Asthma, Perennial Allergic Rhinitis
Conditions
Keywords
cockroach, immunotherapy, sublingual immunotherapy (SLIT), inner city asthma
Brief summary
This trial is a follow-up study of the ICAC-12 Phase I/II trial (NCT00829985), and is designed to study biomarkers of the immune response to allergen immunotherapy and the safety of this therapy in a pediatric population.
Detailed description
Over the past two decades, scientific evidence has shown that the combination of cockroach allergy and cockroach exposure is one of the most important factors contributing to the dramatic increase in asthma morbidity seen in inner city children with asthma. Therefore, a major goal of the National Institute of Allergy and Infectious Diseases (NIAID) Inner City Asthma Consortium (ICAC) is ultimately to conduct a large multi-center trial of cockroach sublingual immunotherapy (SLIT) in inner-city asthma. As a step toward achieving this goal, ICAC is conducting a clinical trial comparing two doses of glycerinated German cockroach (Blattella germanica) allergenic extract to placebo, administered under the tongue (sublingual).
Interventions
BIOLOGICALCockroach Sublingual Immunotherapy (SLIT) - Low Dose
Participants are randomized to receive daily doses of glycerinated German cockroach (Blattella germanica) allergenic extract formulated in 50% glycerin at a concentration of 1:20 weight per volume \[w/v\] placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The extract was also administered during the preliminary dosing visits, up to three escalating doses, or until the maximum study dose (420 microliters, 1:20 w/v) was achieved.
OTHERPlacebo
Participants are randomized to receive either daily (low dose) or twice-daily (high dose) placebo treatment placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The placebo was also administered during the preliminary dosing visits, up to three or seven escalating doses, or until the maximum study dose (420 or 840 microliters, 1:20 weight per volume \[w/v\]) was achieved.
BIOLOGICALCockroach Sublingual Immunotherapy (SLIT) - High Dose
Participants are randomized to receive twice-daily doses of glycerinated German cockroach (Blattella germanica) allergenic extract formulated in 50% glycerin at a concentration of 1:20 weight per volume \[w/v\] placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The extract was also administered during the preliminary dosing visits, up to seven escalating doses, or until the maximum study dose (840 microliters, 1:20 w/v) was achieved.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Have a history of perennial allergic rhinitis, asthma, or both, before study entry. For those with asthma: 1. a diagnosis of asthma will be defined as a report by the participant that they have had a clinical diagnosis of asthma made by a physician over a year ago 2. the participant's asthma must be well controlled as defined by: ii. a forced expiratory volume at one second (FEV1) greater than or equal to 80% predicted value with or without controller medication ii. albuterol use for no more than 3 days per week in each of the previous 2 weeks for asthma symptoms (not including exercise prophylaxis) * Are sensitive to German cockroach (Blattella germanica) as documented by a positive (\>/=3 mm greater than negative control) skin prick test result and detectable German cockroach specific IgE (\>/=0.35 kUA/L) * Have no known contraindications to therapy with glycerinated German cockroach allergenic extract or placebo * Parent or legally authorized representative (LAR) of child is willing to sign the written Informed Consent prior to initiation of any study procedure
Exclusion criteria
* Are pregnant or lactating. Females must be abstinent or use a medically acceptable birth control method throughout the study (e.g. oral, subcutaneous, mechanical, or surgical contraception) * Cannot perform spirometry or peak flow at screening * Have an asthma severity classification at recruitment of severe persistent, using the National Asthma Education and Prevention Program (NAEPP) classification, as evidenced by at least one of the following: 1. requires a dose of greater than 500 mcg of fluticasone per day or the equivalent of another inhaled corticosteroid 2. have received more than 2 courses of oral or parenteral corticosteroids within the last 12 months 3. have been treated with depot steroids within the last 12 months 4. have been hospitalized for asthma within the 6 months prior to recruitment 5. have had a life-threatening asthma exacerbation that required intubation, mechanical ventilation, or that resulted in a hypoxic seizure within 2 years prior to recruitment * Do not have access to a phone (needed for scheduling appointments) * Have received allergen immunotherapy in the last 12 months prior to recruitment or who plan to initiate or resume allergen immunotherapy during the study * Have previously been treated with anti-IgE therapy within 1 year of recruitment * Have received an investigational drug in the 30 days prior to recruitment or who plan to use an investigational drug during the study * Have in the last 3 months prior to recruitment experienced on average \>/=1 day per week any of the symptoms below: 1. nausea or vomiting 2. abdominal pain or cramps severe enough to interfere with daily activities (excluding those associated with menstruation). 3. diarrhea * Refuse to sign the Epinephrine Auto-injector Training Form Participants who meet any of the following criteria are not eligible for enrollment and may not be reassessed. Participants are ineligible if they: * Do not primarily speak English * Plan to move from the area during the study period * Have a history of idiopathic anaphylaxis or anaphylaxis grade 2 or higher * Have unstable angina, significant arrhythmia, uncontrolled hypertension, history of autoimmune disease, or other chronic or immunological diseases that in the opinion of the investigator might interfere with the evaluation of the investigational agent or pose additional risk to the patient (e.g., gastrointestinal disease, gastroesophageal reflux disease, chronic infections, scleroderma, hepatic, and gallbladder disease) * Are using tricyclic antidepressants or beta-adrenergic blocker drugs (either oral and/or topical route\[s\] of administration)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in German Cockroach-Specific Serum IgE Over Time | Baseline through 3 months of treatment | Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum IgE. This result is an indicator of immune modulation over time, however its clinical significance is unclear. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in German Cockroach-Specific Serum IgG Over Time | Baseline through 3 months of treatment | Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum immunoglobulin G (IgG). This result is an indicator of immune modulation over time, however its clinical significance is unclear. |
| Change in German Cockroach-Specific Serum IgG4 Over Time | Baseline through 3 months of treatment | Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum immunoglobulin subclass 4 (IgG4). This result is an indicator of immune modulation over time, however its clinical significance is unclear. |
| Change in IgE Fragment Antibody Binding (FAB) Activity Over Time | Baseline through 3 months of treatment | Outcome is change in mean IgE FAB activity level from baseline to post-baseline (status post 3 months of treatment). Serum from cockroach sublingual immunotherapy (SLIT)-treated participants were analyzed to determine if treatment inhibits in-vitro cockroach SLIT, using the per protocol allergenic extract doses. This result is an indicator of immune modulation over time, however its clinical significance is unclear.(Reference: Shamji MH et al. The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses. J Immunol Methods 2006;317(1-2): 71-9). |
| Percent of Participants With the Occurrence of Adverse Events (AEs) | Participant enrollment to end of study (up to 3 months post-baseline) | Percent of participants who experienced at least one AE. |
Countries
United States
Participant flow
Recruitment details
Five NIAID ICAC sites in the United States recruited the targeted number of study participants who fulfilled entry criteria between May 2011 and February 2012. Of the ninety-nine subjects enrolled in the study, eighty-nine achieved the milestone of randomization and are included in the Participant Flow: Overall Study Results Section.
Participants by arm
| Arm | Count |
|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose Participants received twice-daily doses of glycerinated German cockroach (Blattella germanica) allergenic extract formulated in 50% glycerin at a concentration of 1:20 weight per volume \[w/v\] placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The extract was also administered during the preliminary dosing visits, up to seven escalating doses, or until the maximum study dose (840 microliters, 1:20 w/v) was achieved. | 30 |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose Participants received daily doses of glycerinated German cockroach (Blattella germanica) allergenic extract formulated in 50% glycerin at a concentration of 1:20 weight per volume \[w/v\] placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The extract was also administered during the preliminary dosing visits, up to three escalating doses, or until the maximum study dose (420 microliters, 1:20 w/v) was achieved. | 31 |
| Placebo Participants received daily (placebo-low dose) or twice-daily (placebo - high dose) doses of placebo placed under the tongue (sublingual route) to dissolve. The treatment course and study duration was 3 months. Note: The placebo was also administered during the preliminary dosing visits, up to three or seven escalating doses, or until the maximum study dose (420 or 840 microliters, 1:20 weight per volume \[w/v\]) was achieved. | 28 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Housing situation precluded ability to k | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 3 | 2 | 3 |
| Overall Study | Questionable onset of epilepsy | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 10.2 years STANDARD_DEVIATION 3.6 | 11.0 years STANDARD_DEVIATION 3.3 | 10.8 years STANDARD_DEVIATION 3.7 | 10.7 years STANDARD_DEVIATION 3.5 |
| German Cockroach Prick Skin Test Wheal Size | 5.0 mm | 5.0 mm | 5.8 mm | 5.3 mm |
| German Cockroach-Specific IgE Fragment Antibody Binding (FAB) Activity | 84.9 Percent antibody binding | 78.3 Percent antibody binding | 80.8 Percent antibody binding | 81.5 Percent antibody binding |
| German Cockroach-Specific Serum Immunoglobulin E (IgE) Levels | 6.7 kU/L | 4.9 kU/L | 9.2 kU/L | 6.4 kU/L |
| German Cockroach-Specific Serum Immunoglobulin G (IgG) Levels | 4.1 mg/mL | 4.3 mg/mL | 5.1 mg/mL | 4.5 mg/mL |
| German Cockroach-Specific Serum Immunoglobulin Subclass 4 (IgG4) Levels | 0.1 mg/mL | 0.1 mg/mL | 0.5 mg/mL | 0.2 mg/mL |
| Region of Enrollment United States | 30 participants | 31 participants | 28 participants | 89 participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 8 Participants | 26 Participants |
| Sex: Female, Male Male | 21 Participants | 22 Participants | 20 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 34 | 25 / 33 | 21 / 32 |
| serious Total, serious adverse events | 0 / 34 | 0 / 33 | 2 / 32 |
Outcome results
Primary
Change in German Cockroach-Specific Serum IgE Over Time
Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum IgE. This result is an indicator of immune modulation over time, however its clinical significance is unclear.
Time frame: Baseline through 3 months of treatment
Population: Intent-to-treat population with complete data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Change in German Cockroach-Specific Serum IgE Over Time | 2.0 Ratio |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Change in German Cockroach-Specific Serum IgE Over Time | 2.7 Ratio |
| Placebo | Change in German Cockroach-Specific Serum IgE Over Time | 1.2 Ratio |
Comparison: Analysis compared cockroach SLIT -high dose, Placebo - high dosep-value: 0.00195% CI: [1.2, 2.3]Mixed Models Analysis
Comparison: Analysis compared cockroach SLIT - low dose, placebo - low dosep-value: <0.000195% CI: [1.7, 3.1]Mixed Models Analysis
Secondary
Change in German Cockroach-Specific Serum IgG4 Over Time
Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum immunoglobulin subclass 4 (IgG4). This result is an indicator of immune modulation over time, however its clinical significance is unclear.
Time frame: Baseline through 3 months of treatment
Population: Intent-to-treat population with complete data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Change in German Cockroach-Specific Serum IgG4 Over Time | 1.6 Ratio |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Change in German Cockroach-Specific Serum IgG4 Over Time | 1.5 Ratio |
| Placebo | Change in German Cockroach-Specific Serum IgG4 Over Time | 1.0 Ratio |
Comparison: Analysis compared cockroach SLIT - high dose, placebo - high dosep-value: 0.0695% CI: [1, 2.4]Mixed Models Analysis
Comparison: Analysis compared cockroach SLIT - low dose, placebo - low dosep-value: 0.1395% CI: [0.9, 2.2]Mixed Models Analysis
Secondary
Change in German Cockroach-Specific Serum IgG Over Time
Outcome is the ratio of geometric means for baseline versus post-baseline German cockroach-specific serum immunoglobulin G (IgG). This result is an indicator of immune modulation over time, however its clinical significance is unclear.
Time frame: Baseline through 3 months of treatment
Population: Intent-to-treat population with complete data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Change in German Cockroach-Specific Serum IgG Over Time | 1.3 Ratio |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Change in German Cockroach-Specific Serum IgG Over Time | 1.1 Ratio |
| Placebo | Change in German Cockroach-Specific Serum IgG Over Time | 1.0 Ratio |
Comparison: Analysis compared cockroach SLIT - high dose, placebo - high dosep-value: <0.000195% CI: [1.1, 1.4]Mixed Models Analysis
Comparison: Analysis compared cockroach SLIT - low dose, placebo - low dosep-value: 0.1195% CI: [1, 1.2]Mixed Models Analysis
Secondary
Change in IgE Fragment Antibody Binding (FAB) Activity Over Time
Outcome is change in mean IgE FAB activity level from baseline to post-baseline (status post 3 months of treatment). Serum from cockroach sublingual immunotherapy (SLIT)-treated participants were analyzed to determine if treatment inhibits in-vitro cockroach SLIT, using the per protocol allergenic extract doses. This result is an indicator of immune modulation over time, however its clinical significance is unclear.(Reference: Shamji MH et al. The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses. J Immunol Methods 2006;317(1-2): 71-9).
Time frame: Baseline through 3 months of treatment
Population: Intent-to-treat population with complete data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Change in IgE Fragment Antibody Binding (FAB) Activity Over Time | -7.2 Percent antibody binding |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Change in IgE Fragment Antibody Binding (FAB) Activity Over Time | 19.2 Percent antibody binding |
| Placebo | Change in IgE Fragment Antibody Binding (FAB) Activity Over Time | 5.7 Percent antibody binding |
Comparison: Analysis compared cockroach SLIT - high dose, placebo - high dosep-value: 0.2195% CI: [-33.2, 7.5]Mixed Models Analysis
Comparison: Analysis compared cockroach SLIT - low dose, placebo - low dosep-value: 0.295% CI: [-7.1, 34.1]Mixed Models Analysis
Secondary
Percent of Participants With the Occurrence of Adverse Events (AEs)
Percent of participants who experienced at least one AE.
Time frame: Participant enrollment to end of study (up to 3 months post-baseline)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cockroach Sublingual Immunotherapy (SLIT) - High Dose | Percent of Participants With the Occurrence of Adverse Events (AEs) | 59 Percentage of population |
| Cockroach Sublingual Immunotherapy (SLIT) - Low Dose | Percent of Participants With the Occurrence of Adverse Events (AEs) | 76 Percentage of population |
| Placebo | Percent of Participants With the Occurrence of Adverse Events (AEs) | 66 Percentage of population |