Tree Nut Allergy
Conditions
Keywords
Walnut allergy, Tree nut allergy, Oral immunotherapy, Food allergy, Desensitization, Sustained unresponsiveness
Brief summary
The purpose of this study is to determine if walnut oral immunotherapy can be used in participants allergic to tree nuts to reduce tree nut allergy and induce changes in the participant's immune system.
Detailed description
Randomized, placebo controlled, Phase 1-2 study conducted at Arkansas Children's Hospital Research Institute (ACHRI) in tree nut allergic participants, ages 6-45 years with randomization following a 2:1 (active:placebo) format. The overall objectives were to evaluate the efficacy of walnut oral immunotherapy (WOIT) for induction of desensitization to walnut (secondary outcome) and a test tree nut (primary outcome) when compared to placebo after 38 weeks of treatment as assessed by double-blind, placebo-controlled food challenges (DBPCFC) to walnut and a test tree nut in tree nut allergic participants (defined by allergic reaction to \</= 2 grams of walnut and test tree nut proteins during DBPCFC at study entry). Placebo participants were crossed-over to active therapy after unblinding at week 38. Participants were followed long-term (up to 6 years) on open-label WOIT treatment and assessed at yearly intervals based on pre-specified criteria for clinical outcomes of desensitization to walnut and a test tree nut (defined as safely consuming 5 grams of walnut and test tree nut protein during DBPCFC while on daily WOIT) and sustained unresponsiveness to walnut and a test tree nut (defined as safely consuming 5 grams of walnut and test tree nut protein during DBPCFC and 10 grams during an open feeding while off therapy for 4-6 weeks). Secondary outcomes were evaluated including safety and immune mechanistic parameters.
Interventions
DRUGWalnut Protein Powder
Blinded study product dosing begins with a 1-day oral desensitization protocol to walnut for subjects in the active arm. Starting at 0.1 mg protein and increasing to a maximum of 6 mg or until allergic symptoms develop. Subjects continue daily dosing of blinded OIT (walnut) with build-up every 2 weeks to a maximum daily dose of 1500mg at week 34, followed by 4 weeks of daily maintenance dosing. OFC to walnut and second tree nut occurs at week 38 then treatment is unblinded and open-label maintenance dosing occurs.
DRUGOat Powder (placebo)
Blinded study product dosing begins with a one-day oral desensitization protocol with placebo (oat) powder. Subjects in the placebo group will undergo the same protocol as those in the active group with placebo OIT dosing. Unblinding to treatment assignment will occur after the 38 week oral food challenge. Placebo subjects will cross-over to active, open-label treatment with walnut powder after the 38 week oral food challenge. beginning with initial escalation day, through build-up and maintenance dosing per the same protocol sequence as noted for active, walnut powder. Subjects will complete an oral food challenge to walnut and the second tree nut at week 38 then will continue on long-term, open-label maintenance dosing until the end of study using same protocol design.
DRUGOpen-label Walnut Protein Powder
Open-label treatment phase begins after the 38 week oral food challenge with unblinding of treatment assignment. For those on active treatment, daily maintenance dosing occurs for up to a total of 298 weeks. For those on placebo treatment, cross-over to active, open-label treatment occurs using the same active treatment protocol. Placebo-crossover subjects will complete an oral food challenge to walnut and the second tree nut at week 38 of active therapy then continue on long-term, open-label maintenance dosing until the end of study using same protocol design. All subjects may reach a qualifying IgE to walnut/second tree nut early and will undergo an OFCs on and 4 weeks off OIT. All subjects will have OFCs on and 4 weeks off OIT at week 142 and at week 298, unless both walnut/second tree nut OFCs are passed at previous OFC prompting addition of these foods into the diet.
Sponsors
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Subjects will be randomized in a 2:1 ratio to either active treatment (final dose 1500mg walnut protein (WP), n=20) or placebo (n=10). Subjects will do a 1-day desensitization to enable subjects to tolerate 6 mg of WP or placebo (initial day escalation). After the initial escalation day obtaining at least 1.5mg and up to 6mg of WP or placebo, dosing build-up will be every 2 wks thru dose 24 (34 wks). A maintenance dose will be given for 4 wks, then a 5g protein OFC to walnut & a 5g protein OFC to a 2nd tree nut (\ 38 wks), then the study will be unblinded. Placebo subjects that fail the OFC will cross-over to active treatment and escalate to 1500mg target dose. Subjects will be followed for 298 wks (\ 6 yrs) total on active treatment including an OFC (both on & off therapy) to walnut and 2nd tree nut at 142 wk & end of study. Subjects with reduced serum specific IgE to \<5kU/L to walnut and 2nd tree nut at yearly visits before the end of study at 298 wks are eligible for a tolerance OFC.
