Food Allergy, Peanut Allergy
Conditions
Keywords
allergy, food, peanut, threshold, immunotherapy
Brief summary
The primary objective of this study is to determine whether allowing ingestion of sub-threshold amounts of peanut in those with a high threshold (tolerate at least 143 mg peanut protein on supervised double-blind, placebo-controlled oral food challenge \[DBPCFC\]) will be associated with attaining even higher thresholds over time in children with high threshold peanut allergy compared to those avoiding peanut. The secondary clinical objectives include assessing the development of sustained unresponsiveness (SU, a surrogate term for tolerance without daily ingestion), effects on quality of life, and safety compared to those avoiding peanut. Additionally, this study will phenotype the allergic response to peanut based on threshold and response to exposure. Mechanistic study objectives will determine the immune and molecular basis of the high threshold endotype, identify predictors of response to exposure, and determine mechanisms and biomarkers of remission.
Interventions
BIOLOGICALPeanut Protein
up to 3 level teaspoons peanut butter or equivalent (approximately 3400 mg)
OTHERContinued peanut avoidance
Standard of care avoidance of peanut
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Scott Sicherer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Although a double-blind, placebo controlled oral food challenge test is used in screening to identify participants eligible to continue to randomization in the study, those randomized to peanut ingestion versus avoidance have participants aware and unmasked regarding the study arm to which they were randomized
Intervention model description
150-200 children undergoing DBPCFC to peanut to identify 72 with high threshold peanut allergy for randomization in trial.
Eligibility
Sex/Gender
ALL
Age
4 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
-Subject and/or parent guardian must be able to understand and provide informed consent. Inclusion criteria for screening DBPCFC: * Age 4-14 years * either sex * any race, any ethnicity * who are enrolled while strictly avoiding peanut * have a history of sensitization (detectable peanut IgE \>0.35 kUA/L) Inclusion criteria for randomization: * On screening DBPCFC are able to ingest \>= 143 mg peanut protein but \< 5043 mg peanut protein. * All children will have documented consent and assent as is appropriate for age.
Exclusion criteria
Individuals who meet any of these criteria are not eligible for enrollment as study participants: * Inability or unwillingness of a participant to give written informed consent or comply with study protocol * Serum peanut-specific IgE antibody level \> 50 kUA/L * Recent (within the past 2 years) life-threatening (grade 3) anaphylactic reaction to peanut. * Any disorder in which epinephrine is contraindicated such as known hypertension or cardia rhythm disorders. * History of chronic disease requiring therapy (other than asthma, atopic dermatitis, rhinitis). * On a build-up phase of any allergen immunotherapy. * For those with a history of asthma, the following are assessed and any of the following is an exclusion (markers of current uncontrolled or moderate to severe asthma): 1. FEV1 value \<80% predicted (only for participants age 7 years or older and are able to perform spirometry) 2. ACT or cACT \< 20 3. \>Step 3 controller therapy as defined for children 0-4, 5-11 and \>=12 years of age by EPR-3 tables 4. Use of steroid medications in the following manners: 1. history of daily oral steroid dosing for \>1 month during the past year, 2. having 1 burst or steroid course within the past 6 months, or 3. having \>1 burst oral steroid course within the past 12 months. 5. Asthma requiring \>1 hospitalization in the past year for asthma or \>1 ED visit in the past 6 months for asthma, or any prior intubation/mechanical ventilation for asthma/wheezing. 6. When COVID related institutional restrictions on spirometry are in effect, spirometry will not be performed and peak flow will be used with 80% predicted as cut-off. * Gastrointestinal eosinophilic disorders, esophagitis, gastroenteritis. * Use of short-acting antihistamines (diphenhydramine, etc.) more than one time within 3 days prior to DBPCFC or skin testing.\* * Use of medium-acting antihistamines (hydroxyzine, loratadine, etc.) more than one time within 7 days of DBPCFC or skin testing.\* * Use of systemic steroid medications (IV, IM or oral) for indications other than asthma for \> 3 weeks within the past 6 months * Use of beta-blockers (oral), (ACE) inhibitors, angiotensin-receptor blockers or calcium channel blockers. * Participation in any trials of therapeutic interventions for food allergy in the past year. * Therapy with anti-IgE or other biologics, including within 1 year of enrollment. * Use of investigational drugs within 52 weeks of participation. * Allergy to all of the following: oat, rice, corn, tapioca. * Pregnancy * Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. \*Any subject meeting these criteria during the visits can be rescheduled for the oral food challenge or prick skin testing.\*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Children That Tolerate the Full Challenge | 72 weeks | The difference between the treatment and comparison (avoidance) groups in the percentage of children who by the endpoint double-blind, placebo-controlled oral food challenge (DBPCFC) tolerate a dose at least 2 steps higher than their baseline DBPCFC or 9043 mg of peanut protein. Due to missing data in the primary endpoint, the protocol & SAP specified a priori that missing data would be imputed using multiple imputation and results based on 30 completed-imputed data sets would be combined using Rubin's rule. In the Peanut Protein group, the observed data was so strong that participants with missing data were also imputed as success across all imputations (hence, 100% success rate). In the Peanut Avoidance group, there was more variability in the proportion of successes across imputations and these varying proportions were averaged. Missing data were imputed and results were pooled. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Children With Acute Allergic Reactions | 96 weeks | Safety parameter assessed by number of participants with acute allergic reactions which includes anaphylaxis or gastrointestinal side effects. |
| Mean Change in Food Allergy Quality of Life Parental Burden Instrument | baseline and at 72 weeks | The Food Allergy Quality of Life-Parental Burden (FAQL-PB) Scale is a 17-item instrument. It utilizes a 7-point Likert scale ranging from 0 (not troubled) to 6 (extremely troubled). The number circled for each question is summed to provide a total continuous score range of 0 to 102 with a higher score indicating greater burden on the family. |
| The Percentage of Children That Achieve Sustained Unresponsiveness | 96 weeks | The percentage of children who achieve sustained unresponsiveness or natural tolerance during the study. |
| Mean Change in Peanut-specific IgE | Baseline and 72 weeks | Mean Change in Peanut-specific IgE level at week 72 as compared to baseline. |
| Mean Change in Peanut-specific IgG4 | Baseline and 72 weeks | Mean Change in Peanut-specific IgG4 level at week 72 as compared to baseline. |
| Mean Change in SPT Wheal Size | Baseline and 72 weeks | Change in Skin Prick Test (SPT) mean wheal size at 72 weeks as compared to baseline. A skin test reaction is considered positive if the wheal size for the antigen is at least 3 mm larger than the wheal size of the negative control (saline). |
Countries
United States
Participant flow
Recruitment details
From August 2019 to April 2022 at one clinical site in the US. A total of 129 participants were assessed for eligibility and 73 fulfilled criteria for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Peanut Protein Ingests peanut - . Depending upon reaction threshold, participants may begin with different starting amounts of store bought peanut butter measured with study-supplied kitchen measuring spoons.
