Allergy, Asthma, Wheezing
Conditions
Keywords
Wheezing, Asthma, Allergy, Immunotherapy
Brief summary
In this clinical study we aim to determine the effect of allergy immunotherapy in decreasing asthma and allergy related disease in children who had multiple episodes of wheezing and who are at high risk for developing persisting asthma. These risks include a history of asthma in the parents, allergies to environmental allergens (such as dust mite, cockroach or mouse) and other allergic diseases such as eczema or food allergies. Allergy Immunotherapy is not new and has been practiced for many years to treat asthma and environmental allergies in older children and adults, but has not yet been systematically studied in young children.
Interventions
BIOLOGICALAllergen extracts (subcutaneous injections)
Allergy immunotherapy consists of regular subcutaneous injections of an individualized mixture of allergen extracts according to the allergy sensitization profile of each child. Increasing doses of allergen extract are given in 1-2 injections until a predetermined maintenance dose is reached. This maintenance dose varies by extract and accords to the general practice guidelines of immunotherapy. To increase safety, the cumulative monthly maintenance doses are divided into biweekly visits during the maintenance phase (year 2-3)
OTHERStandard of care
standard of care asthma and allergy treatment
Sponsors
Jacobi Medical Center
Albert Einstein College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Months to 3 Years
Healthy volunteers
No
Inclusion criteria
* Children between 18 months through 3 years who had at least 2 episodes of wheezing prior to enrolment. * Positive skin tests or specific Immunoglobulin E (IgE) antibody titers to at least one of common airborne allergens: Dust Mite, cat, cockroach, mouse, dog, pollen (all allergy testing can be done at the screening visit at the study site). * The child must also fulfill the criteria for high risk of developing persistent asthma by meeting at least one of the following major conditions OR 2 of the following minor conditions: * Major criteria: History of atopic dermatitis and/or parental history of asthma. * Minor criteria: MD-diagnosed allergic rhinitis, wheezing unrelated to colds, blood eosinophils above 4%.
Exclusion criteria
* The child has a severe systemic condition (other than allergy or asthma) including (but not limited to) seizures, major congenital anomalies, physical and intellectual delay, cerebral palsy, chest surgery, tuberculosis, primary or secondary immunodeficiency or cardiac disorder (except a hemodynamically insignificant atrial or ventricular septum defect or heart murmur). * The child was born following 35 or less weeks of gestation. * Parental report that the child received oxygen for more than 5 days in the neonatal period, or required mechanical ventilation at any time since birth. * The child fails to thrive, defined as crossing of two major growth percentile lines during the last year. * The child has chronic lung disease of prematurity (CLDP), cystic fibrosis or any other chronic lung disease. * The child ever received immunotherapy. * The child ever received i.v. gammaglobulins or immunosuppressants (other than corticosteroids for asthma). * History of a life-threatening asthma exacerbation which required intubation and mechanical ventilation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | baseline and every two weeks up to end of study (up to 36 months) | The Asthma Severity Score is a customized score created for this study due to the lack of standardized instruments for this age group. It takes into account asthma symptom severity and frequency, as well as asthma medication dosing and potency. Data was collected at baseline and every 2 weeks through interviews conducted over the phone. If the caregiver could not be reached by the phone, the interview was conducted at the next face-to face opportunity (study or injection visit). The minimum score on this scale is 0 (no asthma symptoms and no asthma medicines used during the 14 day interview period). The maximum score is 224 (uncontrolled severe asthma with severe cough, shortness of breath and wheezing on 14 of 14 days, using Albuterol 2 puffs 4x/day, budesonide/formoterol 160ug/4.5ug 2 puffs twice daily and Montelukast 4mg daily on 14 of 14 days). Scores calculated from the collected data were averaged to produce one reported value at baseline and year 1, 2 and 3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Newly Gained Allergic Sensitizations as Assessed by Serum Specific Immunoglobulin E (IgE) Testing | Baseline and end of treatment (36 months) | Young children with allergies tend to develop additional environmental allergies over time. This study investigated if allergy immunotherapy could be used to prevent the development of new allergic sensitizations. Participants were tested for sensitivity to a panel of 8 common environmental allergens. Testing was conducted via serum specific immunoglobulin E (IgE) testing. A test was considered negative (non-allergic) if the specific IgE level was \<0.35 kIU/L (Kilo International Units/Liter) and positive (allergic) if the levels was \>0.35 kIU/L. A test pair is the result of a serum IgE test, for a specific allergen, done at two different times. Test pairs can be negative-negative, negative-positive (newly gained allergic sensitization), positive-negative (lost sensitization) or positive-positive. Reported values indicate the total number of newly gained allergic sensitization (negative-positive) for the group. |
| Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | Baseline and every 12 months until end of treatment (36 months) | T regulatory cells are thought to play a role in mediating the effects of immunotherapy in increasing allergen tolerance and dampen the clinical expression of allergy. However, existing studies have not found clear relationship between numbers of T regulatory cells in blood and effect of immunotherapy. The aim of this analysis was to observe potential changes in T regulatory cell numbers in response to immunotherapy in this age group. Peripheral blood cells were acquired and analyzed for T regulatory (Treg) cell markers. In molecular biology, CD4+ (cluster of differentiation 4), a particular cell marker, is a glycoprotein found on the surface of immune cells such as T helper cells and certain groups of T regulatory cells. Testing was done at baseline and then every 12 months. Reported values represents the percentage of CD4+ that are Treg cells. |
| Incidence Rate of Systemic Corticosteroid Bursts (CSB) Per Child | From baseline through end of study (maximum 36 months) | Any reported use of consequent systemic corticosteroid use due to asthma exacerbation counted as one corticosteroid burst (CSB). For example, if a child used 5 days of prednisolone due to asthma exacerbation, this counted as one corticosteroid burst (CSB). An interval of at least 7 days was determined to be necessary to count 2 courses of systemic corticosteroids as separated bursts. The presented data reflect the intention-to-treat analysis. The time between baseline and each participant's study end time was counted towards the years in study. The incidence rate describes the number of CSB per child per year in study. |
Countries
United States
Participant flow
Recruitment details
58 children were recruited from one tertiary treatment center, Jacobi Medical Center, which is the largest city hospital in the Bronx, New York. The referral population consists of primarily low-income, Medicaid beneficiaries residing in the Bronx.
Pre-assignment details
There was no run-in phase. After consents were signed (by the parents), the 58 participants were immediately randomized into treatment or control group. 8 of the 58 participants were withdrawn from the study immediately after randomization, so only 50 participants began protocol treatment.
Participants by arm
| Arm | Count |
|---|---|
| No Immunotherapy, Receive Standard of Care Asthma Treatment This group only receives standard of care asthma and allergy treatment. This does not receive allergy immunotherapy.
Both the experimental group and the control group receive otherwise standard of care asthma and allergy treatment. | 23 |
| Allergen Immunotherapy This group receives initially weekly, later biweekly subcutaneous injections of a mixture of allergen extracts, tailored to the individual child's allergy sensitization profile. The maximum number of injections at each visit is 1-3 injections per child. In addition to allergy immunotherapy. this group receives standard of care asthma and allergy treatment
Allergen extracts (subcutaneous injections): Allergy immunotherapy consists of regular subcutaneous injections of an individualized mixture of allergen extracts according to the allergy sensitization profile of each child. Increasing doses of allergen extract are given in 1-3 injections until a predetermined maintenance dose is reached. For safety, the cumulative monthly maintenance doses are divided into biweekly visits during the maintenance phase.
Both the experimental group and the control group receive otherwise standard of care asthma and allergy treatment. | 27 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 3 | 6 |
| Overall Study | Withdrawal by Subject | 7 | 12 |
Baseline characteristics
| Characteristic | No Immunotherapy, Receive Standard of Care Asthma Treatment | Allergen Immunotherapy | Total |
|---|---|---|---|
| Age, Continuous | 3.1 years STANDARD_DEVIATION 0.8 | 3.0 years STANDARD_DEVIATION 0.8 | 3.1 years STANDARD_DEVIATION 0.8 |
| Number of children with asthma related Emergency Department visits prior to enrollment | 21 Participants | 25 Participants | 46 Participants |
| Race/Ethnicity, Customized Ethnicity Black/African American | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic/Latino | 15 Participants | 20 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown/not reported | 3 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 18 Participants | 24 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 27 |
| other Total, other adverse events | 0 / 23 | 22 / 27 |
| serious Total, serious adverse events | 7 / 23 | 6 / 27 |
Outcome results
Primary
Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months)
The Asthma Severity Score is a customized score created for this study due to the lack of standardized instruments for this age group. It takes into account asthma symptom severity and frequency, as well as asthma medication dosing and potency. Data was collected at baseline and every 2 weeks through interviews conducted over the phone. If the caregiver could not be reached by the phone, the interview was conducted at the next face-to face opportunity (study or injection visit). The minimum score on this scale is 0 (no asthma symptoms and no asthma medicines used during the 14 day interview period). The maximum score is 224 (uncontrolled severe asthma with severe cough, shortness of breath and wheezing on 14 of 14 days, using Albuterol 2 puffs 4x/day, budesonide/formoterol 160ug/4.5ug 2 puffs twice daily and Montelukast 4mg daily on 14 of 14 days). Scores calculated from the collected data were averaged to produce one reported value at baseline and year 1, 2 and 3.
