Clinical trial NCT06664918: Effectiveness and Safety of Milk Ladders in Children with IgE-Mediated Cow's Milk Protein Allergy
Official title: Effectiveness and Safety of the 4-Step Versus 6-Step Milk Ladder in Children with IgE-Mediated Cow's Milk Protein Allergy: Protocol for an Open-Label Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cow Milk Allergy
Food Allergy
Keywords: IgE-mediated cow's milk allergy
children
milk ladder
Lead sponsor: Medical University of Warsaw
Sponsor class: OTHER
First posted: 2024-10-30
Enrollment: 92
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cow's milk protein allergy (CMPA) is one of the most common food allergies in early childhood. The first-line treatment of CMPA is the elimination of cow's milk proteins (CMPs) from the child's or maternal diet.

Available data from the literature indicate that most children with CMPA acquire tolerance to CMPs with age. An assessment of tolerance acquisition to CMPs is commonly performed using milk ladder. However, scientific evidence regarding the effectiveness and safety of the milk ladder in children with CMPA is limited. Currently, there is no standardised milk ladder protocol, and different versions of the ladder and recommend by scientific societies in various countries.

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. This is an open-label, randomised superiority trial with two parallel arms and a 1:1 allocation ratio.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Age between 1 and 5 years.
* Diagnosis of IgE-mediated CMPA confirmed according to ESPGHAN guidelines, by a positive OFC with CMPs. In high-risk children (i.e., with a history of anaphylaxis), diagnosis based on positive skin prick testing and/or elevated specific IgE to CMPs is sufficient.
* On a therapeutic elimination diet for at least 6 months or up to 12 months of age.12
* Eligible regardless of the risk of systemic reaction (anaphylaxis) and asthma.
* Good overall health status.
* Parents without language barriers.
* Written informed consent signed by parents.
* Good cooperation with the child's guardians.

Exclusion Criteria:

* Uncontrolled asthma, defined as the presence of shortness of breath, chest tightness, cough, and/or auscultatory changes despite treatment.
* Signs of exacerbation of a chronic disease.
* Signs of acute infectious disease (i.e., acute runny nose, cough, subfebrile fever, or fever).
* Signs of exacerbation of another allergic disease (i.e., conjunctivitis, allergic rhinitis, atopic dermatitis).
* Anaphylaxis due to CMPs in the last 6 months.
* Used antihistamines within 3-10 days before the challenge (depending on the characteristics of the drug and the reason for use).
* Acquired tolerance to baked CMPs or higher steps of the milk ladder.
* Use of immunosuppressive drugs or immunotherapy

Primary outcomes:
measure: The percentage of children who acquired tolerance to non-heated cow's milk proteins
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Secondary outcomes:
measure: Percentage of children who experienced anaphylaxis
timeFrame: during the observation period (12 or 20 weeks, depending on the study arm)
measure: Percentage of children who required adrenaline administration
timeFrame: during the observation period (12 or 20 weeks, depending on the study arm)
measure: Change in BMI-for-age z-score
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
measure: Assessment of parents' anxiety about adverse events during their child's OFC
timeFrame: 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
measure: In a subgroup of children with atopic dermatitis, the percentage of children with mild, moderate, and severe atopic dermatitis
timeFrame: 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
measure: Percentage of children with full compliance to the intervention protocol
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
measure: Percentage of children with negative OFCs to each cow's milk form after receiving the full planned amount for each OFC
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
measure: Percentage of children with negative OFCs to each cow's milk form after receiving any tolerated dose
timeFrame: after the end of the observation period (12 or 20 weeks, depending on the study arm)
measure: Change in total score of The Food Allergy Questionnaire of Life - Parent Form (FAQLQ-PF)
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
measure: Change in length/height-for-age z-score
timeFrame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Other outcomes:
Locations:
city: Warsaw
country: Poland
facility: Medical University od Warsaw, Department od Pediatrics
city: Warsaw
country: Poland
facility: Medical University od Warsaw
Study officials:
affiliation: Medical University od Warsaw
name: Andrea Horvath
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Warsaw
name: Hanna Szajewska
role: PRINCIPAL_INVESTIGATOR
affiliation: Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; New York Univeristy, Grossmann School of Medicine
name: Anna Nowak-Węgrzyn
role: PRINCIPAL_INVESTIGATOR
References: