Allergy Immunotherapy for the Reduction of Asthma | NCT01028560

Allergy Immunotherapy for the Reduction of Asthma | NCT01028560 | Trialant

Sponsor/Collaborators Module

Name	Class
Jacobi Medical Center	OTHER

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
No immunotherapy, receive standard of care asthma treatment	Active Comparator	This group consists of children who do not receive allergy immunotherapy. Both groups - the experimental as well as the control group receive otherwise standard of care asthma and allergy treatment	Other: Standard of care
Allergen immunotherapy	Experimental	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	Biological: Allergen extracts (subcutaneous injections) Other: Standard of care

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Allergen extracts (subcutaneous injections)	Biological	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)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	baseline and every two weeks up to end of study (up to 36 months)

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Gabriele de Vos, M.D., M.Sc.	Einstein, Jacobi Medical Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Jacobi Medical Center		The Bronx	New York	10461	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
14583928	Background	Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003;(4):CD001186. doi: 10.1002/14651858.CD001186.
16461125	Background	Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma. J Allergy Clin Immunol. 2006 Feb;117(2):263-8. doi: 10.1016/j.jaci.2005.09.054.

Arm/Group Information

ID	Title	Description
FG000	No Immunotherapy, Receive Standard of Care Asthma Treatment	This group consists of children who do not receive allergy immunotherapy. No placebo injections were used. The control group received standard of care asthma and allergy treatment, excluding allergy immunotherapy (subcutaneous or other routes). Standard of care: standard of care asthma and allergy treatment (medications, advice to environmental remediation)
FG001	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 (medications, advice to environmental remediation) 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. 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. Standard of care: standard of care asthma and allergy treat

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00027 subjects4 of 27 withdrew consent immediately after randomization and are excluded from outcome analysis FG00131 subjects4 of 31 withdrew consent immediately after randomization and are excluded from outcome analysis
Started Study Protocol	Only participants who started the study protocol were included in the analysis (total n=50)	FG00023 subjects FG00127 subjects
COMPLETED		FG00017 subjects FG00113 subjects
NOT COMPLETED		FG00010 subjects FG00118 subjects

Type	Comment	Reasons
Lack of Efficacy		FG0003 subjects FG0016 subjects
Withdrawal by Subject		FG0007 subjects FG001

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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.
BG001

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
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.	All participants were included in this analysis that started immunotherapy, regardless if they completed it or not (intention to treat analysis)	Posted		Least Squares Mean	Standard Error	score on a scale		baseline and every two weeks up to end of study (up to 36 months)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	No Immunotherapy, Receive Standard of Care Asthma Treatment	This group consists of children who do not receive allergy immunotherapy. Both groups - the experimental as well as the control group receive otherwise standard of care asthma and allergy treatment Standard of care: standard of care asthma and allergy treatment

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Asthma related hospitalization	Respiratory, thoracic and mediastinal disorders		Non-systematic Assessment	asthma exacerbation requiring hospitalization

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Local allergic reaction after immunotherapy injectionss	Skin and subcutaneous tissue disorders		Non-systematic Assessment	22 of 27 (81%): erythema or induration or edema of ≤ 2.5 cm in diameter) 2 of 27 (7%): erythema or induration or edema of > 2.5 cm in diameter but < 50% surface area of upper arm 9 of 27 (33%): mild delayed local reaction

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Gabriele de Vos, M.D.	Jacobi Medical Center / Albert Einstein College of Medicine	7184152809		gabriele.de-vos@einstein.yu.edu

Condition Browse Module

ID	Term
D012135	Respiratory Sounds
D001249	Asthma
D006967	Hypersensitivity

ID	Term
D012818	Signs and Symptoms, Respiratory
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D001982	Bronchial Diseases

Intervention Browse Module

ID	Term
D007279	Injections, Subcutaneous
D059039	Standard of Care

ID	Term
D007267	Injections
D004333	Drug Administration Routes
D004358	Drug Therapy
D013812	Therapeutics

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Ethnicity

Title	Measurements
Hispanic/Latino	BG00015 BG00120 BG00235
Black/African American	BG0005 BG0017 BG00212
Unknown/not reported	BG0003 BG0010 BG0023

ID	Title	Description
OG000	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.
OG001	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.

Title

Denominators

Categories

Score at baseline

Title	Measurements
	OG00021.95± 3.74 OG00125.68± 3.53

Score at Year 1

Title	Measurements
	OG00027.72± 3.52 OG00127.85± 3.34

Score at Year 2

Title	Measurements
	OG00031.40± 4.16 OG00129.68± 4.03

Score at Year 3

Title	Measurements
	OG00033.00± 5.23 OG00131.15± 5.11

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Non-Inferiority Type
OG001	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.	Mixed Models Analysis		0.38		Slope	0.19	Standard Error of the Mean	0.22	2-Sided	95	-0.24	0.63	The above is the slope for immunotherapy group . The (quadratic) slope is for 1 month increase in time.	Other
OG000	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.	Mixed Models Analysis	The above (quadratic) slope is for control group	0.013		Slope	0.55	Standard Error of the Mean	0.22	2-Sided	95	0.11	0.99	The above is the (quadratic) slope is for control group and is for 1 month increase in time.	Other
OG000 OG001	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.	contrast testing post mixed model		0.978	Post estimation means were tested between the intervention arms after LME model at year 1 and the p- values were adjusted using Bonferroni correction.	Mean Difference (Final Values)	0.13	Standard Error of the Mean	4.97	2-Sided	95	-11.76	12.03	The difference is IT-Control group and the confidence interval is Bonferroni CI	Other
OG000 OG001	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.	contrast testing post mixed model]		0.77	Post estimation means were tested between the intervention arms after LME model at year 2 and the p- value was unadjusted p value	Mean Difference (Final Values)	-1.72	Standard Error of the Mean	5.89	2-Sided	95	-15.83	12.38	The difference is IT-Control group and the confidence interval is Bonferroni CI	Other
OG000 OG001	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.	contrast testing post mixed model		0.80	Post estimation means were tested between the intervention arms after LME model at year 3 and the p- values were adjusted using Bonferroni correction.	Mean Difference (Final Values)	-1.85	Standard Error of the Mean	7.39	2-Sided	95	-19.54	15.84	The difference is IT-Control group and the confidence interval is Bonferroni CI	Other

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.

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.

Posted

Number

Newly gained allergic sensitizations

Baseline and end of treatment (36 months)

test pairs (baseline and at 36+/-6months

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG00015 OG00115
test pairs (baseline and at 36+/-6months	OG000103 OG001

Title

Denominators

Categories

Title	Measurements
	OG00012 OG00116

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Chi-squared		0.677	Chi-square test (proportion of new sensitizations versus unchanged or lost sensitizations in each group, intention-to treat analysis).													Superiority

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.

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).

Posted

Least Squares Mean

Standard Error

% of CD4+ cells are Treg cells

Baseline and every 12 months until end of treatment (36 months)

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG00013 OG00114

Title

Denominators

Categories

Baseline average Treg %

- ParticipantsOG00013
- ParticipantsOG00114

Title	Measurements
	OG0004.87± 0.65

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Covariance Pattern Model with autoregressive covariance structure with REML (Restricted Estimation of Maximum Likelihood) with time and role as categorical variable was modeled.	covariance pattern (rep. measure) model	Within group difference p-values ( baseline vs 3-years) in control and intervention arm were 0.56 and 0.20 respectively.	0.5460	Test of parallelism (group x time) hypothesis P-value.	Slope	0.56			2-Sided	95	-2.18	3.29			The estimated slope reported is for year 3 from the covariance pattern model with autoregressive covariance structure.

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".

Participants with available data (intention to treat population)

Posted

Mean

95% Confidence Interval

Number of CSB per child per year

From baseline through end of study (maximum 36 months)

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG00023 OG00127

Title

Denominators

Categories

Title	Measurements
	OG0001.28(1.03 to 1.60) OG0011.55(1.26 to 1.90)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Poisson regression	Poisson regression model with robust variance with contributed person years used as offset was modeled.	0.289	Poisson regression model for treatment arm adjusting for gender, race and history of hospitalization was used to analyze the corticosteroid burst and the time period contributed by each child in years were fitted as offset.	Rate ratio	1.27			2-Sided	95	0.82	1.96