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

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.

Study Overview

• Status: Unknown
• Conditions: IgE-mediated Milk Allergy
• Intervention / Treatment: Other: Milk

• Study Type: Interventional
• Enrollment (Anticipated): 114
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Clinico San Carlos
    • Contact: Inmuculada Cerecedo, MD, PhD; Phone Number: 7454 + 34 91 330 30 00; Email: inmaculada.cerecedo@salud.madrid.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dietary intervention; Meals containing Milk and Milk	Other: Milk; Meals containing Milk and Milk
No Intervention: Historical cohort; Standard care

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospital San Carlos, Madrid
• Investigators: Study Chair: Inmaculada Cerecedo, e: MD, PhD, Hospital Clinico San Carlos

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2018
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): August 30, 2021

Study Registration Dates

• First Submitted: February 2, 2018
• First Submitted That Met QC Criteria: March 14, 2018
• First Posted (Actual): March 15, 2018

Study Record Updates

• Last Update Posted (Actual): June 26, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Food Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Milk Hypersensitivity
• Other Study ID Numbers: Milk Ladder

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No