The Impact of Proton-pump Inhibitors on Threshold Dose Distributions

Background and Rationale:

Antacids might influence the structure/degradation and therefore the allergenicity of food proteins. This study intends to perform double-blind placebo-controlled food challenges in walnut allergic patient to determine threshold dose distribution curves and to investigate the impact of antacids (proton-pump inhibitors) on the allergy eliciting dose of walnut and the severity of the clinical manifestation in walnut allergic patients.

Objective(s):

Primary study objectives:

Investigation of effect of Omeprazole on the threshold dose-distribution curve and the severity of the clinical manifestation of walnut allergic patients.

Secondary study objectives:

Determination of minimal eliciting dose of walnut protein in walnut allergic patients Calculation of the dose of walnut protein leading to an allergic reaction in 5% (ED05) and 10% (ED10) of walnut allergic population Analyse differences in walnut threshold distributions curves and severity related to allergen sensitisation pattern and geographical location.

Outcome(s):

Primary outcome Change in the threshold dose of walnut that induces an allergic reaction after the intake of therapeutic doses of omeprazole Change in the severity of walnut allergy after the intake of therapeutic doses of omeprazole.

Secondary outcome Determination of threshold dose-distribution curve in walnut allergy and calculation of the dose of walnut protein leading to allergic reactions in patients with confirmed food allergy to walnuts.

Study design:

Multicentre, randomised, placebo-controlled; cross-over design.

Selection criteria:

Key inclusion criteria

• positive case history of immediate allergic reaction(s) to walnut
• age ≥ 18 years
• presence of specific IgE to walnut defined as a positive (≥ 3 mm wheal diameter) skin prick test and/or a serum IgE to walnut ≥ 0.35 kU/L ( ImmunoCAP).

Key exclusion criteria

• intake of drugs interfering with Omeprazole or the allergic response under food challenge
• pregnancy, breastfeeding
• acute allergic disease
• any contraindication to adrenaline or to food challenge.

Measurements and procedures:

Skin-prick-testing with different extracts, blood sampling for immunological testing, double-blind placebo controlled food challenge with walnut with/without previous Omeprazole.

Study Product / Intervention:

Omeprazole: Omeprazole Sandoz capsules 40 mg® One treatment run of 5 days, 40 mg (1 capsule) per day

Control Intervention (if applicable):

Placebo capsules containing mannitol Two treatment runs of 5 days, 1 capsule per day

Number of Participants with Rationale:

Two clinical centers will participate in this study, Madrid-Spain (ES) and Zürich-Switzerland (CH). These two centers have been included because the allergens involved in walnut allergy differ, and this will allow to study geographical differences related to the allergen sensitization profile. In Spain patients are sensitized to stable walnut allergens such as lipid transfer proteins (LTP) and storage proteins, whereas in Switzerland patients allergic to walnut are sensitized to labile allergens homologous to Bet v 1.

The final study population for each center will consist of 30 subjects with a challenge confirmed walnut allergy. This sample size will allow to build the probabilistic models to determine threshold dose distribution curves of walnut and calculate the ED05 and ED10. At the same time a population of n=60 will allow to find differences between patients treated with omeprazol and placebo analysed by discrete time survival analysis, given that for a hazard ratio of 2.5, and an anticipated 30% of right censoring, with a confidence level of 95% (α=0.05) and a 90% statistical power (β=0.10) a sample size of 36 subjects is enough.

Due to our experience the investigators will have to include 60 patients at each site with a positive case history of walnut allergy undergoing food challenges to identify 30 patients at each site with a positive food challenge

Statistical Considerations:

The final study population for each center will consist of 30 subjects with a challenge confirmed walnut allergy. This sample size will allow to build the probabilistic models to determine threshold dose distribution curves of walnut and calculate the ED05 and ED10. At the same time a population of n=60 will allow to find differences between patients treated with omeprazol and placebo analysed by discrete time survival analysis, given that for a hazard ratio of 2.5, and an anticipated 30% of right censoring, with a confidence level of 95% (α=0.05) and a 90% statistical power (β=0.10) a sample size of 36 subjects is enough.

GCP Statement:

This study will be conducted according to the standards established by ICH-GCP, The Clinical Trials Directive (2001/20/EC), the Declaration of Helsinki and any applicable local laws. The study will require approval from the Local Ethics Committees and authorization from the National Medicines Agency in each country (AEMPS, Swissmedic) prior to initiation.