Effectiveness and Safety of Milk Ladders in Children with IgE-Mediated Cow's Milk Protein Allergy

Introducing baked milk into the diet of children with cow's milk protein allergy (CMPA) has been shown to potentially accelerate the development of tolerance to raw milk. However, there is no standardised milk ladder protocol, and different scientific societies across countries recommend varying versions.

This study aims to assess the effectiveness and safety of the 4-step milk ladder (4-ML) compared to the 6-step milk ladder (6-ML) in children with IgE-mediated CMPA.

We will perform an open-label randomised trial with two parallel arms in two departments of the same academic hospital. A total of 92 children with IgE-mediated CMPA will be allocated to introduce cow's milk into their diet according to either 4-ML or 6-ML with a 4-week break period between subsequent steps. Oral food challenge (OFCs) with tested products at each subsequent step of the milk ladder will be conducted in hospital settings. The primary outcome will be the percentage of children with tolerance to non-heated cow's milk proteins defined as no allergic reaction to non-heated cow's milk (120-240 ml depending on the age of the patient) during the last OFC; measured at the end of the 12-week observation period for the 4-ML and 20-week observation period for the 6-ML. Secondary outcomes will include the percentage of children with a negative OFC to each milk ladder step; the percentage of children with anaphylaxis (both those who were treated and who were not treated with adrenaline); the percentage of children with exacerbation of atopic dermatitis; growth; compliance; and quality of life of the caregivers and parents' anxiety about adverse events during their child's OFC.

The statistical analyses will be conducted with StatsDirect. The Mann-Whitney U test will be used to compare the means of continuous variables if non-normal distribution will be assessed. Proportions will be compared with the Fisher exact test. The difference in study groups was considered significant when the P value will be \<05. The results of this study will be analyzed on the basis of intention to treat.

• Percentage of children who experienced anaphylaxis [Срок оценки: during the observation period (12 or 20 weeks, depending on the study arm)]
• Percentage of children who required adrenaline administration [Срок оценки: during the observation period (12 or 20 weeks, depending on the study arm)]
• Change in BMI-for-age z-score [Срок оценки: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)]
• Assessment of parents' anxiety about adverse events during their child's OFC [Срок оценки: before each OFC, which means before the first OFC and depending on the study arm: after 4,8,12 weeks or after 4,8,12,16,20 weeks]
• In a subgroup of children with atopic dermatitis, the percentage of children with mild, moderate, and severe atopic dermatitis [Срок оценки: before and after each OFC (during the examination following each observation period) which means before and after the first OFC and and before and after subsequent OFCs depending on the study arm: after 4,8,12 weeks or after 4,8,12,16,20 weeks]
• Percentage of children with full compliance to the intervention protocol [Срок оценки: at the end of the observation period (12 or 20 weeks, depending on the study arm)]
• Percentage of children with negative OFCs to each cow's milk form after receiving the full planned amount for each OFC [Срок оценки: at the end of the observation period (12 or 20 weeks, depending on the study arm)]
• Percentage of children with negative OFCs to each cow's milk form after receiving any tolerated dose [Срок оценки: after the end of the observation period (12 or 20 weeks, depending on the study arm)]
• Change in total score of The Food Allergy Questionnaire of Life - Parent Form (FAQLQ-PF) [Срок оценки: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)]
• Change in length/height-for-age z-score [Срок оценки: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)]