Eligibility
Sex/Gender
ALL
Age
6 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Age 6 to 45 years, either sex, any race, any ethnicity with a convincing clinical history of walnut or another tree nut allergy and either a positive prick skin test (≥ 3mm) or serologic evidence of allergic sensitization (defined as specific IgE \> 0.35 kU/L) to walnut and at least one other tree nut. * A positive 2000 mg oral food challenge at enrollment to walnut and to one other tree nut. * Written informed consent from participant and/or parent/guardian * Written assent from all subjects as appropriate * All females of child bearing age must be using appropriate birth control
Exclusion criteria
* History of severe anaphylaxis to walnut or other tree nuts, defined as symptoms associated with hypoxia, hypotension or neurologic compromise (cyanosis or SpO2 \< 92% at any stage, hypotension, confusion, collapse, loss of consciousness; or incontinence). * Known allergy to oat * Chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy or other respiratory or medical conditions deemed by the investigator to put the subject at increased risk of anaphylaxis or poor outcomes from receiving OIT or undergoing food challenge. * Poor control or persistent activation of atopic dermatitis * Active eosinophilic or other inflammatory (e.g., celiac) gastrointestinal disease in the past 2 years. * Participation in any interventional study for food allergy in the past 6 months * Participant is on build-up phase of immunotherapy (i.e., has not reached maintenance dosing). * Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2) or poorly controlled mild or moderate asthma * Inability to discontinue antihistamines for initial day escalation, skin testing or OFC * Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy within the past year * Use of beta-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB) or calcium channel blockers * Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness of Walnut OIT on Clinical Desensitization to Test Tree Nut as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 at Oral Food Challenge | 38 weeks of therapy | Determine in tree nut allergic subjects the effectiveness of walnut oral immunotherapy on clinical desensitization to a second tree nut (test tree nut) causing allergy when compared to placebo treatment, as measured by the change in cumulative dose from baseline oral food challenge (OFC) to the OFC to the test tree nut at approximately 38 weeks on therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Walnut Protein at Desensitization OFC at Week 38 | 38 weeks | The percentage of subjects reaching a cumulative protein dose of 2000mg at the desensitization oral food challenge to walnut at week 38 |
| Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Test Tree Nut Protein at Desensitization OFC at Week 38 | 38 weeks | Comparison of the number and percentage of subjects in each treatment arm reaching a cumulative protein dose of 2000mg at the week 38 (desensitization) oral food challenge to test tree nut |
| Evaluation of Desensitization to Walnut Protein as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 Oral Food Challenge | 38 weeks | Determine in tree nut allergic subjects the effectiveness of walnut oral immunotherapy on clinical desensitization to walnut causing allergy when compared to placebo treatment, as measured by the change in cumulative dose from baseline oral food challenge (OFC) to the OFC to the walnut at approximately 38 weeks on therapy. |
| Change in Skin Prick Test Wheal Size From Baseline to Week 142 in Active and Placebo Cross-over Subjects Receiving Active Walnut OIT | 142 weeks | Evaluation of walnut OIT on the mast cell responses as measured through change in skin prick testing to walnut in participants who were treated with walnut OIT to week 142. Analysis group combines both active and placebo-crossover participants from baseline through open-label treatment phase until the end of study. |
| Serious Adverse Events Related to Walnut OIT Treatment | 298 weeks active treatment | Incidence of treatment-related serious adverse events during the study |
| Number (Percentage) of Subjects Attaining Sustained Unresponsiveness to Walnut and Test Tree Nut Proteins at Week 298 Oral Food Challenge | up to 298 weeks on active treatment | The percentage of subjects demonstrating sustained unresponsiveness to walnut and to the test tree nut by end of study. Analysis group combines both active and placebo-crossover participants during open-label extension arm through the end of study at week 298. Subjects were able to exit the study at assessment timepoints earlier than week 298 if they are able to pass the sustained unresponsiveness oral food challenge, thus the analysis included all subjects through week 298.. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from allergy clinics, research databases and advertisement. Study recruitment occurred from April 2012 through September 2014.
