurses from the University of Virginia Asthma and 
Allergic Diseases Center will be available in the hotel for this study 24 hours a 
day.  
3. Inoculation with RV-16 Procedures:  Virus inoculation will be done after 
performing a nasal wash as described in procedure #10 as described below.  Each 
patient will be initially inoculated with 0.25 ml of RV type 16 in each nostril after 
obtaining the pre-virus inoculation nose wash. The RV-16 virus solution used for 
inoculation will be diluted in HANK’s balanced salt solution and will be pre-
tittered to contain 300-500 TCID50/ml. (tissue culture infectious dose 50/ml.).  
• Five to 10 minutes after the initial inoculation, another inoculum  of 
0.25 ml. of RV type 16 in each nostril will be administered.  
4. Diary Cards:  Each subject will be responsible for the completion of a daily diary 
card. Most subjects now have computers and our diary cards have been 


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established on-line to enhance capturing data that is being submitted and 
checked for compliance in real-time by our laboratory.  However, subjects will 
also have the option to use hard copies of the diary cards which have been used 
successfully in the past and which are reviewed in detail for completeness by our 
study coordinator at each study visit. At this review, the subject will turn in their 
diary card with their data entries since their last study visit and a new diary will 
be issued. Subjects will be instructed to complete these diary cards twice daily in 
the morning and evening .  Diary cards will be used by each subject to record 
their upper and lower respiratory tract symptom scores beginning at Visit 1 and 
ending at Visit 8. PEF and FEV1 values and the puffs of albuterol required for 
chest symptoms. Upper respiratory tract symptoms recorded will include 
sneezing, nasal discharge, nasal obstruction, sore throat, headache, malaise, or 
chills, using a modification of the Jackson criteria as previously described (16). 
Each symptom will be scored on a severity scale of 0 to 3 (i.e. 0 = symptoms not 
present; 1 = mild, but clearly present; 2 = moderate and uncomfortable; and 3 = 
severe, interfering with sleep or activity (see Appendix 2). The lower respiratory 
symptoms monitored will include cough, chest tightness, wheeze, and shortness 
of breath. Again each symptom will be recorded using the same severity scale  
(see Appendix 1 at the end of this protocol). Each subject will be given an 
albuterol metered dose inhaler containing a puff counter (Ventolin, 
GlaxoSmithKline) which will be used when needed during the study. The puffs 
of albuterol used by each subject during the study will also be recorded twice 
daily on the diary cards. The use of albuterol used to reverse the response to 
methacholine during the study, or used prophylactically prior to exercise will not 
be included in the analysis of albuterol puffs used in response to asthma 
symptoms encountered by the subject during the study. The tests for PEF and 
FEV1 will be done using a Microlife hand held monitor (www.microlifeusa.com). 


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The Microlife monitor is ATS approved for evaluating peak expiratory flows 
(PEF) and FEV1 assessments at home. Daily recordings (before breakfast and 
dinner) will be established at baseline, during treatment with omalizumab or 
placebo, and during the experimental infection with RV. The lung function data 
will be downloaded at every clinic visit (i.e. whenever omalizumab or placebo is 
administered and at follow-up visits during the infection) and will be reviewed 
by the study nurses who will check that proper monitoring and record keeping is 
being done.   
During the hotel stay, subjects will continue to monitor and record their FEV1 
values along with their symptom scores. If any subject experiences a decline in 
FEV1 below 70% predicted, or more than 20% from their baseline value at the 
time of enrollment, they will notify a member of the study team (licensed 
physician or nurse who will be staying in an adjacent hotel room day and night 
during the hotel stay) immediately. Epinephrine, albuterol, and oral steroids will 
also be readily available to the member of the study team (in their hotel room) to 
use for treatment. 
5. Spirometry: 
Spirometry (i.e. basic lung function tests done routinely in clinic to judge lung 
volumes during a maximal expiratory effort for 12 seconds) will be done at each 
visit and in the morning of each day of the hotel stay using methods and 
equipment (e.g. Koko Spirometer , Inspire Health Care, Louisville, CO) approved 
and standardized by the American Thoracic Society (ATS).  Subjects will wear a 
nose clip, and be asked to take a deep breath, and then blow it out for as long as 
possible into the Spirometer.  
6. Methacholine challenge:  
Methacholine challenges will be done according to ATS guidelines (20). During 
this test, subjects will receive an FDA-approved drug called Provocholine.   This 


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drug will be inhaled and cause mild symptoms of asthma to occur. Subjects will 
be asked to breathe in different mists of methacholine that are each slightly 
stronger.  Spirometry testing will follow each dosing strength.  The test will stop 
when lung function decreases by 20%, or after the 10th mist is given.   The test 
will also be stopped if the subject has difficulty breathing. After the test is 
stopped, the subject will be given a treatment of albuterol to open up the 
airways. Each subject will already have done a methacholine challenge as part of 
the screening process in order to be eligible for this study. The methacholine 
challenges in this study will be done at Visit 1 (-8 weeks), at Visit 5 (within 2 days  
prior to RV-16 inoculation), on Day 4 of the hotel stay, and at Visit 8 (Day 21). 
 
 
7. Impulse oscillometry:    
Impulse oscillometry is a means of assessing respiratory system impedance in a 
spontaneously breathing patient. In practice, the subject breathes through a mouth 
seal in line with a loudspeaker that generates a pulse wave lasting 0.1 second that is 
transmitted down the airways. By generating sound waves of varying frequencies 
throughout the respiratory cycle, the instrument can evaluate airway patency and 
resistance at many different levels within the respiratory tree during normal 
breathing. While spirometry is relatively insensitive with regards to the small 
airways, oscillometry may provide us with the precision required to evaluate these 
airways that are more likely to be involved in asthma, particularly during a RV 
infection. Repeated measurements do not alter pulmonary function, it is suitable for 
bedside measurements, and it is not effort dependent.  
  
      8.  Limited Physical Examination: 


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At each study visit a physical examination focused on the respiratory tract will 
be done. This exam will include an examination of the nose, throat, ears, lungs, 
and cervical adenopathy which may manifest changes during the RV cold.   
9. Exhaled Nitric Oxide (eNO) 
Exhaled Nitric Oxide (eNO) measurement will be performed using a portable 
NioxMino® Nitric Oxide analyzer (Aerocrine AB, Sweden). These measurements 
are easily done by having subjects exhale normally for 12 seconds into a hand 
held eNO monitor.  
10. Nasal Washes:   
Nasal washes will be obtained at study visits planned at enrollment (8 weeks 
prior to virus inoculation) and at 6 and 2 weeks before virus inoculation. Washes 
will also be collected on the day of inoculation (day 0), daily during the hotel 
stay post inoculation days 1-4, and at follow-up visits (days 7, 14, and 21 after 
virus inoculation as note in Appendix 1. The nasal washes will be obtained as 
described in our previous studies, but with minor modifications to improve 
subject comfort and the quality of the sample obtained (8, 16). A small amount (2 
ml) of phosphate buffered saline (PBS), pH 7.4 will be instilled, using a Mucosal 
Atomization Device (Wolfe Tory Medical, Inc; www.wolfetory.com) into each 
nostril (i.e. each nostril treated separately) with the subject sitting upright and 
holding their breath. Wash fluid and secretions will then be aspirated with gentle 
suction through a BBG Nasal Aspirator (Codan, US Corp., Santa Ana, CA) 
inserted only into the anterior nares. The combined washes from both nares 
result in volumes of 3 to 4 ml of fluid and secretions.  After the wash; a plastic 
transfer pipette will be used to vigorously mix secretions with wash fluid. One 
ml of this mixture will be transferred to a vial containing veal infusion broth 
(Bartels Viral Transport Medium, Trinity Biotech, U.S.A.), which will be 
transported to Dr. Turner’s laboratory for culture. (IBC # 129-01) The remaining 


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wash solution and secretions will be frozen and stored at -80°C for PCR-based 
viral analyses and for immunoassays. The replication, and clearance, of RV in the 
upper airway during the 21 days post RV inoculation will be evaluated by titers 
of virus in culture in Dr. Turner’s laboratory and by qPCR in our laboratory. The 
Bio-Rad Cytometric Bead Assay (Bio-Plex System, Hercules, CA) will be used to 
measure cytokines and chemokines selected to evaluate (1a) the response to RV 
(IL-8, IL-12, IFN-γ, IL-1β, IP-10, and IFN-α2 and IFN-beta, the latter type I 
interferons), and (2) Th2 associated inflammation (IL-5, IL-13, and eotaxin). Cys 
LT’s will also be measured (Cayman Chemical Co.). To help differentiate the 
local production of these biomarkers from vascular leakage, the same 
assessments will be done in serum and ratios of each metabolite/biomarker 
detected in the nasal fluid and serum will be compared. In addition, albumin will 
also be measured in nasal wash supernatants and sera to judge vascular leakage 
as described in our previous investigation (16). 
11. Light nasal scraping:  After the nasal wash an additional nasal specimen will 
be obtained by using a ASI Rhino-Pro® nasal mucosal curette plastic device to do 
a light scrapping along the inferior turbinate of each nostril to collect epithelial 
cells. This will be done using a headlight and a disposable nasal speculum to 
spread the nares (Bionix) to enhance visibility of the turbinates.  
12. Nasal lining fluid:  An additional nasal specimen will be obtained by 
applying a small piece (1 X 1 cm) of sterile gauze (Surgicel®), routinely used by 
ENT surgeons at UVA during surgical procedures to provide hemostasis,  to 
inferior turbinate for 4 to 5 minutes in each nostril to collect a sample of epithelial 
cell lining fluid (about 0.2 ml).  
13.  Each subject will be given boxes of tissues and ZIP lock freezer bags to put all 
used tissues into after nose blowing to monitor mucous/secretion weights 
during the hotel stay. A detailed protocol for how the tissues and bags will be 


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replaced and the used tissues in bags weighed (3 times daily) is included in the 
Regulatory Binder for this investigation.  
14. Blood tests:  Blood samples will be obtained by venipuncture for isolation and 
analysis of basophils, dendritic cells, and RV and allergen specific T-cells as 
indicated in the protocol (Section 7.2). The evaluation of these cells will be done in 
collaboration with Drs. Judith Woodfolk and Larry Borish in the UVA Asthma and 
Allergic Diseases Center. (IBC #s: 134-02 and 115-00). Blood samples (8ml) for 
eosinophil counts (8 ml) and to test for sero-conversion to RV-16 will also be 
obtained as described in the protocol (Section 7.2) and noted in Appendix 5. 
14.  Administration of Study Drug (Omalizumab vs. Placebo) 
After subjects are randomized, injections will be given monthly, or bi-monthly 
throughout the study, depending on the subject’s weight and total IgE level 
using the prescribing guidelines provided by the manufacturer (21).  All 
injections will be given in clinic as indicated at UVA.  Following the injection, 
subjects must stay in the clinic for 2 hours after receiving the first three 
injections and for 30 minutes after subsequent injections. .  An EpiPen unit will 
be given to each subject and they will be instructed how to treat any allergic 
symptoms observed after the Omalizumab or the placebo is given, although 
reactions following injections of Omalizumab are uncommon as described 
below.  
• Throughout the study, each subject will receive $75/week for a total of 7 weeks 
and $125/week for the last 4 weeks of daily monitoring of their symptom 
(CURTS and CLRTS) scores and lung function tests at home. This is included as 
part of the payment of $1870 given to subjects who complete the study and is 
noted in a pro-rated scale given to subjects in their informed consent form. Each 
subject will also receive an additional $45 for each of the 3 clinic visits for sample 
collection scheduled at 8 weeks, 4 weeks, and 2 weeks before virus inoculation.  


