European Research Area:

Transcription

1 2nd WS on Food Allergy in ERA-European European Research Area: Clinical studies for allergen dose response Barbara Ballmer-Weber Associate Professor Allergy Unit Department of Dermatology University Hospital Zürich

2 Very small quantities of food allergens can provoke reactions in susceptible individuals! How small? How many? Relation of individual sensitivity and severity of reaction? Reproducibility of individual sensitivity?

3 Avoid food or any products containing the food to which a consumer is allergic Labelling rules generally cover only deliberately added ingredients (exception:: CH) may contain delegates risk to consumer decreases food choice

4 Definitions: Threshold A limit below which a stimulus causes no reaction Oxford English Dictionary A dose at or below which a response is not seen in an experimental setting Kroes et al. Food Chem Toxicol 2000

5 Definitions: : NOEAL, LOAEL, Threshold Dosis LOAEL: lowest observed adverse effect level Threshold dose NOAEL: no observed adverse effect level

6 Clinical studies for allergen dose response? gaps? optimal study design to define threshold doses? inherent problems? current status? gaps

7 Design?

8 Factors affecting the determination of threshold doses for allergenic food: how much is too much? Taylor et al. J Allergy Clin Immunol 2002; 109: s: diagnostic tool starting doses: : mg 500mg food first dose reactors (no NOAEL) different protocols no consensus on threshold doses uncertainties regarding establishment of threshold doses EU-Project: Adverse Reaction to Food

9 starting dose no first dose reactors below published thresholds 0/29 reactors: : NOAEL 30min final dose cumulative:: normal serving confirm food allergy if negative open provocation

10 Endpoint what is an allergic symptom?

11 DBPCFC for allergen dose response: endpoint? skin oral gastrointestinal eye/nose lung caridiovascular subjective itch itch nausea pain itch thightness chest pain dizziness vertigo objective flush urticaria angioedema swelling blisters vomiting diarrhea conjunctivitis rhinitis lung function drop of blood pressure

12 0.2mg 0.4mg 1.0mg 5.0mg 25mg 100mg 400mg OAS emesis, urticaria, dyspnea sloael: : 0.4mg or 0.6mg oloael: : 25mg or 31.6mg discrete versus cumulative dose?

13 Patients? Anaphylaxis? Correlation threshold-severity severity of symptoms?

14 Wensing et al., JACI 2002

15 Risk of oral food challenges Perry et al. J Allergy Clin Immunol 2004; 114: Reaction severity and median percentage of challenge food ingested milk n = 90 egg n = 56 peanut n = 71 soy n = 21 wheat n = 15 mild moderate severe total n = 253 More severe reaction significantly related to lower dose reaction (p=0.05) particular for milk!

16 Matrix? Capsules? Liquids? Chocolates?

17 Clinical studies for allergen dose response capsules: young patients? dissolve in the GIT bypass oral mucosa

18 Presentation of allergen in different food preparations affects The nature of the allergic reaction a case series Grimshaw et al. Clin Exp Allergy Immunol 2003; 33: cumulative dose (mg protein) % fat 22.9% fat 12-31x more peanut to elicit symptoms first symptoms more severe no OAS subjects allergens in high fat food matrix are more slowly released/absorbed absorbed too high thresholds

19 EU-FAREDAT: DBPCFC with peanut/soy chocolate bars mg 50g soy 2mg 25g peanut Centrally produced provocation material (DK) Triangle test Homogeneity of allergenic material distrubution in the active meal was controlled by histamine release

20 EuroPrevall: : DBPCFC Centrally produced provocation material (Industry, IFR) Stringent quality control measures Homogeneity of allergenic material, microbiology Perfect blinding (professional tasters) Exact dosing Low fat matrix, protein free

21 Status?

22 IgE sensitisation allergy

23 Print screen FDA report

24 Summary of published LOAEL food range of LOAEL (mg protein) n = peanut 0.25 to hazelnut 1 to milk 0.36 to egg 0.13 to soy 88 to FDA report 2006

25 Considerable differences between studies peanut ground peanut peanut flour peanut butter egg egg white dried egg white whole egg dried whole egg cooked egg (vs( raw) milk whole milk non-fat dry milk infant formula

26 Published clinical threshold challenge trials Food LOAEL subjective (protein) LOAEL objective (protein) Author peanut 0.1 mg 2 mg Hourihane 1997 peanut 0.1 mg 10 mg Wensing 2002 peanut 10 mg 100 mg Flintermann 2006 hazelnut <1 mg 1 mg Wensing 2002 wheat 15 mg Scibilia 2006 soy 5.3 mg 241 mg Ballmer-Weber 2006 egg 2.9 mg Osterballe 2003 milk 0.36 mg Morisset 2003

27 EU-FAREDAT: food provocation with soy chocolate bars 30 patients 1-69 years 19 f, 11 m 2mg 50g Ballmer-Weber et al.: JACI 2007

28 NOEAL and LOAEL in soy allergy (n=23) dose soy (g) discrete cumulative (protein) symptoms none OAS urticaria NOAEL sloael 45x oloael Ballmer-Weber et al.: JACI 2007

29 NOEAL and LOAEL in soy allergy (n=23) dose soy (g) discrete cumulative (protein) symptoms none OAS urticaria NOAEL sloael oloael 200x Ballmer-Weber et al.: JACI 2007

30 Cumulative proportion of responses Log (threshold dose (mg)) HCL Predicted subjective/objective / / / 22 The proportion (%) of soy allergic patients experiencing a clinical reaction at different doses (10, 100 and 1000 mg) of soy. Ballmer-Weber et al.: JACI 2007

31 EuroPrevall

32 DBPCFC: advances in EuroPrevall optimised DBPC dose escalating study procedure uniform protocols for all EuroPrevall centers high patient number: low doses (NOEAL, n>29) database: precise informations subjective and objective symptoms discrete and cumulative doses severity of symptoms centrally produced high standard meals

33 Dosing for challenges in EUROPREVALL Dosis protein peanut hazelnut celeriac egg milk shrimp 1 3 μg 12 ug 18 ug 188 ug ul 0.09 ul 15 ug 2 30 μg 120ug 180 ug 1.88 mg 0.24 ul 0.9 ul 150 ug μg 1.2mg 1.8 mg 18.8 mg 2.4 ul 9 ul 1.5 mg 4 3 mg 12 mg 18 mg 188 mg 240 ul 90 ul 5 30 mg 120 mg 180 mg 1.88 g 0.8 ml 900 ul 15 mg 150 mg mg 400 mg 600 mg 6.25 g 1.2 ml 3 ml 500 mg mg 1.2 g 1.8 g 18.8 g 2.4 ml 9 ml 1.5 g mg 4 g 6 g 62.5 g 8 ml 30 ml 5 g 9 3 g 12 g 18 g - 24 ml 90 ml 15 g total 4.4 g 18 g 27 g 90 g 36 ml 130 ml 22 g

34 Dose of Protein Amount to be fed to patient high allergen ready to eat dessert 3g 300ml 1g 100ml 300mg 30ml 100mg 10ml 30mg 3ml low allergen ready to eat dessert 3mg 100ml 300µg 10ml 30µg 1ml 3µg Mix 1.0ml of low allergen dessert with 9ml of blank dessert (previously chilled overnight) for a minimum of 2 minutes. Feed 1.0ml to the patient.

35 - peanut - hazelnut - celeriac - egg - milk - fish apple peach (shrimp)

36

37 DBPCFCs in Europrevall (n= 103) positive tolerant placebo

38 60 50 patients (n) subjective (n=20) objective (n=39) 10 0 peanut hazelnut celeriac egg milk apple peach fish total n=6 n=14 n=5 n=13 n=12 n=4 n=4 n=1

39 DBPCFCs in Europrevall (n= 103) hazelnut peanut celeriac milk egg sloael 3 μg 3 μg 30 μg 30 μg 30 mg oloael 300 μg 30 mg 3mg 300 μg 300 mg

40 GAPS

41 Gaps after Europrevall - reproducibility of threshold? - thresholds in anaphylaxis? - Which dose during the dose escalation study induces the symptoms and where is the location of reaction - matrix effect? Is it really the fat? - DBPCFC: reflection of real life? - useful statistical models for risk calculation - risk markers for low dose responders?