Time frame: baseline and every two weeks up to end of study (up to 36 months)
Population: All participants were included in this analysis that started immunotherapy, regardless if they completed it or not (intention to treat analysis)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at baseline | 21.95 score on a scale | Standard Error 3.74 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 1 | 27.72 score on a scale | Standard Error 3.52 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 2 | 31.40 score on a scale | Standard Error 4.16 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 3 | 33.00 score on a scale | Standard Error 5.23 |
| Allergen Immunotherapy | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 3 | 31.15 score on a scale | Standard Error 5.11 |
| Allergen Immunotherapy | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at baseline | 25.68 score on a scale | Standard Error 3.53 |
| Allergen Immunotherapy | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 2 | 29.68 score on a scale | Standard Error 4.03 |
| Allergen Immunotherapy | Asthma Severity as Measured by the Asthma Severity Score (Averaged up to 36 Months) | Score at Year 1 | 27.85 score on a scale | Standard Error 3.34 |
Comparison: Linear mixed effects model (LME) with random coefficients model was fitted with Restricted Maximum Likelihood estimation. The functional form of the model was quadratic and the model adjusted for gender, race, ethnicity and number of asthma hospitalizations since birth. Unequal data collection were smoothed over two month period with a median score values.p-value: 0.3895% CI: [-0.24, 0.63]Mixed Models Analysis
Comparison: Linear mixed effects model (LME) with random coefficients model was fitted with Restricted Maximum Likelihood estimation. The functional form of the model was quadratic and the model adjusted for gender, race, ethnicity and number of asthma hospitalizations since birth. Unequal data collection were smoothed over two month period with median score values.p-value: 0.01395% CI: [0.11, 0.99]Mixed Models Analysis
Comparison: Linear mixed effects model (LME) with random coefficients model was fitted with Restricted Maximum Likelihood estimation. The functional form of the model was quadratic and the model adjusted for gender, race, ethnicity and number of asthma hospitalizations since birth. Unequal data collection between immunotherapy and control groups were smoothed over two month period with a median score values.p-value: 0.97895% CI: [-11.76, 12.03]contrast testing post mixed model
Comparison: Linear mixed effects model (LME) with random coefficients model was fitted with Restricted Maximum Likelihood estimation. The functional form of the model was quadratic and the model adjusted for gender, race, ethnicity and number of asthma hospitalizations since birth. Unequal data collection between immunotherapy and control groups were smoothed over two month period with a median score values.p-value: 0.7795% CI: [-15.83, 12.38]contrast testing post mixed model]
Comparison: Linear mixed effects model (LME) with random coefficients model was fitted with Restricted Maximum Likelihood estimation. The functional form of the model was quadratic and the model adjusted for gender, race, ethnicity and number of asthma hospitalizations since birth. Unequal data collection between immunotherapy and control groups were smoothed over two month period with a median score values.p-value: 0.895% CI: [-19.54, 15.84]contrast testing post mixed model
Secondary
Incidence Rate of Systemic Corticosteroid Bursts (CSB) Per Child
Any reported use of consequent systemic corticosteroid use due to asthma exacerbation counted as one corticosteroid burst (CSB). For example, if a child used 5 days of prednisolone due to asthma exacerbation, this counted as one corticosteroid burst (CSB). An interval of at least 7 days was determined to be necessary to count 2 courses of systemic corticosteroids as separated bursts. The presented data reflect the intention-to-treat analysis. The time between baseline and each participant's study end time was counted towards the years in study. The incidence rate describes the number of CSB per child per year in study.