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Additionally, each subject will receive $575 for the RV challenge, and $45 for 
each of the 3 clinic visits (on days 7, 14, and 21 after virus inoculation) during the 
resolution of the infection. Total payment/subject will be $1870. 
Participants from the Richmond area (VCU and J. Sargent Reynolds), 
Staunton/Harrisonburg area (JMU and Mary Baldwin), Lexington area (Washington 
and Lee), or the Lynchburg area (Liberty University), will also be reimbursed $30.00 per 
trip for their travel expenses to UVA for visits number 1 through 8. No travel or 
reimbursement is needed for Visit # 9, because the ACT questionnaire for this visit will 
be completed on-line.   
Note:  Subjects will receive study drug or placebo and an EpiPen at no cost to them.  
The cost of all study procedures and the hotel stay are paid for by the study. 
 
7.5 Study Arm Assignment Procedures7.5.1  Blinding and Randomization  
Individual assignment to the Omalizumab or placebo during randomization 
for this blinded study will be displayed on occluded labels [or sealed 
disclosure envelopes] provided to the site pharmacist.   The occluded label 
must be removed at the time drug is dispensed and must be then attached to 
a medication label form.  
 
7.5.2 Securing Blinding and Randomization Information 
Randomization lists will be maintained in a secured area by the individual(s) 
responsible for maintaining the blind.  During site visits, the site monitor will check the 
occluded labels (or disclosure envelopes) to ensure that they are intact and in a secure, 
yet accessible, location for study personnel.   If any of the occluded labels or disclosure 
envelopes is opened, the site monitor will verify that the Principal Investigator, the 


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SMC  of the study and the NIAID Medical Officer have been notified and that a written 
account has been completed and forwarded to the above individuals.   
Jim Patrie from the Department of Public Health Sciences will carry out the statistical 
plans for this study and will keep the blind which will only be accessed if the stopping 
rules described above (8.1.1 and 8.1.2 below) apply. 
 
7.5.3 Requirements for Unblinding 
Prior to the end of the study, a subject may be unblinded only for safety reasons. 
If a clinically significant event occurs and knowledge of treatment assignment is 
required, the blind may be broken.. The Principal Investigator  will immediately notify 
NIAID Medical Officer that an unblinding might or has occurred and provide  the 
reasons for  the unblinding. 
   
7.5.4 Documenting an Unblinding 
Any unblinding (opening of a label or disclosure envelope) will require a full written 
account of the event(s) that necessitated the unblinding of the treatment assignment for 
an individual participant (s).  This account will be made in the participant (s) study file 
and in the final study report and will include the reason(s) for the unblinding, the name 
of NIAID Medical Officer who was notified, the names of the unblinded individual staff 
members, and the date and time the unblinding occurred. Documentation of an 
unblinding will be promptly provided to the SMC and NIAID Medical Officer and must 
be incorporated in the final study report. 
 
7.6 
Mechanistic studies 
This investigation will also evaluate whether establishing an IgE blockade with 
omalizumab will have an effect on Th2 inflammatory mediators (e.g. eosinophil cationic 


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protein and cysteinyl leukotriene measured in nasal washes) which may be of 
importance to measure in order to understand the mechanisms of rhinovirus induced 
flares of asthma. In addition, Th2 and Th1 associated biomarkers, along with several 
innate immune biomarkers and airway pH will be monitored in this study. Thus, by 
establishing an IgE blockade, the administration of omalizumab may be a novel method 
for deciphering the mechanisms of RV induced changes in the lower airway and may 
help determine which Th2 associated pathways will be directly affected by the 
reduction in serum IgE.  We also expect to see significant differences in the frequencies 
of CD4+ and CD8+ regulatory T-cell subsets present in the circulation of subjects from 
the omalizumab and placebo treated groups during the infection. Using nasal wash 
supernatants (i.e. from the end organ where it is known that RV replicates vigorously), 
it will be of interest to determine  whether we will be able to detect differences in 
cytokines and chemokines generated in direct response to RV (e.g. IL-8, IP-10, IL1beta,  
IL-12, INF-γ, and IFN-α2) between subjects enrolled in these two groups.  


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8. SAFETY PROCEDURES 
8.1  Stopping Rules 
8.1.1  Study Stopping Rules 
Study enrollment  and investigational product(s)/intervention(s) and study procedures 
will be suspended pending expedited (within 48 hours) review of all pertinent data by 
the Institutional Review Board, the SMC, and the NIAID, if any one of the following 
occurs:  
o Consistent with the study design, we plan to enroll 8 subjects in during the 
spring months of 2014, 2015, and 2016 and 7 subjects in the fall of 2014, and 
2015.  
 If, after inoculation with the RV-16 pool, two subjects experience severe 
asthma exacerbations requiring oral steroids for > 5 days annually (during 
the spring and fall enrollments),  or if 1 subject requires treatment in the ER, 
or hospitalization, the stopping rule will apply until further expedited review 
by the SMC, the UVA IRB, and the NIAID. Among the last 23 asthmatic 
subjects challenged with RV, only one subject required intervention with a 5 
day course of oral steroids, but did not require treatment in the ER or 
hospitalization.  Because the exclusion criteria (see below) obviates the 
enrollment of subjects who have required treatment in the ER, or 
hospitalization during the last 3 years (or any intubation ever requiring 
management in an intensive care unit), we suspect that it is not likely that the 
above stopping rules will be encountered.  
o  Lower respiratory tract infections have not yet occurred during experimental 
(or even natural) infections with rhinovirus in an immune competent host, 
because this pathogen is not known to be a cause of pneumonia.  It is 
conceivable that one or two subjects could acquire another respiratory tract 


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pathogen that could cause a lower respiratory tract infection.  If 2 subjects 
developed a significant lower tract infection (not including bronchitis) 
following RV-16 inoculation and this will lead to stopping the study for 
further review.   
o Death:   One death will lead to stopping the study until an expedited review 
is completed to determine whether the death might have resulted from any of 
the study procedures. 
o An anaphylactic reaction leading to death or two reactions leading to 
hospitalization as a result of Omalizumab administration, will lead to 
stopping the study until an expedited review is complete. 
o Periodic safety reviews identify specific events (serious and non-serious) 
occurring more commonly in the drug treatment group than in the placebo 
group (such as known consequences of asthma or other events that 
commonly occur in the study population independently of drug therapy) the 
enrollment will pause pending a safety data review by the SMC, and the 
NIAID. 
 
 
 
8.1.2 Individual Stopping Rules 
• At subjects request – Subject withdrawal 
• At PIs request and discretion (for medical reasons or if subject was 
noncompliant with appointments, or completion of diary cards, etc.) 
• Pregnancy 
• A severe asthma exacerbation that requires management in the emergency 
room (ER) including treatment with systemic steroids, hospitalization, or the 


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use of systemic (oral) steroids at any time during the study. Thus far, no 
subjects infected with rhinovirus experimentally have required treatment in 
the ER or hospitalization for asthma symptoms. 
• The use of inhaled cortico-steroids during the study will also exclude the 
subject from further participation, because this medication will confound the 
anti-inflammatory effects of omalizumab. However, the need for ICS by 
subjects during our RV-16 challenges to date has not occurred. 
• Anaphylactic reaction to Omalizumab 
• A decrease in platelet count of grade 1 severity or higher after the first 
injection of Omalizumab. 
• A blood hemoglobin level < 10.0 g/dL, in keeping with a NCI-CTCAE grade 
one adverse event. 
• An absolute neutrophil count of < 1000/ mcl 
• Signs and symptoms similar to serum sickness (fever, arthralgia and rash) as 
noted in the manufacturer’s prescription/product information report (PLI). 
 
8.1.3 
Early Discontinuation of Investigational 
Product(s)/Intervention(s) with continued study participation/follow-up 
Participants terminated from the study due to safety reasons linked to product 
(s)/intervention (s) will be monitored as described in Section 8.1.4. 
 
8.1.4 
Follow-up after early study termination 
Participants who are prematurely terminated from the study will be followed to 
monitor safety for a minimum of 30 days or until resolution or stabilization of the 


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disqualifying event whichever is longer or until the SMC, the NIAID Medical Officer 
and the Principal Investigator determine that the follow-up is complete. 
 
8.1.5 
Participant Replacement 
The protocol accounts for a 20% drop out rate to achieve the power estimated to test the 
hypothesis of this investigation.  Although it is not anticipated that more than 20% of 
subjects enrolled will be unable to complete the study, we are prepared to enroll 
additional subjects to meet the target sample enrollment of 42 subjects. Subjects who do 
not get inoculated will be replaced. 
8.2 
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 21 CFR 312; 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 
(Version 4.0, May 2009)  ).  These criteria have been reviewed by the study investigators 
and the IND sponsor and have been determined appropriate for this study population. 
 
 
8.2.1 Definitions  
8.2.1.1 Adverse Events and Suspected Adverse Reactions 
Adverse events (AE) 


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An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a Study Agent(s)/Intervention(s) and that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) Study Agent(s)/Intervention(s), whether or not related to the 
medicinal (investigational) Study Agent(s)/Intervention(s).  Any medical condition that is 
present at the time that the subject is screened will be considered as baseline and not recorded as 
an AE.  However, if the condition deteriorates or changes in severity at any time during the study 
it will be recorded and reported as an AE.  
 
