An interventional study of Implementation of cow's milk in decreasingly heated forms and Implementation of heated cow's milk in Food Allergy and Cow Milk Allergy, sponsored by Universitaire Ziekenhuizen KU Leuven. Recruiting at 5 sites in Belgium. Open to participants aged 1 Year to 18 Years. Per ClinicalTrials.gov, last updated 2026-05-08.
Sponsored by Universitaire Ziekenhuizen KU Leuven · Not applicable, Interventional, and Diagnostic
This interventional study aims to validate an early heated protein introduction protocol in cow's milk allergic children who already developed tolerance towards extensively heated cow's milk, in order to speed up the development of complete cow's milk tolerance. Natural complete tolerance induction towards cow's milk takes several years of strict cow's milk avoidance with high risk of anaphylaxis by accidental cow's milk intake. By shortening the time towards complete tolerance, not only the quality of life of both children and parents ameliorates drastically, the time frame for potential anaphylactic reactions is also strongly reduced and can be considered as a preventive strategy to reduce allergic reactions too. Moreover, this strategy has proved efficient for hen's egg allergy. The main question this study wants to answer is whether a 12 months stepwise heated cow's milk introduction (either by gradual reduction of the cooking time or by the use of the Flemish Milk Ladder) in 20'-cooked cow's milk tolerant subjects, results in a larger proportion of complete cow's milk tolerant children after 12 months compared to natural tolerance induction (with 20' cooked milk introduction only).
WP 1: Gradual introduction of less heated cow's milk proteins in 20'-cooked cow's milk tolerant children.
When inclusion criteria are met and informed consent from the parents (and when old enough, assent from the children) is obtained, children will be included in the trial. During the inclusion visit an open 20' cooked milk oral food challenge (OFC) needs to be passed in the hospital. Each visit a validated pedQuality of life (QoL) questionnaire will be taken and blood will be drawn to determine baseline specific IgE (sIgE) and IgG4 to cow's milk. Subjects (n=75) are randomized in a 1/1/1 ratio across three arms for 12 months to study the arm's tolerance inducing capacity (see Arms and Interventions for more information). After 6 months patients are invited for an intermediate visit. After 12 months, a OFC with unheated milk will be performed in all children during their challenge visits. Three months after the OFC, the children will be invited for a termination visit. Children who did not pass the OFC with unheated cow's milk after 12 months, will be invited to an observational 48 months follow-up study, in order to later-on retrieve the potential moment of complete cow's milk tolerance induction by clinical files.
WP2: Study of the immunological mechanisms (Treg and Breg induction and switch to IgG4-producing B cells).
Venous blood will be taken from all 75 children recruited for WP1 at enrolment and at the challenge and termination visit and from 15 healthy age-matched children, after obtaining children's oral or written assent (where appropriate) and parent's informed consent. Peripheral blood mononuclear cells (PBMCs) will be isolated and stimulated by cow's milk proteins as well as a positive control. Membrane markers associated with regulatory activity on T cells will be studied by flow cytometry (FC), as well as cytokine production in the supernatant by meso scale discovery. Furthermore, B cells will be studied after PBMC stimulation by FC. Cow's milk specific IgG4 and cytokine production will also be studied in this culture supernatant.
WP3: In vitro BATs to mimic the outcome of OFC.
In vitro Basophil activation tests (BATs) will be fine-tuned by preparing extracts for 20', 15', 10', 5' cooked and fresh cow's milk. Fine-tuning will include the comparison of new protein extract batches with the first batches, the absence of background basophil activation upon contact with the lowest dose of allergen extract and the comparison of basophil activation of healthy and of allergic children in different phases of cow's milk tolerance, who should show differences depending on the grade of tolerance. After fine-tuning, BATs will be performed as described above with 3 (or 5) extracts from cow's milk at baseline, challenge visit and termination visit in all children recruited within the study.
147 studies on the registry are indexed under Milk Hypersensitivity; 26 are open to participants now.
This study's planned enrollment of 90 is above the median of 68 across 95 interventional studies indexed under Milk Hypersensitivity.
Browse Milk Hypersensitivity studies →Universitaire Ziekenhuizen KU Leuven is the lead sponsor of 963 studies on the registry; 267 are open to participants now.
Of its 5 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
Compared within Milk Hypersensitivity, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Food Hypersensitivity. The counts are of registry records indexed under each term, refreshed daily. How we classify →
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Exclusion Criteria:
Step 1: open introduction of 20' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 3 months. Step 2: open introduction of 15' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 3 months. Step 3: open introduction of 10' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 3 months. Step 4: open introduction of 5' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 3 months.
Other: Implementation of cow's milk in decreasingly heated forms
The first 5 steps of the Flemish Milk Ladder (each containing a, b and c part) will be gradually introduced at home, each step for 21 days (2-3X a week during 3 consecutive weeks after which 3 days "rest"). We consider the 6th step the equivalent of tolerance induction so step 6 will be allowed once the OFC with uncooked milk is passed.
Other: Implementation of cow's milk in decreasingly heated forms
Step 1: open introduction of 20' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 12 months.
Other: Implementation of heated cow's milk
For work package 2, 15 healthy age-matched subjects are included to compare immunological mechanisms with.
Other: No intervention
Implementation of cow's milk in decreasingly heated forms in cow's milk allergic subjects, tolerant to heated cow's milk, to assess the influence on tolerance induction.
Implementation of heated cow's milk in cow's milk allergic subjects, tolerant to heated cow's milk, to assess the influence on tolerance induction.
Healthy subjects undergo no intervention.
Complete cow's milk tolerance after 12 months of stepwise heated cow's milk introduction
We here want to test the hypothesis that a total period of 12 months stepwise heated cow's milk introduction (either by gradual reduction of the cooking time or by the use of the Flemish Milk Ladder) in 20'-cooked cow's milk tolerant subjects, results in a larger proportion of complete cow's milk tolerant children after 12 months compared to natural tolerance induction (with 20' cooked milk introduction only).
Time frame: 12 months
Time to complete tolerance in all three arms
We will study how long it takes for the subjects of each arm to develop complete tolerance toward cow's milk.
Time frame: 12 months
Quality of life in all three arms
We will compare Quality of life (QoL) in each arm by comparing the questionnaires filled out by subjects and their parents in each arm.
Time frame: 12 months
Clinical reactions
We will compare the presence of clinical reactions after food introduction at home in each arm. Clinical reactions could be anaphylaxis, rhinitis, atopic dermatitis and so forth.
Time frame: 12 months
Side effects
We will compare the presence of side effects after food introduction at home in each arm. Side effects could be development of unpleasant taste, refusal of other food, development of eosinophilic esophagitis and so forth.
Time frame: 12 months
IL-10-producing cow's milk specific regulatory T and B cells
We will study the induction of IL-10-producing cow's milk specific Treg cells and Breg cells in vitro paralleling tolerance induction. Blood samples are drawn at enrolment, at challenge and termination visit.
Time frame: Three times in 12 months
BATs to mimic the outcome of cow's milk provocation tests
We will study whether we can correlate the results of the in-house developed in vitro Basophil activation tests (BAT) with different heated cow's milk-containing extracts to the results of the cow's milk provocation test after 12 months. Blood samples are drawn at enrolment, at challenge and termination visit.
Time frame: Three times in 12 months
Plan to share: No
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