Time frame: From baseline through end of study (maximum 36 months)
Population: Participants with available data (intention to treat population)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Incidence Rate of Systemic Corticosteroid Bursts (CSB) Per Child | 1.28 Number of CSB per child per year |
| Allergen Immunotherapy | Incidence Rate of Systemic Corticosteroid Bursts (CSB) Per Child | 1.55 Number of CSB per child per year |
Comparison: Null hypothesis = Incidence rate of CSB in each group are same. Poisson regression adjusting for gender, race and history of hospitalization was used to analyze the corticosteroid burst.p-value: 0.28995% CI: [0.82, 1.96]Poisson regression
Secondary
Number of Newly Gained Allergic Sensitizations as Assessed by Serum Specific Immunoglobulin E (IgE) Testing
Young children with allergies tend to develop additional environmental allergies over time. This study investigated if allergy immunotherapy could be used to prevent the development of new allergic sensitizations. Participants were tested for sensitivity to a panel of 8 common environmental allergens. Testing was conducted via serum specific immunoglobulin E (IgE) testing. A test was considered negative (non-allergic) if the specific IgE level was \<0.35 kIU/L (Kilo International Units/Liter) and positive (allergic) if the levels was \>0.35 kIU/L. A test pair is the result of a serum IgE test, for a specific allergen, done at two different times. Test pairs can be negative-negative, negative-positive (newly gained allergic sensitization), positive-negative (lost sensitization) or positive-positive. Reported values indicate the total number of newly gained allergic sensitization (negative-positive) for the group.
Time frame: Baseline and end of treatment (36 months)
Population: In the intention to treat analysis, only 30 children (15 in each group) had serum tests available at baseline and after 36 months of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Number of Newly Gained Allergic Sensitizations as Assessed by Serum Specific Immunoglobulin E (IgE) Testing | 12 Newly gained allergic sensitizations |
| Allergen Immunotherapy | Number of Newly Gained Allergic Sensitizations as Assessed by Serum Specific Immunoglobulin E (IgE) Testing | 16 Newly gained allergic sensitizations |
p-value: 0.677Chi-squared
Secondary
Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells
T regulatory cells are thought to play a role in mediating the effects of immunotherapy in increasing allergen tolerance and dampen the clinical expression of allergy. However, existing studies have not found clear relationship between numbers of T regulatory cells in blood and effect of immunotherapy. The aim of this analysis was to observe potential changes in T regulatory cell numbers in response to immunotherapy in this age group. Peripheral blood cells were acquired and analyzed for T regulatory (Treg) cell markers. In molecular biology, CD4+ (cluster of differentiation 4), a particular cell marker, is a glycoprotein found on the surface of immune cells such as T helper cells and certain groups of T regulatory cells. Testing was done at baseline and then every 12 months. Reported values represents the percentage of CD4+ that are Treg cells.
Time frame: Baseline and every 12 months until end of treatment (36 months)
Population: Only 27 participants had yearly data for Treg cells from baseline through 36 months (+/- 6 months). Data for 23 participants were not included in the analysis because either parents declined to have blood drawn or because results were not returned from the outside laboratory (despite many efforts to retrieve these data).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | Baseline average Treg % | 4.87 % of CD4+ cells are Treg cells | Standard Error 0.65 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 1st Year Treg percentage | 5.09 % of CD4+ cells are Treg cells | Standard Error 0.66 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 2nd Year Treg percentage | 5.26 % of CD4+ cells are Treg cells | Standard Error 0.72 |
| No Immunotherapy, Receive Standard of Care Asthma Treatment | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 3rd Year Treg percentage | 5.499 % of CD4+ cells are Treg cells | Standard Error 0.92 |
| Allergen Immunotherapy | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 3rd Year Treg percentage | 7.08 % of CD4+ cells are Treg cells | Standard Error 0.77 |
| Allergen Immunotherapy | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | Baseline average Treg % | 5.90 % of CD4+ cells are Treg cells | Standard Error 0.62 |
| Allergen Immunotherapy | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 2nd Year Treg percentage | 5.76 % of CD4+ cells are Treg cells | Standard Error 0.74 |
| Allergen Immunotherapy | Peripheral Blood T Regulatory Cells as a Percentage of CD4+ (Cluster of Differentiation 4) Cells | 1st Year Treg percentage | 5.30 % of CD4+ cells are Treg cells | Standard Error 0.73 |
Comparison: Covariance Pattern Model with autoregressive covariance structure with REML (Restricted Estimation of Maximum Likelihood) with time and role as categorical variable was modeled.p-value: 0.54695% CI: [-2.18, 3.29]covariance pattern (rep. measure) model