Sublingual Immunotherapy of Birch Pollen Associated Apple Allergy

Study Overview
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Brief Summary
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More than 70% of birch pollen allergic patients suffer from allergic reactions to certain foods, e.g. stone fruits, hazelnut and some vegetables. However, specific immunotherapy (SIT) with birch pollen extract is not effective for the treatment of associated food allergy in a substantial number of patients. Based on our previous clinical and immunological investigations of birch pollen related food allergy (BPRFA) the investigators hypothesize that for effective SIT of this abundant food allergy the disease-eliciting food allergens should be employed. To prove this concept, the investigators aim to sublingually administer the major apple allergen, Mal d 1, to birch pollen-allergic patients with concomitant apple allergy and evaluate clinical and immunological effects of this treatment. The investigators choose Mal d 1 as model food allergen because (i) its cross-reactivity with Bet v 1 has been well characterized,(ii) apple is the most frequent trigger for BPRFA and (iii) recombinant(r)Mal d 1 was well tolerated after sublingual administration to 20 birch pollen-allergic patients in a previous study. Sublingual administration of a defined concentration of GMP-rMal d 1 will be compared with equal doses of GMP-rBet v 1 as a positive control and placebo-treatment. Clinical parameters will include skin prick tests (SPT) and objective and subjective assessment of apple and birch pollen-induced allergic symptoms. Immunological parameters will comprise the analysis of antibody and T cell responses to Mal d 1 and Bet v 1 as well as the evaluation of basophil activation. The proposed pilot study will be a first investigation of the concept to specifically treat BPRFA with the involved food allergens and thus, represents an important step in the development of an efficient and safe therapy in the future.

Official Title
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Sublingual Immunotherapy of Birch Pollen Associated Apple Allergy

Conditions
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Birch Pollen Related Apple Allergy, Birch Pollen Allergy

Intervention / Treatment
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* Drug: rMal d 1
* Drug: rBet v 1
* Other: placebo drops


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: otherwise healthy persons between 18 und 50 years of age; positive history of rhinoconjunctivitis to birch pollen oral allergy syndrome(OAS) to apple positive skin prick test (SPT) reaction to birch pollen and apple specific IgE for Bet v 1 and Mal d 1 Exclusion Criteria: Exclusion criteria Persons who due to their physical or mental state are not able to provide informed consent. Persons with underlying illnesses such as severe cardiopulmonary, malignant and/or autoimmune diseases Persons suffering from Hyper-IgE syndrome Persons receiving SIT during the past 5 years persons suffering from severe allergic reactions to apple such as generalized urticaria, asthma and/or anaphylaxis persons suffering from severe bronchial asthma to birch pollen persons suffering from pathological alterations of the lips and oral mucosa persons who are prescribed a treatment with immune-suppressive drugs, anti-histamines, leukotriene-antagonists or psychotropic drugs with anti-histaminic effects persons using ß-blockers Pregnant woman

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment with rMal d 1<br>these apple and birch pollen allergic patients are treated with daily sublingual application of 25µg recombinant Major apple allergen, Mal d 1 during 4 months | Drug: rMal d 1<br>* 25 µg daily as sublingually administered drops, 16 weeks<br>|
| Active Comparator: treatment with rBet v 1<br>These apple and birch pollen allergic patients are treated with daily sublingual application of 25µg recombinant Major birch pollen allergen,Bet v 1 during 4 months | Drug: rBet v 1<br>* 25 µg daily administered sublingually as drops over 16 weeks<br>|
| Placebo Comparator: treatment with placebo drops<br>These apple and birch pollen allergic patients are treated daily with placebo applied sublingually during 4 months | Other: placebo drops<br>* 25 µg of placebo Drops daily administered sublingually over 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| allergen concentration to induce allergic reactions in the oral cavity as a measure of efficacy (oral provocation test) | To measure the clinical effects on apple-induced OAS, open food challenges (OFC) with every 30 minutes increasing doses of GMP-rMal d 1 will be performed before and after the treatment period. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T cell proliferation and cytokine production as a measure of tolerance induction | PBMC isolated from heparinised blood before, during and after sublingual administration of the treatment will be stimulated with titrated concentrations of rMal d 1 and rBet v 1, respectively. Proliferative and cytokine responses will be determined. | 1 year | 
| allergen specific antibody response | measurement of IgE, IgG and IgA antibodies specific for Bet v 1 and Mal d 1 | 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mal d 1, Bet v 1, sublingual immunotherapy,