Suspected Adverse Reactions (SAR) 
Any adverse event for which there is a reasonable possibility that the drug caused the 
event."     For the purposes of IND safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the adverse 
event.  
 
8.2.1.2 
Adverse Events Associated with Study Procedures 
The following clinical situations, when associated with study procedures are defined as 
expected adverse events and will be recorded on the AE CRF.  These situations do not 
limit the principal investigator from reporting any other events, associated or not with 
these procedures, from being recorded and reported as AEs.    
What risks are expected due to the intervention in this protocol? 
 
Expected Risks related to Omalizumab vs. 
placebo:  
Frequency 
 
• Injection Site Reaction  
Occurs frequently, 


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• Body Pain  
• Fatigue  
• Arthralgia 
• Hair loss  
• Fracture  
• Leg pain  
• Arm pain  
• Dizziness  
• Pruritus 
• Dermatitis  
• Earache  
Occurs infrequently 
(however, none of these 
symptoms have been shown 
to occur more frequently 
than in subjects treated with 
placebo in controlled trials). 
 
• Anaphylaxis  
  
Occurs rarely 
 
 
 
Expected Risks related to Rhinovirus-16 
inoculation and infection: 
Frequency 
 
• . Cold symptoms such as mild fever, 
wheezing, cough, and chest tightness.   
• A decline in absolute blood neutrophil 
counts. 
 
• Bacterial sinus infection 
 
• Lower respiratory tract infection (bronchitis) 
Occurs frequently, 
 
Occurs frequently, but not 
known to be clinically 
significant. 
Occurs infrequently. 
 
Occurs infrequently. 
Rhinovirus is not known to 
cause pneumonia. 
• Cold symptoms could cause severe wheezing 
and shortness of breath. requiring additional; 
treatment  
Occurs infrequently 
 
Expected Risks related to Spirometry Testing 
(excluding use of Methacholine)  
Frequency 
  
• Mild light-headedness and coughing  
Occurs frequently, 
 
• Chest soreness  
• Mild respiratory fatigue 
• Mild shortness of breath 
 
X  Occurs rarely 
 


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• Chest Tightness  
• Fainting  
 
Expected Risks related to use of Methacholine  
Frequency  
• Mild asthma symptoms  
Occurs frequently, 
 
• Coughing 
• Fainting  
• Chest tightness 
• Shortness of breath 
• Wheezing  
 
X  Occurs infrequently 
 
• Bronchoconstriction 
X Occurs rarely 
 
Expected Risks related to impulse oscillometry 
Frequency 
• Mild light-headedness and coughing, 
shortness of breath, and/or chest tightness 
X Occurs infrequently and is 
easily reversed with inhaled 
albuterol 
 
 
 
Expected Risks related to Albuterol (if needed 
following Methacholine testing) 
Frequency 
 
• Headache 
• Dizziness 
• Insomnia 
• Tremor  
• Sweating 
• Nausea  
• Vomiting  
• Dry Mouth  
• Increased pulse rate  
• Mild throat irritation 
• Cough  
X Occurs infrequently 
 
• Allergic reaction  
• Chest pain 
 
X Occurs rarely 
 


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Expected Risks related to Nasal Washes  
Frequency 
• Discomfort during the nasal wash procedure  
• Mild coughing  
X  Occurs infrequently 
Expected Risks related to Nasal Scrapings 
 
• Mild to moderate discomfort for 30 seconds 
during the procedure 
• Sneezing 
 
• Epistaxis 
• Occurs frequently 
 
• Occurs frequently 
 
• Occurs infrequently & 
easily stopped with 
standard treatment 
(external pressure 
applied to the nose). 
Expected Risks related to obtaining nasal lining 
fluid 
 
• Mild discomfort for 3 to 5 minutes during 
the procedure 
• Sneezing 
• Occurs frequently 
 
• Occurs frequently 
Expected Risks related to monitoring nasal 
mucous and secretion weights 
None. 
Expected Risks related Blood Draws 
Frequency 
• Pain at venipuncture site  
X Occurs frequently, 
 
• Bruising at venipuncture site 
• Fainting 
X  Occurs infrequently 
 
• Infection  
X Occurs rarely 
 
 
Expected Risks related to hotel stay 
(confinement)  
Frequency 
• Boredom 
• Sense of isolation  
X Occurs occasionally, 
although subjects are 
predominantly college 
students who study for their 
classes during the hotel stay. 
 
 


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Expected Risks related to use of EpiPens 
(supplied for this study)   
Frequency 
 
• Tachycardia 
• Nausea and Vomiting  
• Pale Skin   
• Dizziness  
• Tremors  
• Headache  
• Anxiety  
X Occurs infrequently 
 
 
Reproductive Risks  
Frequency 
 
• Potential risk to fetus if become pregnant 
during study 
X Occurs rarely 
 
 
Privacy Risks  
Frequency 
 
• Privacy risk  
X Occurs rarely 
 
 
 
 A summary of safety tests/procedures/observations to be performed is 
described in Section 7 and Appendix 5. 
• Note: 
1. - Only subjects at low risk for significant asthma symptoms will be enrolled (as 
described above in the exclusion criteria).  
2. -Clinical monitoring will be conducted during RV challenge. Additionally,  
after subjects receive injections of omalizumab they will be monitored for signs 
and symptoms of anaphylaxis as described in Section 7.2. All subjects will be 
provided with EpiPen and instructions about how and when to use it. However, 
needing to use EpiPen, based on the reports of the frequency of anaphylaxis, is 
unlikely. 


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8.2.1.3  Serious Adverse Event (SAE)  
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the outcomes described 
below: 
1. Death.  A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up.    
2.  A life-threatening event.  An adverse event or suspected adverse reaction is 
considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.. 
3. An inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5. 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 subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
6. Congenital anomaly or birth defect. 
 
Additionally, SAEs will be reported as described in Section 8.2.4. 
 
 


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8.2.1.4 Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or it is not listed at the specificity or severity that has 
been previously observed; or, if an investigator brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan or 
elsewhere in the IND application.                                                                                                                         
The Principal Investigator will ensure the timely reporting of unexpected adverse 
events as described in table in Section 8.2.2.2. 
 
8.2.1.5 Safety Monitoring Committee  
The Safety Monitoring Committee (SMC) will provide independent safety monitoring in a timely 
fashion and to provide recommendations regarding the safe continuation of the study. The  SMC 
will evaluate adverse events, including SAE, against the known safety profile of the study 
product to assess for possible changes to the overall risk of the study.  The SMC , along with the 
PI and the NIAID Medical Officer, will conduct periodic reviews of cumulative safety data 
including, but not limited, to SAEs. The SMC will be available to communicate with the NIAID 
Medical Officer on safety events as needed to discuss individual specific SAEs or clusters of 
SAEs developing during the study and results of periodic safety reports.  
8.2.2 Collecting, Recording and Managing Adverse Events 
8.2.2.1 Identifying Adverse Events 
Any adverse event that occurs from the moment the subject has signed the consent form 
will be recorded and is reportable. Collection of AEs/SAEs will be completed after the 
completion of the 8 week period of treatment with omalizumab (before virus 
inoculation) and again through the final visit after the infection (Day 28).   
Adverse events may be discovered through any of these methods: 


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1.  Observing the participant. 
2.  Questioning the participant, with standardized questions/procedures. 
3.  Receiving an unsolicited complaint from the participant. 
4. 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.  
 
8.2.2.2 
  Recording AEs 
Throughout the study all identified adverse events (serious and non-serious) will be 
recorded for all randomized participants on all appropriate source document and 
adverse event case report forms regardless of their severity or relation to the study.    
 
A complete description of all adverse events will include event description, time of 
onset, investigator assessment of severity, relationship to study agent(s) or 
procedures/intervention(s), time of resolution/stabilization of the event, expectedness, 
determination of whether the AE qualifies as a SAE, and action taken.  A change in the 
severity of the AE will also be documented.  The PI will document assessment of 
severity and relationship on the source documents or the on the CRF.  
 
Will all adverse events, as defined in this protocol, be collected/recorded? 
   Yes 
 
 How will adverse event data be collected/recorded?  
 Paper AE forms/source documents (please attach a copy of this form if 
possible) 
How will AEs be classified/graded?  
Please refer to Section 8.2.3.1 


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What scale will the PI use when evaluating the relatedness of adverse events to the 
study participation?  
Please refer to Section 8.2.3.2    
 
When will recording/reporting of adverse events/unanticipated problems begin? 
 After subject signs consent 
When will the recording/reporting of adverse events/unanticipated problems end? 
 At the end of Visit 9 (28 days post inoculation)    
 Please complete the following table to describe details of Adverse Event, Unanticipated 
Problem, and Protocol Violation reporting to the IRB.  
 
 
 
 
 
 
 
Type of Event 
To whom will it be reported*: 
Time Frame for 
Reporting 
How reported? 
Any event resulting in death that is deemed 
DEFINITELY related to (caused by) study 
participation 
(Note:  An internal event is one that occurs in a 
subject enrolled in an UVa protocol.) 
IRB-HSR 
 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected adverse event  
And Unexpected Non-Serious Adverse Event 
IRB-HSR 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that are not adverse 
events or protocol violations  
 
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event.  
Unanticipated Problem report form.  
 
http://www.virginia.edu/vprgs/irb/HSR_docs/Forms/Reporting_Requirements-
Unanticipated_Problems.doc ) 
  


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Protocol Violations (Note the IRB-HSR only 
requires that MAJOR violation be reported, unless
otherwise required by your sponsor, if applicable.
 
 
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event.  
 
Protocol Violation and Enrollment Exception Reporting Form 
 http://www.virginia.edu/vprgs/irb/hsr_forms.html 
 
Go to 3rd bullet from the bottom. 
  
