Early Supplementation for Cow's Milk Allergy Prevention (ESCAPE-PL)

Early Supplementation for Cow's Milk Allergy Prevention in Breastfed Infants in Poland (ESCAPE-PL): a Protocol for Randomised Controlled Trial

Cow's milk allergy (CMA) is a common food allergy in infants and young children that can have a significant impact on the individual and their family due to dietary restrictions, risk of nutritional deficiencies, social limitations, and decreased quality of life. It also represents a financial burden for families and healthcare resources.

There is an ongoing debate about the significance of early exposure to cow's milk proteins within hours or days after birth and its relationship to the risk of developing CMA later in life. Current recommendations for early introduction of cow's milk proteins in infants who cannot be breastfed vary and are inconsistent due to a lack of clear evidence. This knowledge gap underscores the need for further research to provide a definitive understanding of the relationship between early exposure to cow's milk proteins and the development of CMA, which will ultimately inform evidence-based prevention strategies to improve the health and well-being of affected individuals and their families.

This trial aims to investigate whether early supplementation with various nutritional interventions (cow's milk formula [CMF], amino acids formula [AAF], donor human milk [DHM], or high-pressure processed "pascalized" donor human milk [DHM-P]) could serve as an effective strategy for the primary prevention of CMA in breastfed neonates.

This study is an open-label randomized, controlled, head-to-head trial with four parallel arms and allocation 1:1:1:1.

Study Overview

• Status: Not yet recruiting
• Conditions: Cow's Milk Allergy; Food Allergy
• Intervention / Treatment: Other: Cow's milk formula [CMF]; Other: Amino-acid formula [AAF]; Other: Donor human milk [DHM]; Other: High-pressure processed "pascalized" donor human milk [DHM-P]

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andrea Horvath, Assoc Prof; Phone Number: 22 317 9444; Email: andrea.horvath@wum.edu.pl

Study Locations

• Poland
  • Masovian
    • Warsaw, Masovian, Poland, 02-091
      • Medical University of Warsaw
      • Contact: Andrea Horvath, Assoc Prof; Phone Number: 22 317 9444; Email: andrea.horvath@wum.edu.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

1. Healthy newborns of mothers who express the intention to exclusively breastfeed for first 6 months of infant's life
2. Full-term infants (defined as gestational age of at least 37 weeks)
3. Infant birth weight at least 2500 g and ≤ 4500 g
4. Age at enrolment <24 h of life
5. Regardless of any atopic condition in parents
6. Written informed consent of the caregiver

Exclusion criteria:

1. Infants of parents who intend to partially or fully formula feed
2. Serious congenital anomalies or any other medical condition that would preclude the consumption of any of the study formulas, or interfere with nutrition or growth
3. Contradictions to exclusive breastfeeding
4. Multiple pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CMF	Other: Cow's milk formula [CMF]; At least 10 ml daily of cow's milk formula (Bebiko 1 NUTRIFlor Expert®, Nutricia; formula with galactooligosaccharides and without probiotics); and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
Experimental: AAF	Other: Amino-acid formula [AAF]; At least 10 ml daily of amino-acid formula (Nutramigen Pureamino®, Reckitt Benckiser Group PLC); and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
Experimental: DHM	Other: Donor human milk [DHM]; At least 10 ml daily of donor human milk; and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
Experimental: DHM-P	Other: High-pressure processed "pascalized" donor human milk [DHM-P]; At least 10 ml daily of high-pressure processed "pascalized" donor human milk; and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
A cumulative incidence of cow's milk allergy confirmed by open oral food challenge	At 4-6 and 12 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A cumulative incidence of sensitization to cow's milk protein (cut-off levels for specific IgE level ≥0.35 allergen units [UA/mL] and ≥3 mm of wheal size in the skin prick test against cow's milk		at 6 and 12 months of age
A point prevalence of cow's milk allergy confirmed by open oral food challenge		at 4-6, and 12 months of age
An incidence of sensitization to cow's milk protein (cut-off levels for specific IgE level ≥0.35 allergen units [UA/mL] against cow's milk)		at 4-6, and 12 months of age
In a subgroup of children with confirmed cow's milk allergy, the percentage of children with tolerance acquisition to cow's milk	Tolerance acquisition to cow's milk will be assessed by subsequent OFC with baked milk (in the form of biscuit or muffin); if baked milk is tolerated, the assessment of tolerance acquisition will be continued with the use of milk ladder.	at 9 and/or 12 months
Percentage of children who received a full 3-day nutritional supplementation (3x10 ml according to the randomization) and then were exclusively or predominantly breastfed until 4 months of age		Up to 4 month of age
A total score in the Cow's Milk-related Symptom Score (CoMiSS)	The total CoMiSS score ranges from 0 to 33, a score of ≥10 indicates CMA.	at 4-6 and 12 months of age
Percentage of children exclusively breastfed		at 4 and 6 months of age
Percentage of children with mixed feeding		at 4 and 6 months of age
Change in Body Mass Index (BMI)-for-age z-score	weight and length will be checked each month in a telephone interview or parental report, or during follow-up visit assessed by study physician; change in mean value will be assessed between baseline and each time point	at 4, 6 and 12 months of age
Change in length-for-age z-score	length will be checked each month in a telephone interview or parental report, or during follow-up visit assessed by study physician; change in mean value will be assessed between baseline and each time point	at 4, 6 and 12 months of age
Adverse events related to the nutritional intervention (according to the randomization)	defined as any harmful events that may occur during the trial; the process of decision whether an adverse event is related to the intervention (attribution) will be made by the non-blinded principal investigator	up to 12 months of age
A cumulative incidence of atopic dermatitis (defined as meeting the UK Working Party diagnostic Criteria)		at 6 and 12 months of age
A cumulative incidence of allergic rhinitis (confirmed by study physician)		at 6 and 12 months of age
A cumulative incidence of feeding difficulties who will be screened with The Montreal Children's Hospital Feeding Scale (MCH-FS scale)	Total score range from 14 to 98, score of 46 or higher indicates feeding difficulties.	at 6 and 12 months of age
Human milk energy value (kcal/100 mL)		at 4-14 days postpartum and 6 months of age
Total and true protein concentrations in human milk samples (g/100 mL)		at 4-14 days postpartum and 6 months of age
Fat concentration in human milk samples (g/100 mL)		at 4-14 days postpartum and 6 months of age
Lactose concentration in human milk samples (g/100 mL)		at 4-14 days postpartum and 6 months of age
Dry mass content g/100 mL		at 4-14 days postpartum and 6 months of age
IgA-anty CMA concentration in human milk samples (pg/mL)		at 4-14 days postpartum
IL-1B, IL-6, IL-10, and TGF-beta concentrations in human milk samples (pg/mL)		at 4-14 days postpartum

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Collaborators: Medical Research Agency, Poland
• Investigators: Study Chair: Andrea Horvath, Assoc Prof, MD, Medical University of Warsaw; Principal Investigator: Aleksandra Wesołowska, Assoc Prof, Medical University of Warsaw; Principal Investigator: Hanna Szajewska, Prof, MD, Medical University of Warsaw

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: July 23, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 14, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Food Hypersensitivity; Milk Hypersensitivity
• Other Study ID Numbers: ABM30

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The anonymized datasets used and/or generated during this study will be made available from a corresponding author on reasonable request, after the publication of results, no later than 3 years from the completion of data analysis.
• IPD Sharing Time Frame: After the publication of results, no later than 3 years from the completion of data analysis.
• IPD Sharing Access Criteria: The anonymized datasets used and/or gener.ated during this study will be made available from a corresponding author on reasonable request
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No