GOAt Milk Formula-based Ladder Versus Cow's Milk Ladder

Efficacy and Safety of a Four-step Goat Milk Formula-based Ladder Versus a Four-step Cow's Milk Ladder in Children With IgE-mediated Cow's Milk Allergy: Protocol for the Exploratory GOAL Randomised Controlled Trial.

Children with immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) who react to small amounts of baked cow's milk may require prolonged elimination. Preliminary observations suggest that some may tolerate products prepared with a low-αs1-casein goat milk formula. This study will compare a four-step goat milk formula-based ladder (4-GMFL) with a four-step cow's milk ladder (4-CML).

This exploratory open-label, multicentre, randomised trial will enroll 92 children aged 1-5 years with IgE-mediated CMA, allocated 1:1 to the 4-GMFL or 4-CML group. Both ladders comprise muffin, pancake and baked hard cheese, introduced at 4-week intervals and assessed by open, physician-supervised oral food challenges (OFCs) in hospital, followed by a final OFC with 120 mL of non-heated pasteurised cow's milk at week 12.

The primary outcome will be tolerance to non-heated cow's milk protein at this final step, defined as a negative OFC with 120 mL of pasteurised cow's milk containing 3.96 g of protein. Secondary outcomes will include tolerance to individual ladder products, allergic reactions, anaphylaxis, intramuscular adrenaline use, anthropometric changes, food allergy-related quality of life, caregiver anxiety and adherence. Molecular sensitisation profiles will be explored as potential predictors of OFC outcomes.

Goat's milk differs from cow's milk in casein composition, protein structure and digestibility. Recent data suggest that these differences may modify IgE recognition and allergenic potential. This study is based on the hypothesis that repeated exposure to goat milk formula-containing products may provide a different pattern of allergen exposure from that achieved with a conventional cow's milk ladder.

This study aims to assess the effectiveness and safety of the 4-step goat milk formula-based ladder (4-GMFL) compared to the 4-step cow's milk ladder (4-CML) in children with IgE-mediated cow's milk allergy.

An exploratory open-label randomised trial with two parallel arms in two departments: the Department of Paediatrics, Medical University of Warsaw, and the Department of Paediatrics and Allergy, Copernicus Memorial Hospital, Medical University of Lodz, will be performed. A total of 92 children with IgE-mediated cow's milk allergy will be allocated to introduce cow's milk into their diet according to either 4-GMFL or 4-CML with a 4-week break period between subsequent steps. Oral food challenge (OFCs) with tested products - muffin with goat or cow's milk formula, pancake with goat or cow's milk formula, baked goat or cow's milk hard cheese, pasteurised cow's milk - at each subsequent steps of the ladders will be conducted in hospital settings. In both groups, the final 4th ladder step is identical and will assess whether tolerance to the assigned ladder products is accompanied by tolerance to cow's milk protein.

The primary outcome will be the between-group difference in the proportion of children who acquire tolerance to non-heated pasteurised cow's milk, as determined by a negative OFC at the final step of the 4-GMFL or 4-CML. Cow's milk will be administered at the end of the observation period (12 weeks). The challenge dose will consist of 120 mL of pasteurised cow's milk, corresponding to 3.96 g of cow's milk protein.

Secondary outcomes will include between-group difference in the proportion of children with negative OFCs to each ladder steps; between-group difference in the percentage of children with anaphylaxis who required epinephrine administration; between-group difference in the percentage of children with exacerbation of atopic dermatitis; growth; compliance; Food Allergy Quality of Child's Life and 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.

Inclusion Criteria:

• Age between 1 and 5 years.
• Diagnosis of IgE-mediated CMA confirmed according to ESPGHAN guidelines, by a positive OFC with CMPs. In high-risk children (i.e., with a history of anaphylaxis occurring more than 6 months before enrolment) diagnosis may be established without a new OFC, based on a positive SPT wheal at least 3 mm greater than negative saline control and elevated specific IgE to CMPs >0.35 kUa/L.
• On a cow's milk-free, therapeutic elimination diet for at least 6 months, or since before 12 months of age.
• Eligible regardless of the risk of systemic reaction (anaphylaxis) and asthma.
• Overall good health status.
• Parents/legal guardians able to understand the study procedures and communicate effectively with the study team.
• Written informed consent provided by parents/legal guardians.
• Expected good cooperation of the child's parents/legal guardians with the study team.

Exclusion Criteria:

• Uncontrolled asthma, defined as poor control according to the current GINA criteria, recent exacerbation requiring systemic corticosteroids or the need for medium to high-dose inhaled corticosteroids to maintain control
• Signs of acute infectious disease (i.e., acute runny nose, cough, or fever).
• Clinically relevant, uncontrolled exacerbation of another allergic disease that, in the investigator's judgement, could compromise OFC interpretation or safety (i.e., conjunctivitis, allergic rhinitis, atopic dermatitis).
• History of anaphylaxis due to cow's milk proteins within the last 6 months.
• Use of antihistamines within 3-10 days before the OFC, depending on the drug's pharmacokinetics and indication (time-limited contradiction - relative exclusion criterion).
• Documented tolerance to baked CMPs or to higher steps of the milk ladder.
• Use of immunosuppressive drugs or ongoing allergen immunotherapy.