 
How will the endpoint data be collected/recorded?  
 Protocol specific case report forms (attach if in-house) 
 Source documents 
Data and Safety Oversight Responsibility 
Who is responsible for overseeing safety data for this study (i.e., Who is looking at data in 
aggregate form to identify trends?)(Check all that apply) 
 No additional oversight body other than PI (skip question 5.2) 
 NIAID Medical Officer 
 NIAID SMC  
 PI   
 
 
Please check aggregate reviews that will occur by the PI?  (Answer this question ONLY if 
the PI is the ONLY person overseeing the safety data for this study.  (Note: in this case 
you will have checked the first box for question #5.1 "No additional oversight body other than 
PI.”) 
N/A 
 


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How often will aggregate review occur?  Answer this question ONLY if the PI is the ONLY 
person responsible for overseeing the safety if the study 
N/A 
How will a report of the information discussed in questions above be submitted to the 
IRB?   
 Part of IRB-HSR Continuation Status Form 
 Separate report from sponsor/ SMC 
 Other: (specify)      
8.2.2.3 
Recording SAEs 
Serious adverse events will be recorded on the serious adverse event case report form 
and will include a narrative of the event signed and dated by the Principal Investigator.  
8.2.2.4 
Managing Adverse Events 
The site investigator must apply his or her clinical judgment as to whether an AE is of 
sufficient severity to require that the participant immediately be removed from further 
treatment under the protocol. The investigator must institute any necessary medical 
therapy to protect a participant from any immediate dangers. In this regard, if any 
subject experiences asthma symptoms which are not controlled with their albuterol 
metered dose inhaler, or if they experience a decline in their FEV1 by 20% below their 
baseline FEV1 at baseline, they will be treated acutely by the study physicians as 
described in Appendix 6 and followed carefully until the symptoms flare has resolved. 
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 


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from the study and the NIAID Medical Officer and the Principal Investigator determine 
that follow-up is complete. 
If an abnormal value or result from a clinical or laboratory evaluation (e.g., a 
radiograph, an ultrasound, or an electrocardiogram) is determined to be an AE (refer to 
National Cancer Institute’s Common Terminology Criteria for Adverse Events Version , 
Version 4.0, May 2009)  , then the evaluation that produced the value or result can be 
repeated until the value or result returns to normal, or the result can be explained, or 
the usual standard of care does not require further follow-up, and the participant’s 
safety is not at risk.   
8.2.3 Grading and Attribution  
8.2.3.1 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 (Version 4.0, May 2009)  
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.   
All adverse events whether or not 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 (A semi-
colon indicates ‘or’ within the description of the grade.): 
 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 


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Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL (preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc). 
Grade 3 = Severe or medically  significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL (bathing, dressing and undressing, feeding self, using he toilet, taking 
medications, and not bedridden).  
Grade 4 = Life-threatening consequences; or urgent intervention indicated. 
Grade 5 = Death related to AE. 
 
Anaphylaxis is a disorder characterized by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing a 
hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, 
hypotension, cyanosis and loss of consciousness and may lead to death. 
Severity grading of anaphylaxis as per the NCI-CTCAE manual is as follows: 
Grade 1= 
Grade 2= 
Grade 3= Symptomatic bronchospasm, with or without urticaria; parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension 
Grade 4= Life-threatening consequences; urgent intervention indicated 
Grade 5= Death 
 
8.2.3.2 Definition of attribution: 
When evaluating the relatedness of adverse events to the study participation the PI will 
determine the relationship of adverse events to the study 
Unrelated: The event is temporally independent of the study product; and/or the event 
appears to be explained by another etiology. Alternative etiology must be described in 
subject’s records. 


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Related: There is an association between the event and administration of the study product, 
a plausible mechanism for the event to be related to study product and causes other than 
study product have been ruled out and /or the event re-appeared on re-exposure to study 
product. 
8.2.4. SAE Reporting and Procedures  
The Principal Investigator will be notified by the study staff as soon as a staff 
member becomes aware ANY SAE.  In the absence of the Principal Investigator, a 
physician sub-investigator will be notified.  
8.2.4.1. Notifying the NIAID Medical Officer  
The NIAID Medical Officer will be notified by the Principal Investigator by email no 
later than 24 hours after the investigative site becomes aware of the SAE, regardless of 
the presumed relationship to the study product.   
Within another 24 hours, the NIAID Medical Officer must receive the corresponding SAE case 
report form or MedWatch  form generated and signed by the Principal Investigator with the 
description of the SAE and the Principal Investigator’s  assessment of causality and 
expectedness . The SAE case report form  or MedWatch form will be re-submitted by the PI to 
the NIAID Medical Officer with updated relevant medical information in the narrative section 
of the form as needed until the case is closed.  
Submission timelines of MedWatch forms to the FDA is captured in section 8.2.4.3. below. 
Contact information for the NIAID Medical Officer is listed below: 
Lisa M Wheatley, MD, MPH 
Division of Allergy, Immunology and Transplantation 
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane Rm 6B56 
Rockville, MD 20892, USA 
Phone: 240-627-3573 
Email: lisa.wheatley@nih.gov 
 


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8.2.4.2 Unexpected, Non-Serious Adverse Events  
An unexpected, non-serious adverse event that is of Grade 3 severity or higher and 
study related will be recorded and reported to the  NIAID Medical Officer under the 
serious adverse event reporting procedure outlined in the SAE Reporting and Criteria 
Section (Section 8.2.4.1) of the protocol (i.e. within 24 hours).     
 
8.2.4.3. Notifying the FDA 
The IND Sponsor is responsible for FDA safety submissions as follows:  
 
The following process for reporting a serious adverse event ensures compliance with 
the ICH guidelines, 21 CFR 46 and 21CFR §312.32.  
 
• Expedited reporting to the FDA applies if the adverse event is considered  to be: 
o Serious (ref. Section   8.2.1.3), and 
o A Suspected Adverse Reaction  (ref Section 8.2.1.1), and 
o Unexpected (ref. Section  8.2.1.4 )   
These events are called SUSARs (a serious, unexpected suspected adverse 
reaction) 
SAEs that do not strictly fit the above criteria may be reported to the FDA in an 
expedited manner if the IND Sponsor or the NIAID Medical Officer chooses to 
do so.  Expedited events will be reported by the IND Sponsor within 15 calendar 
days after the IND sponsor becomes aware of the SAE; fatal or life-threatening 
events will be reported within 7 calendar days.  Each 7-day report must be 
followed up by a 15-day report. 
 


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• Standard reporting (non-expedited) to the FDA (report in the IND Annual 
Report) applies to all SAEs not meeting the criteria for expedited reporting. The 
Principal Investigator will be responsible for compiling the IND Annual Report. 
 
Adverse Events that are study endpoints do not need to be captured in an expedited or 
standard IND safety report, unless there is evidence suggesting a causal relationship. 
 
 8.2.4.4. Notifying the Safety Monitoring Committee  
The NIAID Medical Officer will submit all expedited SAEs on an ongoing basis to the 
SMC.  Individual or clusters of SAEs may be reported expeditiously to the SMC either 
when specified by the SMC, or upon determination of the NIAID Medical Officer.  
 
8.2.4.5. 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 as described in table in Section 8.2.2.2. 
 
 
8.2.4.6 Reporting Pregnancy  
The investigator will be informed immediately of any pregnancy and will report all 
pregnancies within 24 hours to the NIAID Medical Officer (as described in Section 
8.2.4.1) utilizing the SAE report form.  This report is for tracking purposes only.  All 
pregnancies that are identified during the study will be followed to conclusion and the 
outcome of each will be reported.  The investigator will discuss with the participant 
and/or the treating physician the known possible risks of the investigational product(s) 
on the fetus.  Monitoring of the participant will continue until the conclusion of the 
pregnancy, and a follow-up SAE report form detailing the outcome of the pregnancy 


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will be submitted to the NIAID Medical Officer and Project Manager.  Subjects will be 
terminated from the study due in the event of pregnancy. 
 
8.2.5 Non Serious Adverse Events Reporting  
8.2.5.1 
Notifying the Safety Monitoring Committee  
The study biostatistician or Principal Investigator will provide the NIAID Medical 
Officer with periodic cumulative safety reports (tables and data listings of all AEs, 
including SAEs)  during the 3 years of the study.   
Reports are due as described below and must capture cumulative safety  information 
for the entire cohort of subjects participating in the study in the spring or the fall of each 
year of the study.  
 
• 1 week prior to RV inoculation  
•  After each subject enrolled have completed their last study visit.    
 
The NIAID Medical Officer will review tables and data listings and send the safety 
reports to the SMC for further review. Individual or clusters of AE’s will be reported 
expeditiously to the SMC either when specified by the   SMC, or upon determination of 
the NIAID Medical Officer. 
The PI, the NIAID Medical Monitor will review safety data on an ongoing basis 
including in addition to the periodic reviews listed above. 
 
  


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8.2.5.2 
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 described in table in 
Section 8.2.2.2 
 
8.2.5.3 
 Notifying the FDA  
The IND Sponsor will file all adverse events per 21 CFR 312.32, whether expedited or 
part of the IND Annual Report.  The Principal Investigator will be responsible for 
compiling the IND Annual Report. The SMC and the NIAID Medical Officer will 
conduct the oversight of safety data filed with the FDA by the  Principal Investigator. 
 
8.3 Protocol Deviations (Protocol Violation) 
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. 
 
8.3.1 Protocol Deviation Definition 
A protocol violation is defined as any change, deviation, or departure from the study 
design or procedures of  research project that is NOT approved by the IRB-HSR prior to 
its initiation or implementation, OR deviation from  standard operating procedures, 
Good Clinical Practices (GCPs), federal, state or local regulations. Protocol violations 


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may or may not be under the control of the study team or UVA staff. These protocol 
violations may be major or minor violations. 
 
 
Protocol Deviations: 
The Principal Investigator is responsible for reporting protocol deviations to the IRB 
using the standard reporting form as described in table in Section 8.2.2.2 As a result of 
deviations, corrective actions are to be developed by the site and implemented 
promptly. 
 
Major Protocol Deviation - is a deviation from the IRB approved protocol that may 
affect the subject's rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data.  
If the deviation meets any of the following criteria, it is considered a major protocol 
deviation (example list is not exhaustive):  
1. The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject.  
Examples:  
• A research subject received the wrong treatment or incorrect dose.  
• A research subject met withdrawal criteria during the study but was not 
withdrawn.  
• A research subject received an excluded concomitant medication.  
2. The deviation compromises the scientific integrity of the data collected for the study.  
Examples:  
• A research subject was enrolled but does not meet the protocol's eligibility  
criteria.  
• Failure to treat research subjects per protocol procedures that specifically  
relate to primary efficacy outcomes.(if it involves patient safety it meets the  


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first category above)  
• Changing the protocol without prior IRB approval.  
• Inadvertent loss of samples or data.  
3. The deviation is a willful or knowing breach of human subject protection  
regulations, policies, or procedures on the part of the investigator(s).  
Examples:  
• Failure to obtain informed consent prior to initiation of study-related  
• Procedures 
• Use of outdated  or incorrect consent forms 
• Falsifying research or medical records.  
• Performing tests or procedures beyond the individual's professional scope or 
privilege status (credentialing)  
4. The deviation involves a serious or continuing noncompliance with federal, state, 
local or institutional human subject protection regulations, policies, or procedures.  
Examples:  
• Working under an expired professional license or certification  
• Failure to follow federal and/or local regulations, and intramural research  
• Repeated minor deviations.  
5. 
The deviation is inconsistent with the NIH Human Research Protection Program’s 
research, medical, and ethical principles.  
Examples:  
• A breach of confidentiality.  
• Inadequate or improper informed consent procedure.  
 
