Participants with allergy to tree nuts who follow the introduction procedure A (at home)

Participants with allergy to tree nuts who follow the introduction procedure B (at the hospital)

Participants with allergy to tree nuts who follow strict avoidance of the offending nuts.

Tree Nut Allergy

Procedure A

Procedure B

Control group

Department of Allergy and Clinical Immunology, 2nd University Pediatric Clinic of "Panagiotis & Aglaia Kyriakou" Children's Hospital, Athens, Greece

Re-Introducing Nuts in Allergic Patients

Comparison of Protocols for Re-introducing Tree Nuts in Patients With Allergy to Tree Nuts

Comparison of the frequency and severity of allergic reactions, and the frequency of adrenaline use in two remedies.

Comparison of the proportion of participants who follow the procedure.

The proportion of participants in each group who achieve to consume 300mg of tree nut protein at Final Assessment (cumulative dose of 433mg ), if baseline provocation dose was ≤100mg, or 1000mg (cumulative dose 1433mg), if baseline provocation dose was ≥300mg.

The change in the maximum tolerated dose of the tree nut between baseline and final assessment.

Alterations in SPTs, sIgEs and BAT outcomes between baseline and final assesment.

The effect of two procedures in quality of life of patients as measured by FAQLQ-FAIM at baseline, 6 months and final assessment.The Food Allergy Quality of Life Questionnaires (FAQLQ) are disease-specific health-related quality of life (HRQL) questionnaires for patients with food allergy.The number of items of each FAQLQ ranges from 23 to 30 items, depending on age. Each question is answered on a 7-point scale (0 "no impairment" to 6 "maximal impairment" ).

The effect of each procedure or avoidance in the levels of serum IgG and IgG4.

The effect of each procedure or avoidance in immune response at the level of epigenetics and transcriptomics.

The effect of each procedure or avoidance in the population,the composition and the variety of the gut microbiome.

Maria Pasioti

Principal Investigator

National and Kapodistrian University of Athens

Hellenic Society of Allergology and Clinical Immunology

Oral Immunotherapy for Food Allergy

The institute of Allergy, Immunology and Pediatric Pulmonary Medicine, Assaf Harofeh Medical Center

Predictors of Positive Food Challenge

Nut Cross-Reactivity - ACuiring Knowledge for Elimination Recommendations (NUT-CRACKER) Study

Determining the best diagnostic method that would predict a positive vs. negative oral food challenge in food sensitized patients

To determine how many patients have decreased reactivity following successful desensitization to the same food in OIT

To determine how many patients have decreased component reactivity following successful desensitization to a different food in OIT

Assaf-Harofeh Medical Center

Walnut protein flour that is ingested in gradually increasing amounts up to a maintenance dose.

Oat flour administered in identical increasing amounts as the active walnut protein flour.

Nut Hypersensitivities

Daily ingestion of gradually increasing amounts of walnut protein flour in order to induce desensitization to walnut and an unrelated tree nut.

Walnut Protein Flour

Oat flour that is administered as a placebo in identical increasing doses as the active walnut flour treatment.

Oat flour

Walnut Oral Immunotherapy for Tree Nut Allergy

The determination of the effectiveness of WOIT in inducing clinical desensitization to a second tree nut to which the subject is allergic when compared to placebo. This will be measured by the change in the amount of tree nut the subject can consume during their food challenge at 38 weeks compared to their consumption during the baseline challenge at study entry.

The percentage of subjects who can consume all of the 5000mg of walnut protein without symptoms during the food challenge after the desensitization phase of the study.

The percentage of subjects who are able to consume a cumulative protein dose of 2000 mg of walnut and test tree nut without symptoms during the desensitization oral food challenge.

The percentage of subjects who are able to demonstrate clinical tolerance by consuming all of the walnut and test tree nut without symptoms during the oral food challenge at the end of the study.

The increase in the walnut and test tree nut specific IgG4 over the course of the study as an indication of the impact of WOIT on the immune system.

The decrease in the walnut and test tree nut specific IgE over the course of the study as an indication of the impact of WOIT on the immune system.

Wesley Burks, MD

Professor

University of North Carolina, Chapel Hill

Subjects will be randomized in a 2:1 ratio into either an active treatment group (final dose 1500 mg walnut protein, n=20) or a placebo group (n=10). Subjects will undergo a one-day desensitization protocol designed to enable the subject to tolerate 6 mg of walnut protein or placebo (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of walnut protein or placebo, dosing build-up will occur every two weeks through dose 24 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), after which the study will be unblinded.

Subjects will be randomized in a 2:1 ratio into either an active treatment group (final dose 1500 mg walnut protein, n=20) or a placebo group (n=10). Subjects will undergo a one-day desensitization protocol designed to enable the subject to tolerate 6 mg of walnut protein or placebo (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of walnut protein or placebo, dosing build-up will occur every two weeks through dose 24 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), after which the study will be unblinded. Placebo subjects that fail the OFC will be crossed over to active treatment and escalated as described to the 1500 mg target dose.

Peanut Allergy

walnut powder

Children's Hospital of Philadelphia

Walnut Oral Immunotherapy for Tree Nut Allergy-CHOP

The primary clinical efficacy outcome of the study will be the change from baseline OFC in cumulative dose reached at the desensitization OFC to the test tree nut.

1.The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks)

2.The percentage of subjects that demonstrate clinical tolerance at end of study to walnut and to the test tree nut.

3.The change in immune parameters over time including humoral responses, basophil/effector cell responses, and cytokine responses to tree nuts in cultured cells over time.

4.Incidence of all serious adverse events during the study

Jonathan Spergel

MD, PhD

University of Arkansas

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), after which the study will be unblinded. 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.

Walnut Protein Powder

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 double blind, placebo controlled OFC to walnut and a 5 gram protein OFC to a second tree nut (at ~38 weeks), after which the study will be unblinded. Placebo subjects that fail the OFC will be crossed over to active treatment beginning with initial escalation day.

Oat Powder (placebo)

Arkansas Children's Hospital

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.

Delineate the impact of walnut OIT on the subsequent cellular and humoral response to walnut protein by the following: 1) analysis of walnut and second tree nut specific IgE, IgG and IgG4 response, 2) characterization of allergen specific basophil activation, 3) characterization of mast cell responses through skin prick testing, and 4) analysis of specific T cell cytokine responses and regulatory T cell activation

nut hypersensitivity/juglans regia

Re-Introducing Nuts in Allergic Patients

Predictors of Positive Food Challenge

Walnut Oral Immunotherapy for Tree Nut Allergy

Walnut Oral Immunotherapy for Tree Nut Allergy

Walnut Oral Immunotherapy for Tree Nut Allergy

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