Immunologic Desensitization
Conditions
Keywords
Allergic rhinitis, Immunotherapy, Allergen, Sublingual Immunotherapy
Brief summary
The purpose of this study is to determine if sublingual allergen immunotherapy tablets work by inducing a state of desensitization in mast cells and basophils.
Detailed description
To induce clinical tolerance, a failure to respond to an allergen to which one was previously responsive, is an important objective for physicians, one that plays a significant role in the primary prevention of allergic reactions in the clinical practice of Allergy & Immunology. The tolerance resulting after standard subcutaneous immunotherapy to aeroallergen and insect venom allergens is long lasting and allergen-specific, and may involve antigen-specific T regulatory cells. In contrast, tolerance resulting from drug desensitization protocols is short-lived, and postulated to target mast cells and basophils. Research into the cellular and biochemical processes by which desensitization occurs has revealed that mast cells desensitized to one antigen in vitro, under certain conditions, lose the ability to degranulate to unrelated antigens or to direct FcεRI cross-linking. Preliminary data suggests that this cross-desensitization can happen in patients undergoing incremental desensitization, depending in part on the percentage of IgE targeted to the allergen used for desensitization. This proposal therefore aims to explore desensitization and cross-desensitization in human volunteers undergoing standard sublingual (SL) immunotherapy to grass or ragweed pollen. Subjects will undergo SL immunotherapy with either Timothy or Short Ragweed tablets, taking one tablet per day, or will take a placebo tablet. Titration skin testing to Timothy or Short Ragweed, to one or preferably two additional allergens to which the subject is sensitive, and to codeine as a control for mast cell activation capability through a non-IgE-dependent pathway will be performed to determine the PC3 value (see below). Skin testing, including histamine and diluent controls, will be performed prior to and at one and four weeks after initiation of immunotherapy. At each time point, blood will be obtained to measure total and antigen-specific IgE levels, tryptase and cytokine levels, and basophil activation with the relevant allergens and C5a as a non-IgE-mediated control for basophil activation.
Interventions
DRUGallergen extract tablet
1 allergen extract tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet
DRUGPlacebo tablet
1 placebo tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet
Sponsors
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Verified allergic sensitivity to either Timothy Grass or Short Ragweed pollen (primary allergen) * Verified allergic sensitivity to at least one allergen in addition to the primary allergen
Exclusion criteria
* Negative skin testing to Timothy Grass or Short Ragweed pollen and at least one other environmental allergen * Dermatographism * Severe dermatologic condition that may interfere with skin testing * Pregnancy * H1 receptor antihistamine taken within 7 days of testing * Systemic steroids * Omalizumab taken at any time in the past * Receiving or received allergen immunotherapy * Desensitized to any drug within 6 months * Current uncontrolled or severe asthma * Eosinophilic esophagitis * Significant pulmonary, cardiovascular, renal, hepatobiliary, or neurological diseases, or another disease process felt to put a subject at increased risk for adverse events * Hypersensitivity to any of the inactive ingredients in the allergen extract tablets * History of mental illness or drug or alcohol abuse that could interfere with the ability to comply with study requirements * Inability or unwillingness to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in PC3 | Assessed at 2 weeks and at the end of the study (2 months) | Change in the dose of allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3) |
| Change in Basophil Activation | Assessed at 2 weeks and at the end of the study (2 months) | Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cross-desensitization - PC3 | Assessed at 2 weeks and at the end of the study (2 months) | Change in the dose of an unrelated allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3) |
| Cross-desensitization - Basophil Activation | Assessed at 2 weeks and at the end of the study (2 months) | Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Allergen-specific IgE | Assessed at enrollment, at 2 weeks, and at the end of the study (2 months) | The percent of total serum IgE that is specific for the primary allergen will be compared to the degree (if any) of cross-desensitization seen by skin prick or basophil activation testing |
Countries
United States
Participant flow
Pre-assignment details
After enrollment, allergen skin prick testing was performed to confirm sensitization to the required allergens. Of the 58 subjects enrolled, 37 were determined to lack sensitization to timothy grass pollen or ragweed pollen, plus at least one other environmental allergen. These subjects were excluded from the study prior to randomization. One subjected qualified, but was lost to follow up prior to randomizing.
Participants by arm
| Arm | Count |
|---|---|
| Sublingual Allergen Tablets Subjects will be administered a sublingual allergen tablet customized to their individual allergic sensitization.
allergen extract tablet: 1 allergen extract tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet | 10 |
| Placebo Subjects will be administered placebo sublingual tablets
Placebo tablet: 1 placebo tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Sublingual Allergen Tablets |
|---|---|---|---|
| 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 | 10 Participants | 20 Participants | 10 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 1 / 10 | 0 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
Primary
Change in Basophil Activation
Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls
Time frame: Assessed at 2 weeks and at the end of the study (2 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sublingual Allergen Tablets | Change in Basophil Activation | -4.1100 Change in log dilution of allergen |
| Placebo | Change in Basophil Activation | 0.1300 Change in log dilution of allergen |
Primary
Change in PC3
Change in the dose of allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3)
Time frame: Assessed at 2 weeks and at the end of the study (2 months)
Population: One subject from placebo arm not analyzed due to missing data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sublingual Allergen Tablets | Change in PC3 | -0.2750 Change in log dilution of allergen |
| Placebo | Change in PC3 | -0.0250 Change in log dilution of allergen |
Secondary
Cross-desensitization - Basophil Activation
Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls
Time frame: Assessed at 2 weeks and at the end of the study (2 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sublingual Allergen Tablets | Cross-desensitization - Basophil Activation | -0.2000 Change in log dilution of allergen |
| Placebo | Cross-desensitization - Basophil Activation | -0.1500 Change in log dilution of allergen |
Secondary
Cross-desensitization - PC3
Change in the dose of an unrelated allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3)
Time frame: Assessed at 2 weeks and at the end of the study (2 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sublingual Allergen Tablets | Cross-desensitization - PC3 | -0.0350 Change in log dilution of allergen |
| Placebo | Cross-desensitization - PC3 | 0.8000 Change in log dilution of allergen |
Other Pre-specified
Percent Allergen-specific IgE
The percent of total serum IgE that is specific for the primary allergen will be compared to the degree (if any) of cross-desensitization seen by skin prick or basophil activation testing
Time frame: Assessed at enrollment, at 2 weeks, and at the end of the study (2 months)