Minor Protocol Deviation - A minor protocol deviation is any change, divergence, or  
departure from the study design or procedures of a research protocol that has not been  
approved by the IRB and which DOES NOT have a major impact on the subject's rights,  


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safety or well-being, or the completeness, accuracy and reliability of the study data.  
 
8.3.2 
 Reporting Protocol Deviations 
Upon determination that a protocol deviation has occurred, the study staff will a) notify 
the Principal Investigator, b) notify the NIAID Project Manager (refer to investigator’s 
signature page for contact information) ,  and the NIAID medical Monitor and c) will 
complete the Protocol Deviation form. All major protocol violations must be reported to 
the IRB-HSR immediately upon discovering them, and no later than seven (7) calendar 
days from the time the study team receives knowledge of the event.    
NIAID may request discussion with the Principal Investigator  to determine the effect of 
the protocol deviation on the study participant and his/her further study participation, 
the effect of the protocol deviation on the overall study and corrective actions.  The 
Principal Investigator will complete and sign the Protocol Deviation form and submit it 
to the NIAID Medical Officer and Project Manager   and to the site IRB, per IRB 
regulations (refer to table in Section 8.2.2.2).  Major protocol deviations will be reported 
to the SMC by the NIAID Medical Officer.  The IND sponsor will be responsible for 
notifying the FDA.  
 
 


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9 
SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN 
9.1 
Sample Size, and Power Calculations 
9.1.1 General considerations 
Data will be provided in listings sorted by patient #ID, cohort or treatment group as 
applicable. Tabular summaries will be presented by cohort and treatment group as 
applicable. Categorical data will be summarized by the number and percent of subjects in 
each category. Continuous variables will be summarized by descriptive statistics using 
mean, standard deviation, median, minimum and maximum. Describe here the formal statistical 
tests planned. 
All of the data analyses associated with this Aim will be conducted following the 
guidelines of the intention to treat principle. Missing data will not be imputed.  
9.1.2 
 Patient populations 
Sample Size Justification:  To evaluate the asthmatic response to RV, the primary outcome 
variable for this study will focus on changes in the cumulative lower  respiratory tract  
symptom (CLRTS) scores computed as the sum of the lower respiratory tract symptom scores 
from the day of the RV inoculation through the first four days after virus inoculation in the 
hotel. A total of 42 subjects will be enrolled.  Twenty one subjects will be randomized to 
Omalizumab and 21 subjects will be randomized to placebo. Power Analysis: To account for a 
possible 20% drop out rate, our power calculations assume that 17 subjects per study-group will 
complete the study. Participants who are determined to have developed a naturally acquired 
RV-16 infection prior to experimental inoculation (4-fold rise in RV antibody titers or a positive 
RV RCR in nasal washings) will be dropped from the analysis. Details: A Monte Carlo 
simulation was carried out to estimate the statistical power that we would have with 17 subjects 
per group to detect a clinically meaningful difference between the day 4 mean CLRTS of the 
placebo group and the day 4 mean CLRTS of the Omalizumab group.  In the simulation we 


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assumed that the underlying distributions of the day 4 CLRTS in the placebo and Omalizumab 
study populations are negative-binomial, with means 4.2 and 1.8, respectively.  Note that in our 
previous challenge study of six asthmatics with high total IgE,  ten asthmatics with low levels of 
total IgE, and the nine healthy controls (16),  4.2 was the observed day 4 mean CLRTS in the 
high IgE group, while the mean day 4 CLRTS was 1.0 in the low IgE group.  The power of the 
statistical test was determined based on 10,000 simulation repetitions, in which at each 
repetition we generated 17 observations from each of the two aforementioned negative-
binomial distributions.  We then used a negative-binomial generalize linear model (log-link) 
with one predictor variable, which identified the distribution from which the response (CLRTS) 
was generated, to test the null hypothesis that the means of the two negative-binomial 
distributions are equal. The power to detect a 2.4 unit absolute difference between the day 4 
mean CLRTS (i.e. |4.2 – 1.8|=2.4) was calculated by determining the proportion of times that 
the null hypothesis was rejected when the rejection rule was based on a Wald test with two 
sized type I error rate 0.05.   The power of the test was determined to be 0.83.   
 
Statistical Analyses (Primary Endpoint):  The lower respiratory tract symptom scores 
from the day of RV inoculation (study day 0) through study day 4 of monitoring in the 
hotel will be tallied in consecutive sequence to produce a CLRTS score for each subject. 
The CLRTS score will be integers and they will be analyzed by way of a negative-
binomial generalized linear model (GLM).  The GLM model specification will include 
two variables. One variable will be a classification variable that will identify the group 
(placebo, or omalizumab) to which the subject was randomly assigned, while the 
second variable will denote the subject’s total lower respiratory symptom score on the 
day prior to RV-inoculation.  A linear contrast of means will be used to test our primary 
null hypothesis that the mean of the CLRTS score measurement distribution over the 4 
days after RV inoculation is the same for the 2 study-populations (i.e. placebo and 
omalizumab). The null hypothesis will be rejected if the p-value of the Likelihood Ratio 
test is less than or equal to 0.05. A 95% confidence interval will be constructed to 


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estimate a plausible range of values for the CLRTS score means determined over the 
first 4 days after RV inoculation (i.e. omalizumab CLRTS score mean: placebo CLRTS 
score mean) after adjusting for the lower respiratory tract symptom scores recorded on 
the day prior to RV inoculation. 
 
As a secondary analysis, we will add the subjects’ baseline IgE values to the negative 
binomial regression model as covariate information to insure that the primary pivotal 
comparison findings hold when the CLRTS mean scores of the  placebo and 
omalizumab groups are estimated at a common reference baseline IgE value.  
 
Alternative Approach: If we observe a systematic pattern in the residual plot or the qq-
plot of the standardized Pearson residuals of the negative-binomial GLM (indicative of 
lack of goodness of model fit) we will analyze the CLRTS scores via a randomization 
(permutation) test, and use a bootstrapping procedures to obtain a 95% confidence 
interval for the mean difference between the CLRTS scores of the two study-arms. 
Statistical Analyses (Secondary Endpoints):   In addition to comparing the CLTRS 
scores between subjects enrolled in the omalizumab and placebo groups over the first 4 
days after RV inoculation (primary endpoint), we are also prepared to compare the 
CLTRS scores between the 2 study groups over the first 7 days and during the entire 21 
days of monitoring after RV inoculation.  These comparisons will  be carried out as  
described above.  We are prepared to do this recognizing that we won’t be able to 
administer omalizumab to subjects whose total IgE levels are too high to receive the 
study drug as noted in the exclusion criteria for this study (section 4.2). As a result, the 
total IgE levels for subjects enrolled in this proposed study may, on average, be lower 
than for the subjects enrolled in our previously published study (16). Thus, it is possible 
that the CLRTS scores for the subjects enrolled in this proposed study may peak later 


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than we anticipate, as was observed for asthmatics who had lower levels of total IgE in 
our previous study (16).      
 
We will use one-way analysis of variance (ANOVA) to compare the mean post-
inoculation day 4 change (from baseline prior to RV Inoculation) in methacholine 
sensitivity (MS) [PC20/FEV1 (mg/ml)] between the subjects who were randomized to 
the placebo and omalizumab groups.   A linear contrast of means will be conducted to 
test our primary null hypothesis that the mean of the underlying distribution of 
measurements of change in MS on post-inoculation day 4 is the same for the 2 study-
populations.  The null hypothesis will be rejected if the p-value of the t-test is less than 
or equal to 0.05.  A 95% confidence interval will be constructed to estimate a plausible 
range of values for the mean difference in the change in MS on day 4 between the 2 
populations. In addition, we  will  use a binomial exact test to compare between the 2 
treatment groups the  number of subjects whose FEV1 drops below 70% predicted, or 
by more than 20% from their baseline value (measured prior to RV inoculation), during 
the  post RV inoculation phase.   
 
The FeNO data that we collect on study days 0, 1, 2, 3, and 4 in the hotel will be 
analyzed by way of a linear-mixed effect ANCOVA. The response data will represent a 
set of delta values that will quantify the change in the FeNO concentrations on post-
inoculation study days 0 through 4, from the baseline FeNO values measured just prior 
to the RV inoculation. The ANCOVA model specification will include two factors. One 
factor will identify the group to which the subject was randomly assigned, while the 
second factor will identify the day on which the FeNO was assessed. The FeNO value 
measured just prior to RV inoculation will function as the ANCOVA adjustment factor. 
Linear contrasts will be used to test our primary null hypotheses that on post-
inoculation day 4, the mean change in FeNO was the same in the 2 study groups after 


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adjusting for their baseline FeNO. A two-sided ≤0.05 decision rule will be utilized as the 
rejection criterion for this test.  Linear contrasts will also be used to test our secondary 
null hypotheses that over post-inoculation days 0,1,2,3 and 4 the mean change in FeNO 
will be the same in the 2 study-groups after adjusting for baseline FeNO. The effects of 
omalizumab on FeNO during the months of treatment before the infection will be 
analyzed in a similar manner as the FeNO data collected after RV inoculation.     
 
Data for additional secondary outcome variables will be collected at baseline before 
inoculation, and on post-challenge days 0,1, 2, 3, and 4 in the hotel, and on follow-up 
days 7, 14, and 21 after the subject leaves the hotel. Many of these additional secondary 
outcomes will be analyzed in exactly the same manner as in our previous experimental 
RV challenge study (16). Additionally, the frequency of the CD4+ and CD8+ T-cells 
expressing Foxp3 on post-inoculation day 3 will be compared to the frequency of these 
cells prior to RV inoculation by way of the non-parametric Wilcoxon sign rank test. The 
between group comparison of the change in these cells on post-inoculation day 4 will be 
conducted via the non-parametric Wilcoxon rank sum test. We will also examine the 
relationship between pairs of the secondary outcome variables via linear mixed effects 
regression models.  
 
We will also compare changes in biomarkers of inflammation and bronchial 
hyperreactivity between the omalizumab and placebo treatment groups during the 8 
weeks of drug administration before RV challenge and after RV inoculation to evaluate 
the influence of the infection on these parameters. For each subject, we will be 
measuring FeNO levels (ppb), absolute blood eosinophil counts (cells/mm3), impulse 
oscillometry and PC20 (mg/ml) for methacholine at 4 time points, beginning at 
enrollment (8 weeks before the RV challenge), on the day of inoculation (day 0), during 
peak cold symptoms (days 4 and 7), and at study day 21). The statistical analyses will be 


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focused on comparing changes in theses parameters from baseline between the 
treatment groups at each time point and the analyses will be conducted by way of 
linear-mixed effects models. For each analysis, the set of repeated measurements will 
identify the changes in the biomarker measurements at days: 0, 4, 7 and 21 from the 
measurements at the baseline (i.e. beginning of enrollment). Three potential sources of 
variation in the biomarker change data will be consider in the analysis. One source will 
be the treatment group (omalizumab vs. placebo), the second source will be the 
assessment times (days 0, 4, 7 and 21), and the third source will be treatment group by 
assessment time interaction. The subjects‟ biomarker measurements at enrollment will 
be treated as covariate information in the analysis. Between-group comparisons of the 
mean biomarker change at days 0, 4, 7 and 21 will be based on a set of linear contrasts of 
the least-squared means. A Bonferroni multiple comparison hypothesis rejection rule 
will be utilized in hypothesis testing to maintain an overall false positive rejection rate 
of 0.05. The ACT questionnaire will be evaluated using statistical methods similar to 
evaluating the changes in the CURTS and CLRTS scores. The results will be compared 
at 4 time points when the ACT questionnaire will be completed (i.e., at enrollment, at 
Visit 3 and 5, and at 28 days after viral inoculation when subjects return to receive their 
payment for completing the study). 
 
Missing data:  The longitudinal data analysis methods that we propose to use to 
analyze the primary and secondary outcome data in this study are data efficient (i.e. 
they utilize all of the available data from each individual in the estimation of the 
statistical model parameters). If data imputation is deemed necessary, we will use the 
SAS PROC MI procedure (SAS version 9.2.2 EAS, Cary, NC) to carry out the data 
imputation. The subsequent data analysis will be conducted in accordance with the 
analytical guidelines proposed by Schafer (30).   
 


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9.1.3 Study Participant Baseline Characteristics and Demographics 
Summary of descriptive statistics for baseline and demographic characteristics 
(age, race, sex, body weight, and height) will be provided for all enrolled 
participants.   
9.1.4 Study Endpoints  
The primary endpoint is defined in section 3.1.1 
The secondary endpoints are defined in section 3.1.2. 
9.1.5 Study Completion 
The percent of participants who complete the study, losses to follow-up, time to lost to 
follow-up, and reasons for discontinuation (e.g., adverse events) will be presented.   
 
9.2 Interim Analyses  
Interim analyses are not planned for this study.  
9.3 
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 and will be described in the final report.  These changes will be 
subject to review by the IRB, SMC, NIAID, and the FDA  


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10 
 IDENTIFICATION AND ACCESS TO SOURCE DATA  
10.1 
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 or hospital database and the data will 
be transferred to clinical CRFs, as applicable. 
 
10.2   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.  
 
For purchased investigational product(s)/intervention material(s), the Principal 
Investigator will promptly notify , the NIAID Medical Officer, and the IRB about 
changes to the package insert.      
    
 
 


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10.3 
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 IND sponsor(s), NIAID 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 identify individuals.  
 


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11 
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. 
 
The Principal Investigator, through the use of an independent site monitor will be 
responsible for the regular review of the conduct of the trial, for verifying adherence to 
the protocol, and for confirming the completeness, consistency, and accuracy of all 
documented data and accuracy of source documentation verification.  The reports of the 
site monitor will be submitted to the Principal Investigator and the NIAID Project 
Manager.  NIAID will independently review these reports. 
 
When the CRFs are complete, they will be reviewed and signed by the Principal 
Investigator.  All discrepancies identified by the site monitor or NIAID will be 
reviewed, and any resulting queries will be resolved with the Principal Investigator and 
the CRFs will be amended as needed.  
 


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12 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 current good clinical 
practice (cGCP), as delineated in Guidance for Industry: E6 Good Clinical Practice 
Consolidated Guidance 1, and according to the criteria specified in this study protocol.  
Before study initiation, the protocol the informed consent documents and the CRFs will 
be reviewed and approved by NIAID, SMC , 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 or subject’s legal representative to allow for an informed decision about 
participation in the study.  Prospective participant or subject’s legal representative must 
be given ample opportunity to review the informed consent and inquire about the 
results of the study. All participants (or their legally acceptable representative) must 
read, sign, and date a consent form prior to study participation.  Consent materials for 
participants who do not speak or read English will be translated into the participants’ 
appropriate language. 
 


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The informed consent form will be revised and receive IRB approval 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 form 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 during collection, storage, and reporting of participant 
information. 
Tissue banking 
What samples will be banked?  Nasal wash specimens and blood. 
 
Information Accompanying Specimens  
 
What information will be on the label of the specimen to be banked?  Study code (i.e. 
X for Omalizumab), type of sample (i.e. N = nasal wash, B = blood), subject number, 
and date sample collected. For example, XN 01 (01/01/09) = nasal wash from subject 
number one collected on January 1st 2009). 
  
 
1. What information will be "linked to" or will accompany the specimen?  
Subject number will be on the specimen collected.  This subject number will also 
be on the enrollment log that will be linked to the subject’s name.    
2. If the samples are identifiable please explain why they cannot be coded or de-
identified. N/A  


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Collection and/or Storage of Specimens   
 
3. How much material (e.g. blood, tissue) will be collected and how will it be 
collected?  Blood samples and nasal washes  will be collected in the amounts 
and at the frequency and using methods described previously in this protocol.  
 
4. Who will be responsible for storing the specimens?  Peter Heymann MD  
 
5. Where will the specimens be stored?  Freezer in MR 4-Peter Heymann’s lab  
 
6. Could the loss of confidentiality of the subject's health information 
potentially have a negative impact decisions of health coverage, employment, 
insurability or any other benefit, or cause social stigmatization?     No 
 
7. Will another research institution or entity outside of UVa ever have control 
over the specimens?   
 Nasal scraping samples for analyzing epithelial cell gene expression via RNA 
seq will be sent to a research collaborator at the University of Cincinnati. These samples 
will be de-identified. The only information recorded on the samples is decribed above 
on page 109 (see “Information Accompanying Specimens”). No access to HIPAA 
identifiers will be available to our collaborators. 
 
8. Can participants withdraw their specimens or request that they be destroyed?  
Yes  
 
Privacy Plan for Studies With Consent  
 
1. Describe your plan to protect the identifiable data from improper use and 
disclosure. 
 
___X _ Option # 2 - Health information and/or specimens will be stored with 
HIPAA identifiers. 
• Will any of the data be stored in electronic format?` 
                   Yes`    
If yes, where will it be stored?  
__X___ a Health Systems Computing Services (HS/CS) managed 
server that is configured to store data regulated by HIPAA, 
• Will any of the data be stored in hard copy format (e.g.- on paper)?  YES    
If yes, where will it be stored?  
___X__ case report forms, including diary cards from each subject, 
will be stored in a secure area with limited access.  


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 _____questionnaires/ surveys will be stored in a secure area with 
limited access.  
• Only investigators for this study and clinicians caring for the patient will 
have access to the data.  They will each use a unique log-in ID and 
password that will keep confidential.   
• If specimens stored:  The following security precautions will be 
implemented for specimens stored at UVa:  
 Specimens will be stored in a locked freezer/ or locked room 
 Access to the freezer/room will be limited to study personnel 
 A log book will maintained documenting specimens added to or 
taken from the freezer/room.  
• Each investigator accessing electronic data will sign the University’s 
Electronic Access Agreement available at 
http://www.itc.virginia.edu/policy/form/eaa.pdf and forward the 
signed agreement to the appropriate department as instructed on the 
form. 
If you currently have access to clinical data it is likely that you have already 
signed this form.  You are not required to sign it again.  
• Accessing an electronic database holding the HIPAA identifiers and 
health information from an external site will be done only via the use of a 
VPN#.   
• No identifiable data (data with health information and HIPAA identifiers) 
will be transferred to any other location such as a desktop, laptop, 
memory stick, CD etc.  The researcher will follow all health system 
security policies found at 
https://www.healthsystem.virginia.edu/Intranet/security/Security_Poli
cies/home.cfm 
• The study team may temporarily move data out of the electronic database 
for analysis under the following conditions: 
o HIPAA identifiers, such as name, SS#, (see Table A for full list 
HIPAA identifiers)   WILL NEVER be transported at the same time 
as the health information.  
o HIPAA identifiers will be kept in a secure location with limited 
access.  
o If analysis of data is done on another computer-: 
 That computer will be secured according to, at a minimum, 
security guidelines described at 
http://itc.virginia.edu/security/checklistforPCs.html. 
 the HIPAA identifiers and health information WILL NEVER 
be stored on the additional computer at the same time, 


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 The data will be deleted from the hard drive of the 
additional computer as soon as possible.   
 the data will be securely removed from the server, 
additional computer(s), and electronic media according to 
the University's Electronic Data Removal Policy described at 
https://etg07.itc.virginia.edu/policy/policydisplay?id=IRB-
004 
• The data may not be analyzed for any other study without additional IRB 
approval 
 
2.  Describe your/central registry’s plan to destroy the HIPAA identifiers at the 
earliest opportunity consistent with the conduct of the research. 
Check one option below: 
__X___ NA- the identifiers will not be destroyed.  The identifier will be needed to 
be able to continue to add data in the future.   
 
3.  Do you confirm that you will not reuse the identifiable data (HIPAA identifiers 
or health information) or disclose any of this information to any other person or 
entity except as outlined in this protocol, except as required by law, for authorized 
oversight of the research study, or use it for other research unless approved by the 
IRB-HSR?   
 
This means that after the study is closed at UVA: 
 
• You cannot contact the subject by any method (you cannot call them, send 
a letter, talk to them in person about the study, etc) without additional IRB 
approval 
• You cannot use the data for any research that is not already described in 
your IRB protocol without additional IRB approval (if you change your 
hypothesis you must modify your protocol)  
• You cannot share your research data with another researcher outside of 
your study team without additional IRB approval 
• Any health information with HIPAA identifiers will be shredded or 
discarded by using recycling bins for confidential material found in clinic 
settings.  For large item disposal of confidential material contact Environmental 
Services at 2-4976 or University Recycling at 2-5050.  
 
 
YES 
 
 
 
 
 


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TABLE A:  HIPAA Identifiers 
1.  Name 
2.  All geographic subdivisions smaller than a state, including street address, city, county, precinct, zip code, and their 
equivalent geocodes, except for the initial three digits of the zip code if, according to the current publicly available data from the 
Bureau of the Census: (1) The geographic unit formed by combining all zip codes with the same 3 initial digits contains more 
than 20,000 people and (2) The initial 3 digits of a zip code for all such geographic units containing 20,000 is changed to 000.  
3.  All elements of dates (except year) for dates directly related to an individual, including birth date, admission date, discharge 
date, date of death; and all ages over 89 and all elements of dates (including year) indicative of such age, except that such 
ages and elements may be aggregated into a single category of age 90 or older. 
 [This means you may record the year but not record the month or day of any date related to the subject if the subject is under 
the age of 89.  In addition if the subject is over the age of 89 you may not record their age and  you may not record the month, 
day or year of any  date related to the subject ]  
4.  Telephone numbers 
5.  Fax numbers 
6.  Electronic mail addresses 
7.  Social Security number 
8.  Medical Record number 
9.  Health plan beneficiary numbers 
10.  Account numbers 
11.  Certificate/license numbers 
12.  Vehicle identifiers and serial numbers, including license plate numbers 
13.  Device identifiers and serial numbers 
14.  Web Universal Resource Locators (URLs) 
15.  Internet Protocol (IP) address numbers 
16.  Biometric identifiers, including finger and voice prints 
17.  Full face photographic images and any comparable images  
18.  Any other unique identifying number, characteristic, code that is derived from or related to information about the individual 
(e.g. initials, last 4 digits of Social Security #, mother’s maiden name, first 3 letters of last name.) 
 
 
 
 
 


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13 PUBLICATIONS 
Publication of any data from this study must be carried out in accordance with the 
clinical or mechanistic study agreement. 


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14      REFERENCES 
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%9CGuidance+for+Industry%3A++E6+Good+Clinical+Practice%3A++Consolidated+G
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3,   Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H et al. The anti-IgE antibody 
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A, Gupta N. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for 
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7.Corren, J. Ashby, M., Casale, T.B.; Omalizumab, a Recombinant Humanized, anti-IgE 
Antibody, Reduces Asthma Related Emergency Room Visits and Hospitalizations in 
Patients with Allergic Asthma.  J Allergy Clin Immunol 2003: 111:  87-90. 
 
8. Rakes GP, Aruda E, Ingram JM, Hoover GE, Zambrano, JC, Hayden FG, Platts-Mills 
TAE, Heymann PW. Rhinovirus and respiratory syncytial virus in wheezing children 
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9.Green RM, Custovic A, Sanderson G, Hunt J, Johnston SL, Woodcock A. Synergism 
between allergens and viruses and risk of hospital admission with asthma:  case-control 
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Erwin EA, Shaker MS, Hellems M, Peerzada J, Hayden FG, Hatley TK, Chamberlain R:  
Viral infections in relation to age, atopy, and the season of admission among children 
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11. Gwaltney JM, Moskalski PB, Hendley JO. Interruption of experimental rhinovirus 
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12.. Jackson GG, Dowling HF, Spiessman IG, Board AV. Transmission of the common 
cold to volunteers under controlled conditions. Arch Int Med 1958; 101:267-78. 
 
13. Turner RB, Wecker MT, Pohl G, Witek TJ, McNally E, St George R, Winther B, 
Hayden FG. Efficacy of tremacamra, a soluble intercellular adhesion molecule 1 for 
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19;281(19):1797-804. 
 
14. Halperin SA, Eggleston PA, Beasley P, Surrat P, Hendley JO, Groschel DHM, et al. 
Exacerbations of asthma in adults during experimental rhinovirus infection. Am Rev 
Respir Dis 1985; 132:976-80. 
 
15. Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi JD. An evaluation of 
Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med 2005; 
353(4):341-8. 
 
16. Zambrano JC, Carper HT, Rakes GP, Patrie J, Murphy DD, Platts-Mills TAE, Hayden 
FG, Gwaltney Jr    JM, Hatley TK, Owens AM, Heymann PW:  Experimental rhinovirus 
challenges in adults with mild asthma:  The response to infection in relation to IgE. J 
Allergy Clin Immunol 2003; 111:1008-16. 
 
17.  Heymann PW, Platts-Mills TAE, Johnston SL:  Role of viral infections and antiviral 
immunity in the etiology of wheezing exacerbations among children and young adults.   
Pediatr Infect Dis J 2005;24(11):S217-22. 
 
18. Stallings A, McLaughlin A, Murphy D, Carper H, Platts-Mills T, Heymann P. A 
surveillance study of natural rhinovirus colds in young adults with mild asthma. J 
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19. New NAEPP Guidelines for the Diagnosis and Management of Asthma. U.S. Department 
of Health and Human Services, National Heart, Lung, and Blood Institute, NIH 
Publication (www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm). 
 
20. Spector SL. Bronchial inhalation challenges with aerosolized bronchoconstrictive 
substances. In:  Provocative Challenge Procedures:  Bronchial, Oral, Nasal, and Exercise. 
1983; Vol. 1, Chapt. 8; pp 137-76. 
 
21. Genentech, Inc.: Omalizumab (Xolair ®) full prescribing information (US), July, 
2007. 
http://www.gene.com/gene/products/information/immunological/xolair/insert.jsp, 
accessed 8 April 2008. 
 
22. Hunt J. Exhaled breath condensate:  an evolving tool for non-invasive evaluation of 
lung disease. J Allergy Clin Immunol 2002; 110(1):28-34. 
 
23. Teague WG, Kazerouni N, Khetsurian N, Erdman DD, Redd, SC, Anderson LJ, 
Fitzpatrick A, Erzurum SC, Hunt J, Gaston BM. Effects of naturally acquired rhinovirus 
infection on breath pH and nitrogen oxides in children with Asthma. Proceedings of the 
American Thoracic Society 2006; 3(A281). 
 
24.Adelroth E, Rak S, Haahtela T et al. Recombinant humanized mAb-E25, an anti-IgE 
mAb in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2000; 
106:253-9. 
 
25. Casale TB, Condemi J, LaForce C et al. For the Omalizumab Seasonal Allergic 
Rhinitis Trial Group. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a 
randomized controlled trial. JAMA 2001; 286:2956-67. 
 
26. Chervinsky P, Casale T, Townley R, et al. Omalizumab, an anti-IgE antibody, in the 
treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma 
Immunol 2003; 91:160-7. 
 
27. Kuehr J, Brauburger J, Zielen S et al. Efficacy of combination treatment with anti-IgE 
plus specific immunotherapy in polysensitized children and adolescents with seasonal 
allergic rhinitis. J Allergy Clin Immunol 2002; 109:274-80. 
 
28.Corren J, Casale TB, Lanier B, Buhl R, Holgate S, Jimenez P. Safety and tolerability of 
omalizumab. Clin Exp Allergy 2009; 39:788-97. 
 


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29. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Walace DV. American 
Academy of Allergy, Asthma, and Immunolgy/American College of Allergy, Asthma, 
and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J 
Allergy Clin Immunol 2007; 120:1373-7. 
 
30. Schafer, J.L. (1997), Analysis of Incomplete Multivariate Data, New York: Chapman and 
Hall. 
 
31. Turner RB, Biedermann KA, Morgan JM, Keswick B, Ertel KD, Barker MF. Efficacy 
of organic acids in hand cleansers for prevention of rhinovirus 
infections. Antimicrob Agents Chemother. 2004 Jul;48(7):2595-8. 
 
32. Knight V. The use of volunteers in medical virology. In: Melnick JL, ed. 
Progress in Medical Virology. Vol. 6. Basel: Karger, 1964:1-26 
 
33. Gwaltney JM, Jr., Hendley JO, Hayden FG, et al. Updated recommendations for 
safety-testing of viral inocula used in volunteer experiments on rhinovirus colds. 
Progress in Medical Virology 1992;39:256-263. 
 
34.  Message SD, Laza-Stanca V, Mallia P, Parker HL, Zhu J, Kebadze, Contolli M. 
Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus 
load and Th1/2 cytokine and IL-10 production. PNAS 2008; 105: 13562-67.. 
 
35. Rao SS, Hendley JO, Hayden FG and Gwaltney JM, Jr. Symptom expression in 
natural and experimental rhinovirus colds. American Journal of Rhinology 1995;9:49-52 
 
36.Turner RB, Witek TJ, Jr. and Riker DK. Comparison of symptom severity in natural 
and experimentally induced colds. American Journal of Rhinology 1996;10:167-172. 
 
37. Turner RB, Cetnarowski WE. Effect of treatment with zinc gluconate or zinc acetate 
on experimental and natural colds. Clin Infect Dis 2000;31:1202-8. 
 
 
38. Winther B, Gwaltney JM, Jr., Mygind N, Turner RB and Hendley JO. Sites of 
rhinovirus recovery after point inoculation of the upper airway. JAMA 1986;256:1763-7.  
 
 
39. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR, Busse WW. The effect of an 
experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin 
Immunol. 2000 Jun;105(6 Pt 1):1169-77. 


