Allergic Rhinitis
Conditions
Keywords
Basophils, Mast Cells, IgE, IgE receptors, omalizumab
Brief summary
This research is being done to study the effects of the drug omalizumab (Xolair) in people with cat allergies. The investigators will use omalizumab to study changes in the cells in the nose, skin and blood that cause allergies. The investigators predict that cells in the blood will be effected before cells in the nose or skin.
Detailed description
Omalizumab is a monoclonal antibody directed against Immunoglobulin E (IgE) and is FDA-approved for use in allergic asthma, though its clinical role is not precisely defined. It binds IgE on the same site of the Fc domain as the high affinity IgE receptor (FcεRI), and therefore, blocks the interaction between IgE and mast cells or basophils. It, therefore, may be used as a mechanistic tool in the study of IgE. As IgE levels are reduced with omalizumab, FcεRI expression on human basophils is reduced. This reduction of basophil receptors and allergen induced activation is pronounced within 7 days of the initial administration and is reversible once omalizumab administration is discontinued. The omalizumab-induced reductions in mast cell FcεRI expression and function is unchanged at day 7 and significantly reduced by day 70. These changes were based upon intravenously administered omalizumab at a dose of 0.03 mg/kg/IU IgE/mL in a total of three subjects. We propose to exploit the kinetics of faster omalizumab effects on circulating basophils relative to tissue mast cells to elucidate the role of the basophil versus mast cell activation in nasal airway allergen challenge, which has not been studied to date.
Interventions
DRUGomalizumab
Dosing is based on IgE level and weight given every 2 or 4 weeks
DRUGplacebo
Dosing is based on IgE level and weight given every 2 or 4 weeks
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Ability to understand and provide informed consent * Male or Female (non-pregnant), age 18-50 * Females must be: Surgically sterile (hysterectomy, bilateral oophorectomy, bilateral tubal ligation), OR postmenopausal (at least 1 year since last menses), OR using a medically acceptable form of birth control throughout the duration of the study. * Clinical history of seasonal or perennial allergic rhinitis for at least two years, with or without mild persistent asthma * Positive puncture skin test greater than or equal to 5 mm diluent control * Positive Immunocap to Fel d 1 \> 0.35 kallikrein unit/L * Positive intranasal cat allergen challenge as defined by \> 5 sneezes or a tripling of measured nasal lavage mediators * In vitro assay of basophil responsiveness to cat allergen with greater than 20% histamine release * The use of antihistamines, cromolyn, leukotriene modifiers and other non-steroid (astelin and topical decongestants), nasal medications will be allowed, but they will be withheld for 5 days prior to each nasal allergen provocation session. Inhaled corticosteroids for mild asthma will be permissible. * No known contraindications to therapy with omalizumab
Exclusion criteria
* Asthma with forced expiratory volume at one second (FEV1) \< 80%, moderate to severe asthma classification per National Asthma Education and Prevention Program Expert Panel (NAEP) Standards (1997 National Asthma Education and Prevention Program Expert Panel Report II guidelines) * Serum IgE levels less than 30 IU/mL or greater than 700 IU/mL at the time of enrollment will be excluded * Unexplained elevation of erythrocyte sedimentation rate (ESR), hematocrit \< 32%, white blood cell (WBC) count 2400/microliter lower limit of normal, platelet \< 75000/microliter, creatinine \> 141.4 micromolar/L, or aspartate aminotransferase (AST) \> 100 IU/L * Body weight less than 30 kg or greater than 150 kg will be excluded. * Plans to become pregnant or breastfeed will be excluded from the study * A perforated nasal septum, structural nasal defect, large nasal polyps causing obstruction, evidence of acute or chronic sinusitis * A life expectancy less than 6 months * A terminal illness as determined by the investigator * A history of malignancy, anaphylaxis or bleeding disorder are also exclusion illnesses. * Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements. * Inability or unwillingness of a participant to give written informed consent or comply with study protocol * Use of any investigational drugs within 8 weeks of participation * Contraindications to omalizumab include patients with a previous hypersensitivity to omalizumab * Recent recipient of any licensed or investigational live attenuated vaccine(s) within two months of study initiation such as flu mist. * Prior use of omalizumab * Frequent sinusitis (\>2/ documented episodes per year) or active sinusitis within 2 weeks of enrollment * Use of immunotherapy within the last 5 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Basophil Surface IgE | Change from baseline to 3.5 months | Flow cytometry in mean fluorescence units. 100%\*\[(3.5 month value minus baseline value)/baseline value\] |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Treatment This arm will receive treatment with omalizumab at the dose FDA-approved for the treatment of allergic asthma.