Pre-assignment details
Following consent and enrollment, screening included allergen skin testing, allergen-IgE testing, immune studies and DBPCFCs to placebo, walnut and at least one tree nut. Those meeting inclusion criteria were randomized 2:1 to blinded OIT (walnut vs. placebo) through week 38 when DBPCFCs were conducted. Unblinding of treatment assignment occurred at week 38; placebo subjects crossed over to active (walnut) OIT. OIT after week 38 was given daily as open-label treatment.
Participants by arm
| Arm | Count |
|---|---|
| Walnut Protein Powder 146 weeks for active treatment subjects
Walnut Protein Powder: Dosing begins with a one-day walnut oral desensitization protocol. Starting at 0.1 mg protein and increasing every thirty minutes until a maximum dose of 6 mg is reached or until allergic symptoms develop. After the initial escalation day, subjects will continue daily dosing with dosing build-every two weeks to a maximum dose of 1500mg walnut protein at 34 weeks. A daily maintenance dose (1500mg or the highest dose reached by 34 weeks) will be given for 4 weeks followed by 5 gram oral food challenges to walnut and the second tree nut (at 38 weeks). Active treatment subjects will continue on maintenance dosing for up to a total of 298 weeks of therapy. Subjects reaching a qualifying specific IgE to walnut and the test tree nut at any early time point will receive a tolerance oral food challenge to the tree nuts on and 4 weeks off therapy. All subjects will have an oral food challenge on and off therapy at 142 weeks and at 298 weeks. | 10 |
| Oat Powder 184 weeks for placebo
Oat Powder (placebo): Subjects in the placebo group will undergo the same one-day desensitization protocol as the active treatment group, consuming a maximum dose of 6 mg of oat powder (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of oat powder, the dosing build-up will occur every two weeks through dose 24 (1500mg oat flour) at \
34 weeks. A maintenance dose will be given for 4 weeks followed by a 5 gram protein OFC to walnut and a 5 gram protein OFC to a second tree nut (at \
38 weeks). Placebo subjects that fail the OFC will be crossed over to active treatment beginning with initial escalation day. | 4 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | anxiety | 1 | 1 |
| Overall Study | diagnosis of ulcerative colitis | 1 | 0 |
Baseline characteristics
| Characteristic | Walnut Protein Powder | Total | Oat Powder |
|---|---|---|---|
| Age, Continuous | 8.7 years | 9 years | 9.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 13 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 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 | 10 Participants | 12 Participants | 2 Participants |
| Region of Enrollment United States | 10 participants | 14 participants | 4 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 4 Participants |
| subjects with allergic rhinitis | 6 participants | 9 participants | 3 participants |
| subjects with asthma | 3 participants | 6 participants | 3 participants |
| subjects with atopic dermatitis | 6 participants | 10 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 | 0 / 13 |
| other Total, other adverse events | 9 / 10 | 1 / 4 | 11 / 13 |
| serious Total, serious adverse events | 0 / 10 | 0 / 4 | 0 / 13 |
Outcome results
Primary
Effectiveness of Walnut OIT on Clinical Desensitization to Test Tree Nut as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 at Oral Food Challenge
Determine in tree nut allergic subjects the effectiveness of walnut oral immunotherapy on clinical desensitization to a second tree nut (test tree nut) causing allergy when compared to placebo treatment, as measured by the change in cumulative dose from baseline oral food challenge (OFC) to the OFC to the test tree nut at approximately 38 weeks on therapy.
Time frame: 38 weeks of therapy
Population: Participants completing the 38 week food challenge assessment were included in the analysis of primary outcome which was change in the cumulative tolerated dose during food challenge from baseline to week 38.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Walnut Protein Powder | Effectiveness of Walnut OIT on Clinical Desensitization to Test Tree Nut as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 at Oral Food Challenge | 2.6 grams |
| Oat Powder | Effectiveness of Walnut OIT on Clinical Desensitization to Test Tree Nut as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 at Oral Food Challenge | 0.05 grams |
p-value: 0.001Wilcoxon (Mann-Whitney)
Secondary
Change in Skin Prick Test Wheal Size From Baseline to Week 142 in Active and Placebo Cross-over Subjects Receiving Active Walnut OIT
Evaluation of walnut OIT on the mast cell responses as measured through change in skin prick testing to walnut in participants who were treated with walnut OIT to week 142. Analysis group combines both active and placebo-crossover participants from baseline through open-label treatment phase until the end of study.
