Sublingual Immunotherapy of Birch Pollen Associated Apple Allergy

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.

Study Overview

• Status: Completed
• Conditions: Birch Pollen Allergy; Birch Pollen Related Apple Allergy
• Intervention / Treatment: Drug: rMal d 1; Drug: rBet v 1; Other: placebo drops

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment with rMal d 1; 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; 25 µg daily as sublingually administered drops, 16 weeks
Active Comparator: treatment with rBet v 1; 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; 25 µg daily administered sublingually as drops over 16 weeks
Placebo Comparator: treatment with placebo drops; These apple and birch pollen allergic patients are treated daily with placebo applied sublingually during 4 months	Other: placebo drops; 25 µg of placebo Drops daily administered sublingually over 16 weeks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Austrian Science Fund (FWF)
• Investigators: Principal Investigator: Barbara Bohle, PhD, Prof., Medical University of Vienna; Principal Investigator: Tamar Kinaciyan, MD, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2012
• Primary Completion (Actual): February 28, 2014
• Study Completion (Actual): December 20, 2016

Study Registration Dates

• First Submitted: October 5, 2011
• First Submitted That Met QC Criteria: October 7, 2011
• First Posted (Estimate): October 10, 2011

Study Record Updates

• Last Update Posted (Actual): April 13, 2017
• Last Update Submitted That Met QC Criteria: April 12, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Mal d 1, Bet v 1, sublingual immunotherapy,
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Nose Diseases; Rhinitis, Allergic; Rhinitis; Hypersensitivity; Rhinitis, Allergic, Seasonal
• Other Study ID Numbers: TK01/2011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No