Walnut Oral Immunotherapy for Tree Nut Allergy (WOIT)

• Percentage of subjects who can tolerate a 5000mg oral food challenge to walnut protein following the desensitization phase of the study [ Time Frame: 38 weeks ] [ Designated as safety issue: Yes ]
• The percentage of subjects reaching a cumulative protein dose of 2000mg at the desensitization oral food challenge to walnut and the test tree nut [ Time Frame: 38 weeks ] [ Designated as safety issue: Yes ]
• The percentage of subjects demonstrating clinical tolerance at the end of study to walnut and to the test tree nut [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
• The change in immune parameters over time [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  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
• Incidence of all serious adverse events during the study [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]

The purpose of this study is to determine if walnut oral immunotherapy can be used in subjects allergic to tree nuts to reduce tree nut allergy and induce changes in the subject's immune system.

• Drug: 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 achieving at least 1.5 mg and up to 6 mg of walnut protein, 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 a 5 gram protein oral food challenge to walnut and a 5 gram protein oral food challenge to the second tree nut (at 38 weeks), after which the study will be unblinded. Active treatment subjects will continue on the 1500mg walnut protein daily dose for a maximum of 33 months.
• Drug: 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 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.

• Active Comparator: Walnut Protein Powder
  Intervention: Drug: Walnut Protein Powder
• Placebo Comparator: Oat Powder
  Intervention: Drug: Oat Powder (placebo)

• Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zhong X, Burks AW. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009 Aug;124(2):292-300, 300.e1-97. Epub 2009 Jul 3.
• Hofmann AM, Scurlock AM, Jones SM, Palmer KP, Lokhnygina Y, Steele PH, Kamilaris J, Burks AW. Safety of a peanut oral immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol. 2009 Aug;124(2):286-91, 291.e1-6. Epub 2009 May 27.
• Kulis M, Li Y, Lane H, Pons L, Burks W. Single-tree nut immunotherapy attenuates allergic reactions in mice with hypersensitivity to multiple tree nuts. J Allergy Clin Immunol. 2011 Jan;127(1):81-8. Epub 2010 Nov 18.
• Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011 Mar;127(3):654-60.

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