Cow Milk AllergyNCT06664918
Effectiveness and Safety of Milk Ladders in Children with IgE-Mediated Cow's Milk Protein Allergy
A study testing oral food challenge (OFC) in people with Cow Milk Allergy and Food Allergy, run by Medical University of Warsaw at 2 sites in Poland.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 5 years
- Conditions the study is for
- Cow Milk Allergy, Food Allergy
- What is being tested?
- oral food challenge (OFC)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 92 participants
- Where
- 2 sitesPoland
- Study dates
- 3 Dec 2024to Mar 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 5 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Poland2 sites, 2 recruiting
- Recruiting
Medical University od Warsaw, Department od Pediatrics
Warsaw
Daria Wiszniewska, 783307607, daria.wiszniewska@gmail.com
- Not yet recruiting
Medical University od Warsaw
Warsaw
Andrea Horvath, MD PhD, 22 317 9444, andrea.horvath@wum.edu.pl
About this study
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
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.
Read the 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.
- Conditions
- Cow Milk Allergy, Food Allergy
- Being tested
- oral food challenge (OFC)
- Keywords
- IgE-mediated cow's milk allergy, children, milk ladder
- Medical subject headings
- Milk Hypersensitivity, Food Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
oral food challenge (OFC)Other
oral food challenges with subsequent steps of 4-step milk ladder (muffin, pancake,baked hard cheese, yoghurt/pasteurised cow milk or modified cow milk)
oral food challenge (OFC)Other
oral food challenges with subsequent steps of 6-step milk ladder (cookie, muffin, pancake,baked hard cheese, yoghurt, pasteurised cow milk or modified cow milk)
| Study group | Role | What they receive |
|---|---|---|
| 4-step milk ladder | Experimental | Not described Receives: Other: oral food challenge (OFC) |
| 6-step milk ladder | Active comparator | Not described Receives: Other: oral food challenge (OFC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
The percentage of children who acquired tolerance to non-heated cow's milk proteins
The percentage of children who acquired tolerance to non-heated cow's milk proteins defined as unreactive patients during OFC with non-heated cow's milk (the last step of milk ladder; a pasteurised cow milk or modified cow milk, the amount of 120-240 ml depending on the age of the patient, max. 7.95 g of CMPs)
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Secondary outcomes (10)
Percentage of children who experienced anaphylaxis
Anaphylaxis defined by the clinical criteria of anaphylaxis according to WAO 2020.
Measured: during the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children who required adrenaline administration
Measured: during the observation period (12 or 20 weeks, depending on the study arm)
Change in BMI-for-age z-score
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Assessment of parents' anxiety about adverse events during their child's OFC
using the Subjective Units of Distress Scale (SUDS); parents will rate their level of anxiety on a scale from 1 to 100, where 0 represents no anxiety or complete relaxation, and 100 represents extreme anxiety, the worst ever experienced.
Measured: 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
In a subgroup of children with atopic dermatitis, the percentage of children with mild, moderate, and severe atopic dermatitis
assessed using the oSCORAD23 scale; the maximum score on this scale is 83 points (in the most severe cases, an additional 10 points can be added for changes that disfigure or limit the patient's functioning), the minimum score is 0 points; the more points, the greater intensity of changes
Measured: 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
Percentage of children with full compliance to the intervention protocol
defined as performing all OFCs in the hospital setting and then regular introduction of the milk-containing products according to the individual tolerance following the Study Protocol
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children with negative OFCs to each cow's milk form after receiving the full planned amount for each OFC
This will be reported as a percentage of children with negative OFCs to each cow's milk form (cookie, muffin, pancake, cheese, yoghurt, milk, if applicable) according to the milk ladder protocol, after receiving the full planned amount for each OFC.
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children with negative OFCs to each cow's milk form after receiving any tolerated dose
This will be reported as a percentage of children with negative OFCs to each cow's milk form (cookie, muffin, pancake, cheese, yoghurt, milk, if applicable) according to the milk ladder protocol, after receiving any tolerated dose during the trial.
Measured: after the end of the observation period (12 or 20 weeks, depending on the study arm)
Change in total score of The Food Allergy Questionnaire of Life - Parent Form (FAQLQ-PF)
The questionnaire is divided into three domains: emotional impact, food anxiety, and social and dietary limitations. The total score is calculated as the mean of three subscales. The minimum score is 0, the maximum score is 6. The lower the score, the more life affecting the allergy is.
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Change in length/height-for-age z-score
Measured: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2024
- Study start3 Dec 2024
- Primary completionDec 2028 (estimated)
- Study completionMar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cow Milk AllergyStudies of the same condition, open and under way.
- More trials run by Medical University of WarsawThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 92 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Medical University of Warsaw
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea Horvath-Stolarczyk, Medical University of Warsaw
- Investigators
- Andrea Horvath, Principal investigator, Medical University od WarsawHanna Szajewska, Principal investigator, Medical University of WarsawAnna Nowak-Węgrzyn, Principal investigator, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; New York Univeristy, Grossmann School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06664918
- Sponsor's protocol ID
- ML2024
- Status last verified
- Mar 2025
- First submitted
- 16 Oct 2024
- Last updated
- 18 Mar 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The results of this RCT, whether positive or negative, will be published in a peer-reviewed journal (data will be submitted to the first journal after 3-6 months from study completion). Abstracts will also be submitted to relevant national and international conferences. The datasets used and/or generated during this study will be made available from a given author upon reasonable request, after the publication of results, no later than 3 years from the completion of data analysis.