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40. Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ, Meyer J, 
Lackie PM, Sanderson G, Holgate ST, Johnston SL . Rhinovirus infects the lower 
airway.J Infect Dis. 2000 Jun;181(6):1875-84. Epub 2000 Jun 5. 
41.  Iwane MK, Prill MM, Lu X, Miller EK, Edwards KM, Hall CB, Griffin MR, Staat MA, 
Anderson LJ, Williams JV, Weinberg GA, Ali A, Szilagyi PG, Zhu Y, Erdman DD. 
Human rhinovirus species associated with hospitalizations for acute respiratory illness 
in young US children. J Infect Dis 2011;204:1702-1710. 
42.  Linder JE, Kraft DC, Mohamed Y, Lu Z, Heil L, Tollefson S, Saville BR, Wright PF, 
Williams JV, Miller EK. Human rhinovirus C: Age, season, and lower respiratory illness 
over the past 3 decades. J Allergy Clin Immunol 2013;131:69-77. 
43.  Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, Printz 
MC, Lee WM, Shult PA, Reisdorf E, Carlson-Dakes KT, Salazar LP, DaSilva DF, Tisler 
CJ, Gern JE, Lemanske RF Jr. Wheezing rhinovirus illnesses in early life predict asthma 
development in high-risk children. Am J Respir Crit Care Med 2008;178:667-672. 
44. Soto-Quiros M, Avilla L, Platts-Mills TA, Hunt JF, Erdman DD, Carper H, Murphy 
DD, Odio S, James HR, Patrie J, Hunt W, O’Rourke A, Davis MD, Steinke JW, Lu X, 
Kennedy J, Heymann PW. High titers of IgE antibody to dust mite allergen and risk for 
wheezing among asthmatic children infected with rhinovirus. J Allergy Clin Immunol  
2012;129:1499-1505. 
45.  Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, 
Holgate ST, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate 
immune response to infection with rhinovirus. J Exp Med 2005;201(6):937-947. 
46.  Baraldo S, Contoli M, Bazzan E, Turato G, Padovani A, Marku B, Calabrese F, 
Caramori G, Ballarin A, Snijders D, Barbato A, Saetta M, Papi A. Deficient antiviral 
immune responses in childhood: distinct roles of atopy and asthma. J Allergy Clin 
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47. Alam R, Sim TC, Hilsmeier K, Grant JA. Development of a new technique for 
recovery of cytokines from inflammatory sites in situ. J Immun Methods 1992; 155: 25-29. 
 
 
 
 
 
 


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Appendix 4:  Outline for Screening Visits to Determine Eligibility for 
RV Challenges for Subjects Receiving Omalizumab or Placebo Prior to 
and During the Experimental Infection (all under the screening protocol 
IRB-HSR# 12656)   
 
Screening subjects for this study was started under IRB HSR #12656 during the fall of 
2012 and will be on-going until study completion.  Screening to participate will require 
2 visits and those who meet all of the criteria described below will be eligible for 
enrollment as study participants.  The following screening procedures will be done: 
Screening Visit 1: (Done at UVA for those subjects attending UVA or living in the 
Charlottesville area, or at VCU for those attending VCU or living in the 
Richmond area.) 
o Signing the screening consent form 
o Questionnaire (“Rhinovirus Infection and Asthma” screening questionnaire). 
o Blood for total IgE  and RV-16 Serology. 
o Subject’s weight (kg) 
Screening Visit 2: (This visit will be competed in Charlottesville at the Elson 
Student Health Respiratory Research Unit, or the CRU at UVA) 
o Skin testing 
o Methacholine challenge 
o FeNO 
o Blood for HLA typing (needed for developing tetramers for subjects who qualify 
for participation), and CBC and differential cell count to document neutrophil 
counts and hemoglobin values to meet the enrollment criteria.  
Note: The test results for neutralizing antibody to RV-16 and the CBC and differential 
cell count need to be documented within 6 weeks prior to the enrollment and will be 
repeated (in 5 to 10 ml of blood) for subjects who complete their screening more than 6 
weeks before enrollment. 


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Appendix 5. Schedule of Events (*only for those on biweekly dosing of 
omalizumab/ placebo 
 
 
  
  
Visit 1 
  
Visit 2* 
ONLY if 
receiving bi- 
monthly 
injections 
  
Visit 3 
  
  
Visit 4  
  
Visit 5 
  
       Hotel 
    Admission 
  
Rhinovirus 
Inocu- 
lation 
  
  
  
  
Hotel 
Stay 
  
  
Visit  6 
  
Visit 7 
  
Visit 8 
  
Visit 9 
  
  
8 weeks 
before 
hotel stay 
  
6 weeks before 
hotel stay 
  
 4 weeks 
before 
hotel stay 
  
2 weeks 
before 
hotel stay 
  
Within 2 
days before 
Day 0 
  
Day 0 
Cold virus 
Inocu- 
lation 
Post 
Inocu- 
lation 
Days 1 - 4 
Post 
Inocu- 
lation  
Day 7 
Post-
Inocu-
lation  
Day 14 
Post- 
Inocu- 
lation 
Day 21 
Post-
Inocu- 
lation  
Day 28 
Sign consent 
  
X 
  
  
  
  
  
  
  
  
  
  
Randomization 
X 
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy 
Testing  
X 
 X 
X 
X 
 X 
X x 
 Day 4 only 
  
  
X 
  
Urine LTE4 
  
  
  
  
X 
  
Day 4 only 
  
  
  
  
Injection of study drug  
X 
X* 
X  
X* 
X 
  
  
  
X* 
  
  
Nasal Wash 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Nasal lining fluid 
 
 
 
 
 
X 
Day 4 only 
 
X 
 
 
Nasal scraping 
X 
 
 
 
X 
 
Day 2 only 
X 
 
X 
 
Nasal mucous weights 
 
 
 
 
 
X 
X 
 
 
 
 
Spirometry 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Exhaled Nitric Oxide 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood for blood counts 
X 
  
X 
X 
X 
  
X 
X 
X 
X 
  
Blood for immune cells 
X 
  
  
  
X 
  
Day 4 only 
  
  
X 
  
Blood for antibody 
titers 
X 
  
  
  
X 
  
  
  
  
X 
  
Completion of Diary 
Cards ** 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
Daily 
  
ACT questionnaire 
X 
  
X 
  
  
X 
  
  
  
  
X 
Impulse oscillometry 
X 
  
  
  
X 
  
Day 4 only 
X  
  
X 
  
Methacholine Challenge 
X 
  
  
  
X 
  
Day 4 only 
  
  
X 
  


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Rhinovirus -16 
Inoculation*** 
  
  
  
  
  
X 
  
  
  
  
  
Limited Physical Exam  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
  
 
Appendix 5 Legend: 
*  As described in the protocol (Section 7.2), the dose and frequency (monthly, or bi-
monthly) of omalizumab administered will be based on each subject’s weight and total 
IgE level as recommended by the manufacturer. Because the inclusion criteria for this 
study require each subject to have a total IgE level > 125 IU/ml, it is expected that most 
subjects will be receiving the study drug bi-monthly. 
**  Refer to Appendix 1 and Appendix 2 
* * *  Subjects will not be challenged with RV 16 if their FEV1 drops below 70 % 
predicted [in keeping with the exclusion criteria for this study (Section 4.2)], or if their 
FEV1 drops by more than 20% from their baseline value at the time of enrollment. 
 
Note:  
-  AE’s will be evaluated by the MO and SMC  for all enrolled subjects 1) during the 
week prior to RV inoculation and 2) at the end of their participation in the study. All 
SAEs will evaluated by the NIAID MO as soon as the SAE CRF form or MedWatch  
form is received from the PI. 
-All visits, except for the visits on the day of virus inoculation (day 0) and days 1 – 4 
(during the hotel stay), and on day 7 will occur within a 24 hours window prior to or 
following the planned visit scheduled according to the protocol 
- At each study visit a physical examination focused on the respiratory tract will be 
done. This exam will include an examination of the nose, throat, ears, lungs, and 
cervical adenopathy which may manifest changes during the RV cold.   
- Tests to be conducted in nasal washes will include eosinophil cationic protein, 
cysteinyl leukotriene, Th2 and Th1 associated biomarkers (e.g. IFN-γ), innate Immune 
biomarkers (e.g. IL-8, IP-10, IL-1beta, IFN-α2)  
- Blood will be also tested for eosinophil cationic protein along with CBC and 
differential count at each at all visits. Immune cell analyses will include CD4+ and 
CD8+ regulatory and effector T-cell subsets present in the circulation along with 
dendritic cell and basophil analyses. 
- Diary cards, lung function (FEV1) monitors, albuterol inhalers with puff counters, and 
EpiPens (with instructions provided by research nurses) will be provided to each 
participant at enrollment.  
- Injection of study drug is shown for those who will receive their injections every other 
week. Even though subjects will need to have total IgE levels > 125 IU/ml to participate 


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in this study, it is possible that a small number of subjects will have a low enough 
weight to receive their injections monthly. These subjects will receive their injections on 
Visits number 1, 3, 5, and 8.  
- Twenty-eight (28) days after inoculation with RV-16 (i.e., Visit 9), subjects will return 
to clinic to complete the ACT questionnaire (see Appendix 3), report any adverse 
events, and receive their payment for participation. 
 
 


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Appendix 6: Treatment Guidelines for Asthma Symptom 
Exacerbations 
 
 
Treatment guidelines should symptom exacerbations occur during the study: 
 
If a study participant experiences an increase in lower respiratory tract symptoms, or a 
decline in lung function, the following plan describes how subjects will be treated. 
 
• For FEV1 value dropping between 20-29%20% from the baseline value 
not responding to albuterol, start on inhaled corticosteroids (Flovent 110 
mcg./puff, 2 puffs bid) and discontinue when symptoms return to baseline. 
• For FEV1 value dropping between 30- 49% from the baseline value not 
responding to albuterol, check oximetry and start on inhaled corticosteroid 
as above and 3 to 5 days of oral steroids (Prednisone 50 mg/day). 
• For FEV1value dropping 50% or more from the baseline value. 
Transportation to the emergency room will be recommended and 
arranged. Individual stopping rules will apply as described in the Complete 
Clinical Protocol (Section 8.1.2). Further follow-up and management with 
the subject’s primary care doctor; Dr. Heymann and his study team will 
continue to be involved and available for follow-up and evaluation  30 days 
afterward for any subject who requires oral steroids, a visit to the ER, or 
hospital admission. 
 
These treatment plans are in keeping with recommendations from the Guidelines for the 
Diagnosis and Management of Asthma (16). 
 
Note: Baseline FEV1 values apply to the FEV1 measurements established at the 
scheduled visit with 2 days of RV-16 inoculation. Also note that young adults rarely 
become febrile during a natural or experimental infection with rhinovirus. However, if 
subjects develop a temperature greater than or equal to 101 degrees F, Dr. Heymann, 
together with back-up from the allergy fellow on call will be contacted (paged) for 
evaluation. 
 
 
 
 
 
 


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