omalizumab: IgE 30-100 int. units/mL: 30-90 kg: 150 mg every 4 weeks \>90-150 kg: 300 mg every 4 weeks
IgE \>100-200 int. units/mL:
30-90 kg: 300 mg every 4 weeks \>90-150 kg: 225 mg every 2 weeks
IgE \>200-300 int. units/mL:
30-60 kg: 300 mg every 4 weeks \>60-90 kg: 225 mg every 2 weeks \>90-150 kg: 300 mg every 2 weeks
IgE \>300-400 int. units/mL:
30-70 kg: 225 mg every 2 weeks \>70-90 kg: 300 mg every 2 weeks \>90 kg: Do not administer dose
IgE \>400-500 int. units/mL:
30-70 kg: 300 mg every 2 weeks \>70-90 kg: 375 mg every 2 weeks \>90 kg: Do not administer dose
IgE \>500-600 int. units/mL:
30-60 kg: 300 mg every 2 weeks \>60-70 kg: 375 mg every 2 weeks \>70 kg: Do not administer dose
IgE \>600-700 int. units/mL:
30-60 kg: 375 mg every 2 weeks \>60 kg: Do not administer dose | 14 |
| Placebo placebo: IgE 30-100 int. units/mL: 30-90 kg: placebo every 4 weeks \>90-150 kg: placebo every 4 weeks
IgE \>100-200 int. units/mL:
30-90 kg: placebo every 4 weeks \>90-150 kg: placebo every 2 weeks
IgE \>200-300 int. units/mL:
30-60 kg: placebo every 4 weeks \>60-90 kg: placebo every 2 weeks \>90-150 kg: placebo every 2 weeks
IgE \>300-400 int. units/mL:
30-70 kg: placebo every 2 weeks \>70-90 kg: placebo every 2 weeks \>90 kg: Do not administer dose
IgE \>400-500 int. units/mL:
30-70 kg: placebo every 2 weeks \>70-90 kg: placebo every 2 weeks \>90 kg: Do not administer dose
IgE \>500-600 int. units/mL:
30-60 kg: placebo every 2 weeks \>60-70 kg: placebo every 2 weeks \>70 kg: Do not administer dose
IgE \>600-700 int. units/mL:
30-60 kg: placebo every 2 weeks \>60 kg: Do not administer dose | 4 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Active Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 14 Participants | 18 Participants |
| Age, Continuous | 32.3 years | 30.6 years | 31 years |
| Region of Enrollment United States | 4 participants | 14 participants | 18 participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 14 | 0 / 4 |
| serious Total, serious adverse events | 0 / 14 | 0 / 4 |
Outcome results
Primary
Change in Basophil Surface IgE
Flow cytometry in mean fluorescence units. 100%\*\[(3.5 month value minus baseline value)/baseline value\]
Time frame: Change from baseline to 3.5 months
Population: 2 participants on the Omalizumab subcutaneous group moved and were therefore lost to follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab Subcutaneous | Change in Basophil Surface IgE | -95 percentage of basophil surface IgE | Standard Deviation 3 |
| Placebo Subcutaneous | Change in Basophil Surface IgE | -10 percentage of basophil surface IgE | Standard Deviation 4 |