Publications
Wiszniewska D, Horvath A, Strozyk A, Nowak-Wegrzyn A, Grzela K, Szajewska H. Effectiveness and safety of the four-step versus six-step milk ladder in children with IgE-mediated cow's milk protein allergy: protocol for an open-label randomised controlled trial. BMJ Open. 2025 Apr 14;15(4):e098314. doi: 10.1136/bmjopen-2024-098314.
PubMed 40228856
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT06664918
- Acronym / sponsor ID
- ML2024
- Conditions
- Cow Milk Allergy, Food Allergy
- Keywords
- IgE-mediated cow's milk allergy, children, milk ladder
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 92 participants (estimated)
- Lead sponsor
- Medical University of WarsawUniversity, hospital or other
- Study start
- 3 Dec 2024 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Mar 2029 (estimated)
- First posted
- 30 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 4-step milk ladder | Experimental | Other: oral food challenge (OFC) |
| 6-step milk ladder | Active comparator | Other: oral food challenge (OFC) |
Who may qualify
- Ages
- 1 year to 5 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| oral food challenge (OFC)oral food challenges with subsequent steps of 4-step milk ladder (muffin, pancake,baked hard cheese, yoghurt/pasteurised cow milk or modified cow milk) | Other | 4-step milk ladder |
| oral food challenge (OFC)oral food challenges with subsequent steps of 6-step milk ladder (cookie, muffin, pancake,baked hard cheese, yoghurt, pasteurised cow milk or modified cow milk) | Other | 6-step milk ladder |
Primary outcome
The percentage of children who acquired tolerance to non-heated cow's milk proteins
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
The percentage of children who acquired tolerance to non-heated cow's milk proteins defined as unreactive patients during OFC with non-heated cow's milk (the last step of milk ladder; a pasteurised cow milk or modified cow milk, the amount of 120-240 ml depending on the age of the patient, max. 7.95 g of CMPs)
10 secondary outcomes
Percentage of children who experienced anaphylaxis
Time frame: during the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children who required adrenaline administration
Time frame: during the observation period (12 or 20 weeks, depending on the study arm)
Change in BMI-for-age z-score
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Assessment of parents' anxiety about adverse events during their child's OFC
Time frame: 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
In a subgroup of children with atopic dermatitis, the percentage of children with mild, moderate, and severe atopic dermatitis
Time frame: 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
Percentage of children with full compliance to the intervention protocol
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children with negative OFCs to each cow's milk form after receiving the full planned amount for each OFC
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm)
Percentage of children with negative OFCs to each cow's milk form after receiving any tolerated dose
Time frame: after the end of the observation period (12 or 20 weeks, depending on the study arm)
Change in total score of The Food Allergy Questionnaire of Life - Parent Form (FAQLQ-PF)
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Change in length/height-for-age z-score
Time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm) compared to baseline (before the first OFC)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2025.
- Derived from this study: PubMed 40228856Wiszniewska D, Horvath A, Strozyk A, Nowak-Wegrzyn A, Grzela K, Szajewska H. Effectiveness and safety of the four-step versus six-step milk ladder in children with IgE-mediated cow's milk protein allergy: protocol for an open-label randomised controlled trial. BMJ Open. 2025 Apr 14;15(4):e098314. doi: 10.1136/bmjopen-2024-098314.
- Individual participant dataSharing planned: Yes. The results of this RCT, whether positive or negative, will be published in a peer-reviewed journal (data will be submitted to the first journal after 3-6 months from study completion). Abstracts will also be submitted to relevant national and international conferences. The datasets used and/or generated during this study will be made available from a given author upon reasonable request, after the publication of results, no later than 3 years from the completion of data analysis.
Related trials for Cow Milk Allergy
Recruiting
Evaluation of the Tolerance of a New Formula Based on Hydrolyzed Rice Proteins in Children With Cow's Milk Allergy
IgE-Mediated Cow Milk Allergy
RecruitingPhase 3
A 52-week Study of Remibrutinib in IgE-mediated Food Allergy
IgE-Mediated Food Allergy, Peanut Allergy
Not yet recruiting
Growth And Safety Outcomes In Infants With Cow´s Milk Protein Allergy (CMPA) Fed A Novel Extensively Hydrolyzed Formula (eHF)
Cow Milk Protein Allergy
Not yet recruiting
Partially Hydrolysed Whey Based Formula in Differentiation Between Non IgE Gastrointestinal Cow's Milk Protein Allergy and Milk Intolerance
Cow Milk Protein Allergy, Cow Milk Intolerance
Not yet recruiting
Tolerance and Growth Outcomes of an Extensively Hydrolysed Anti-regurgitation Casein-based Formula in Infants With Cow's Milk Protein Allergy
Cow Milk Protein Allergy, FPIES
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Andrea Horvath principal investigator
Medical University od Warsaw
Hanna Szajewska principal investigator
Medical University of Warsaw
Anna Nowak-Węgrzyn principal investigator
Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; New York Univeristy, Grossmann School of Medicine
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing oral food challenge (OFC) in people with Cow Milk Allergy and Food Allergy, run by Medical University of Warsaw at 2 sites in Poland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Poland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Andrea Horvath, MD, PhD (048223179444, andrea.horvath@wum.edu.pl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The percentage of children who acquired tolerance to non-heated cow's milk proteins (time frame: at the end of the observation period (12 or 20 weeks, depending on the study arm)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06664918, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2025; AzTrials last refreshed its copy on 8 Nov 2026.