Peanut Protein: up to 3 level teaspoons peanut butter or equivalent (approximately 3400 mg) | 38 |
| Avoidance Avoids peanut, standard care
Continued peanut avoidance: Standard of care avoidance of peanut | 35 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
| Overall Study | withdrew after Day 1 of the primary endpoint desensitization visit. | 1 | 0 |
Baseline characteristics
| Characteristic | Peanut Protein | Avoidance | Total |
|---|---|---|---|
| Age, Continuous | 6.0 years | 7.0 years | 7.0 years |
| Ara h2 IgE level | 3.8 kUA/L | 2.6 kUA/L | 2.9 kUA/L |
| Ara h2 IgG4 level | 0.020 mgA/L | 0.050 mgA/L | 0.030 mgA/L |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 33 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Peanut IgE level | 5.5 kUA/L | 4.6 kUA/L | 5.1 kUA/L |
| Peanut IgG4 level | 0.4 mgA/L | 0.4 mgA/L | 0.4 mgA/L |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 24 Participants | 42 Participants |
| Sex: Female, Male Female | 19 Participants | 9 Participants | 28 Participants |
| Sex: Female, Male Male | 19 Participants | 26 Participants | 45 Participants |
| Skin prick test | 8.0 mm | 9.0 mm | 9.0 mm |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 35 |
| other Total, other adverse events | 25 / 38 | 11 / 35 |
| serious Total, serious adverse events | 0 / 38 | 0 / 35 |
Outcome results
Primary
Percentage of Children That Tolerate the Full Challenge
The difference between the treatment and comparison (avoidance) groups in the percentage of children who by the endpoint double-blind, placebo-controlled oral food challenge (DBPCFC) tolerate a dose at least 2 steps higher than their baseline DBPCFC or 9043 mg of peanut protein. Due to missing data in the primary endpoint, the protocol & SAP specified a priori that missing data would be imputed using multiple imputation and results based on 30 completed-imputed data sets would be combined using Rubin's rule. In the Peanut Protein group, the observed data was so strong that participants with missing data were also imputed as success across all imputations (hence, 100% success rate). In the Peanut Avoidance group, there was more variability in the proportion of successes across imputations and these varying proportions were averaged. Missing data were imputed and results were pooled.
Time frame: 72 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peanut Protein | Percentage of Children That Tolerate the Full Challenge | 100 percentage of participants |
| Avoidance | Percentage of Children That Tolerate the Full Challenge | 21 percentage of participants |
Secondary
Mean Change in Food Allergy Quality of Life Parental Burden Instrument
The Food Allergy Quality of Life-Parental Burden (FAQL-PB) Scale is a 17-item instrument. It utilizes a 7-point Likert scale ranging from 0 (not troubled) to 6 (extremely troubled). The number circled for each question is summed to provide a total continuous score range of 0 to 102 with a higher score indicating greater burden on the family.
Time frame: baseline and at 72 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Peanut Protein | Mean Change in Food Allergy Quality of Life Parental Burden Instrument | -7.78 score on a scale |
| Avoidance | Mean Change in Food Allergy Quality of Life Parental Burden Instrument | -9.23 score on a scale |
Secondary
Mean Change in Peanut-specific IgE
Mean Change in Peanut-specific IgE level at week 72 as compared to baseline.
Time frame: Baseline and 72 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Peanut Protein | Mean Change in Peanut-specific IgE | -0.22 kUA/L |
| Avoidance | Mean Change in Peanut-specific IgE | 0.40 kUA/L |
Secondary
Mean Change in Peanut-specific IgG4
Mean Change in Peanut-specific IgG4 level at week 72 as compared to baseline.
Time frame: Baseline and 72 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Peanut Protein | Mean Change in Peanut-specific IgG4 | 3.11 mgA/L |
| Avoidance | Mean Change in Peanut-specific IgG4 | 0.52 mgA/L |
Secondary
Mean Change in SPT Wheal Size
Change in Skin Prick Test (SPT) mean wheal size at 72 weeks as compared to baseline. A skin test reaction is considered positive if the wheal size for the antigen is at least 3 mm larger than the wheal size of the negative control (saline).
Time frame: Baseline and 72 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Peanut Protein | Mean Change in SPT Wheal Size | -3.05 mm |
| Avoidance | Mean Change in SPT Wheal Size | -0.48 mm |
Secondary
Number of Children With Acute Allergic Reactions
Safety parameter assessed by number of participants with acute allergic reactions which includes anaphylaxis or gastrointestinal side effects.
Time frame: 96 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peanut Protein | Number of Children With Acute Allergic Reactions | 25 Participants |
| Avoidance | Number of Children With Acute Allergic Reactions | 11 Participants |
Secondary
The Percentage of Children That Achieve Sustained Unresponsiveness
The percentage of children who achieve sustained unresponsiveness or natural tolerance during the study.
Time frame: 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peanut Protein | The Percentage of Children That Achieve Sustained Unresponsiveness | 68.4 percentage of participants |
| Avoidance | The Percentage of Children That Achieve Sustained Unresponsiveness | 8.6 percentage of participants |