Time frame: 142 weeks
Population: Population analyzed combines active and placebo-crossover participants in the open-label phase of active walnut OIT. Change in skin test wheal size was measured from baseline to week 142 on active therapy. Baseline was defined for each arm as start of active treatment (active day=day 1; placebo arm (placebo cross-over)=week 38 (at start of active treatment period).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Walnut Protein Powder | Change in Skin Prick Test Wheal Size From Baseline to Week 142 in Active and Placebo Cross-over Subjects Receiving Active Walnut OIT | 3.4 mm wheal size |
p-value: <0.001Fisher Exact
Secondary
Evaluation of Desensitization to Walnut Protein as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 Oral Food Challenge
Determine in tree nut allergic subjects the effectiveness of walnut oral immunotherapy on clinical desensitization to walnut causing allergy when compared to placebo treatment, as measured by the change in cumulative dose from baseline oral food challenge (OFC) to the OFC to the walnut at approximately 38 weeks on therapy.
Time frame: 38 weeks
Population: Participants completing the 38 week food challenge assessment were included in the analysis of primary outcome which was change in the cumulative tolerated dose during food challenge from baseline to week 38.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Walnut Protein Powder | Evaluation of Desensitization to Walnut Protein as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 Oral Food Challenge | 4.4 grams |
| Oat Powder | Evaluation of Desensitization to Walnut Protein as Measured by Change in Cumulative Tolerated Dose From Baseline to Week 38 Oral Food Challenge | 0.6 grams |
p-value: 0.01Fisher Exact
Secondary
Number (Percentage) of Subjects Attaining Sustained Unresponsiveness to Walnut and Test Tree Nut Proteins at Week 298 Oral Food Challenge
The percentage of subjects demonstrating sustained unresponsiveness to walnut and to the test tree nut by end of study. Analysis group combines both active and placebo-crossover participants during open-label extension arm through the end of study at week 298. Subjects were able to exit the study at assessment timepoints earlier than week 298 if they are able to pass the sustained unresponsiveness oral food challenge, thus the analysis included all subjects through week 298..
Time frame: up to 298 weeks on active treatment
Population: Those reaching sustained unresponsiveness to walnut and the test tree nut during open-label treatment by the end of study at week 298.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Walnut Protein Powder | Number (Percentage) of Subjects Attaining Sustained Unresponsiveness to Walnut and Test Tree Nut Proteins at Week 298 Oral Food Challenge | 5 Participants |
Secondary
Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Test Tree Nut Protein at Desensitization OFC at Week 38
Comparison of the number and percentage of subjects in each treatment arm reaching a cumulative protein dose of 2000mg at the week 38 (desensitization) oral food challenge to test tree nut
Time frame: 38 weeks
Population: Participants completing the week 38 food challenge assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Walnut Protein Powder | Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Test Tree Nut Protein at Desensitization OFC at Week 38 | 6 Participants |
| Oat Powder | Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Test Tree Nut Protein at Desensitization OFC at Week 38 | 0 Participants |
p-value: <0.01Fisher Exact
Secondary
Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Walnut Protein at Desensitization OFC at Week 38
The percentage of subjects reaching a cumulative protein dose of 2000mg at the desensitization oral food challenge to walnut at week 38
Time frame: 38 weeks
Population: Participants completing the 38 week food challenge assessment were included in the analysis of primary outcome which was change in the cumulative tolerated dose during food challenge from baseline to week 38.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Walnut Protein Powder | Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Walnut Protein at Desensitization OFC at Week 38 | 6 Participants |
| Oat Powder | Number (Percentage) of Subjects Reaching a Cumulative Tolerated Dose of 2000mg Walnut Protein at Desensitization OFC at Week 38 | 0 Participants |
p-value: <0.01Fisher Exact
Secondary
Serious Adverse Events Related to Walnut OIT Treatment
Incidence of treatment-related serious adverse events during the study
Time frame: 298 weeks active treatment
Population: All participants from study enrollment through blinded treatment phase at week 38, to open-label treatment through until exit of study, up to week 298.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Walnut Protein Powder | Serious Adverse Events Related to Walnut OIT Treatment | 0 Participants |
| Oat Powder | Serious Adverse Events Related to Walnut OIT Treatment | 0 Participants |
| Open-label Walnut Protein Powder | Serious Adverse Events Related to Walnut OIT Treatment | 0 Participants |