Efficacy of the Milk Ladder Intervention in the Development of Tolerance and the Recognition of B Cell Epitopes in Babies Who Are Allergic to Cow's Milk Proteins

Study Overview
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Brief Summary
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Food allergies have become a relevant health problem in westernized societies, particularly, with children. Cow's milk (CM), along with hen's eggs, are the most common foods eliciting allergic reactions in children under 4 years of age. The main objective of this intervention study is to evaluate the safety and efficacy of the intervention known as The Milk Ladder in the development of tolerance by children with CM allergies. This will be compared to an historical cohort (CoALE), which investigated the natural history of this allergy. Additionally, the ability of informative epitopes will be evaluated for their potential to predict tolerance and their correlation against clinical variables. The Milk Ladder will be evaluated within a prospective cohort of CM allergic children. This intervention is enacted through the introduction of meals cooked with progressively increasing amounts of cow's milk into the participant's diet. The primary outcome will be the development of tolerance which will be evaluated through a double-blind placebo-controlled food challenge. IgE and IgG4 epitopes will be described using a peptide microarray immunoassay. Quality of life will be determined by administering the FAQLQ-PF disease-specific questionnaire. Finally, within a subgroup of study participants, the ability of different peptides to activate basophils will be analyzed, and CM T cell epitopes will be studied by means of T-cell proliferation and cytokine production assays.

Official Title
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Efficacy of the Milk Ladder Intervention in the Development of Tolerance and the Recognition of B Cell Epitopes in Babies Who Are Allergic to Cow's Milk Proteins

Conditions
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IgE-mediated Milk Allergy

Intervention / Treatment
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* Other: Milk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Babies of both sexes. Age < 12 months. Clinical history of immediate reaction (<2 hours) after the intake of baby's formula and/or foods containing cow's milk. Sensitization to cow's milk proteins demonstrated by: sIgE to cow's milk, alpha-Lactoabumin, beta-Lactoglobulin and/or Casein >0.1KU/l (ImmunoCAP®, ThemoFisher) and/or Skin prick test to cow's milk, alpha-Lactoabumin, beta-Lactoglobulin and/or Casein ≥3mm If the reaction to milk occurred over 3 months before the recruitment, it will be mandatory to confirm reactivity to milk with an oral food test. Parents / legal representatives of the participant voluntary accept to participate. Exclusion Criteria: Delayed reactions (> 2 h) after milk intake. Contact urticaria to milk if ingestion is well tolerated. Previous participation in oral tolerance induction/desensitization protocols. Treatment with any medication that might interfere the evaluation of the primary outcome or any study procedure. Any disease or condition which presents a contraindication to perform an oral challenge, either open or double-blind or any other study procedure. Social circumstances that might interfere with protocol adherence. Egg and/or wheat allergy (this exclusion criterion shall be verified before the beginning of the intervention).

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dietary intervention<br>Meals containing Milk and Milk | Other: Milk<br>* Meals containing Milk and Milk<br>|
| No Intervention: Historical cohort<br>Standard care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants that develop tolerance to milk after the 'Milk Ladder' intervention | Tolerance assessment: participants who successfully pass a double-blind placebo-controlled oral food challenge without experiencing any limiting symptom | 12 months | 
| Number of participants experiencing any adverse reaction | Number of participants experiencing any adverse reaction to milk-containing foods along the intervention assessed by Medical Dictionary for Regulatory Activities (MedDRA), version in place at the end of the study. | 12 months | 
| Change in antigen-specific IgE and IgG4 epitopes repertoire | Serum specific inmunnoglobulin levels using a milk peptide microarray immunoassay | 6 and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life | Change in quality of life total score during the intervention, assessed by the disease-specific questionnaire 'Food Allergy Quality of Life Questionnaire - Parent Form' | 6 and 18 months | 
| Potential T-cell epitopes | Identification of potential T-cell epitopes in serum assessed by a T lymphocyte proliferation assay and cytokine secretion | 12 months | 
| Ability of the milk allergenic peptides to activate basophils | In vitro determination of basophil activation upon antigen stimulation | 12 months |