Food AllergyTEHITINCT06380673
Stepwise Heat-Denaturated Protein Introduction for Tolerance Induction in Food Allergy
A study testing Implementation of cow's milk in decreasingly heated forms and Implementation of heated cow's milk in people with Food Allergy and Cow Milk Allergy, run by Universitaire Ziekenhuizen KU Leuven at 5 sites in Belgium.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Food Allergy, Cow Milk Allergy
- What is being tested?
- Implementation of cow's milk in decreasingly heated forms and Implementation of heated cow's milk
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 5 sitesBelgium
- Study dates
- 22 Apr 2024to 30 Dec 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 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Children (1-18y) had or have a clinical diagnosis of IgE mediated cow's milk allergy based on positive history as well as skin prick testing and/or specific IgE detection by CAPtest in an allergy clinic.
- Children are at least 12 months old before introduction of heated cow's milk is considered.
- Children did not suffer from grade 4 anaphylaxis due to cow's milk-ingestion at presentation.
- Children have specific IgE levels to Bos d 8 below 1.2 kU/mL and/or children passed 20' cooked cow's milk provocation test executed on clinical judgement.
Who cannot join
- Children had grade 4 anaphylaxis due to cow's milk ingestion.
- Children are younger than 12 months old at the moment of passing 20' cooked cow's milk OFC.
- Parents are not able or not willing to adhere to a specific cow's milk protein-containing diet on a regular basis at home.
- Multiple food allergy, not compatible with any of the choices in the Flemish Milk Ladder.
- Parents and/or children are not willing to give IC/assent.
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
Belgium5 sites, 5 recruiting
- Recruiting
Imelda Hospital Bonheiden
Bonheiden
Katrien Coppens, MD
- Recruiting
AZ Sint-Jan
Bruges
Kate Sauer, MD
- Recruiting
AZ Maria Middelares
Ghent
Jasmine Leus, MD
- Recruiting
Jessa Hospital
Hasselt
Sophie Verelst, MD
- Recruiting
UZ Leuven Gasthuisberg
Leuven
Dominique MA Bullens, Prof. Dr., +32016343801, dominique.bullens@kuleuven.be
About this study
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).
Read the detailed description
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.
- Conditions
- Food Allergy, Cow Milk Allergy
- Being tested
- Implementation of cow's milk in decreasingly heated forms, Implementation of heated cow's milk, No intervention
- Medical subject headings
- Food Hypersensitivity, Milk Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Implementation of cow's milk in decreasingly heated formsOther
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 milkOther
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.
No interventionOther
Healthy subjects undergo no intervention.
| Study group | Role | What they receive |
|---|---|---|
| Stepwise introduction using gradually shorter heating of cow's milk proteins | Other | 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. Receives: Other: Implementation of cow's milk in decreasingly heated forms |
| Stepwise introduction using the Flemish Milk Ladder | Other | 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. Receives: Other: Implementation of cow's milk in decreasingly heated forms |
| Control arm with introduction of 20' cooked cow's milk | Other | Step 1: open introduction of 20' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 12 months. Receives: Other: Implementation of heated cow's milk |
| Healthy age-matched subjects | Other | For work package 2, 15 healthy age-matched subjects are included to compare immunological mechanisms with. Receives: Other: No intervention |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 12 months
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Three times in 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2024
- Study start22 Apr 2024
- Primary completion30 Dec 2028 (estimated)
- Study completion30 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Food AllergyStudies of the same condition, open and under way.
- More trials run by Universitaire Ziekenhuizen KU LeuvenThe 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
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitaire Ziekenhuizen KU Leuven
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dominque Bullens, Universitaire Ziekenhuizen KU Leuven
- Investigators
- Jasmine Leus, MD, Principal investigator, Maria Middelares Hospital, GentKatrien Coppens, MD, Principal investigator, Imelda Hospital, BonheidenSophie Verelst, MD, Principal investigator, KU Leuven and Jessa Hospital, HasseltKate Sauer, MD, Principal investigator, AZ Sint-Jan AV
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06380673
- Sponsor's protocol ID
- s68299
- Acronym
- TEHITI
- Status last verified
- May 2026
- First submitted
- 19 Mar 2024
- Last updated
- 8 May 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Stepwise Heat-Denaturated Protein Introduction for Tolerance Induction in Food Allergy
- ClinicalTrials.gov ID
- NCT06380673
- Acronym / sponsor ID
- TEHITI / s68299
- Conditions
- Food Allergy, Cow Milk Allergy
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- Universitaire Ziekenhuizen KU LeuvenUniversity, hospital or other
- Study start
- 22 Apr 2024 (actual)
- Primary completion
- 30 Dec 2028 (estimated)
- Study completion
- 30 Dec 2029 (estimated)
- First posted
- 24 Apr 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.
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).
Detailed description
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Stepwise introduction using gradually shorter heating of cow's milk proteins | Other | Other: Implementation of cow's milk in decreasingly heated formsStep 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. |
| Stepwise introduction using the Flemish Milk Ladder | Other | Other: Implementation of cow's milk in decreasingly heated formsThe 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. |
| Control arm with introduction of 20' cooked cow's milk | Other | Other: Implementation of heated cow's milkStep 1: open introduction of 20' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 12 months. |
| Healthy age-matched subjects | Other | Other: No interventionFor work package 2, 15 healthy age-matched subjects are included to compare immunological mechanisms with. |
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Children (1-18y) had or have a clinical diagnosis of IgE mediated cow's milk allergy based on positive history as well as skin prick testing and/or specific IgE detection by CAPtest in an allergy clinic.
- Children are at least 12 months old before introduction of heated cow's milk is considered.
- Children did not suffer from grade 4 anaphylaxis due to cow's milk-ingestion at presentation.
- Children have specific IgE levels to Bos d 8 below 1.2 kU/mL and/or children passed 20' cooked cow's milk provocation test executed on clinical judgement.
Key exclusion criteria (5 listed)
- Children had grade 4 anaphylaxis due to cow's milk ingestion.
- Children are younger than 12 months old at the moment of passing 20' cooked cow's milk OFC.
- Parents are not able or not willing to adhere to a specific cow's milk protein-containing diet on a regular basis at home.
- Multiple food allergy, not compatible with any of the choices in the Flemish Milk Ladder.
- Parents and/or children are not willing to give IC/assent.
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 |
|---|---|---|
| Implementation of cow's milk in decreasingly heated formsImplementation 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. | Other | Stepwise introduction using gradually shorter heating of cow's milk proteins, Stepwise introduction using the Flemish Milk Ladder |
| Implementation of heated cow's milkImplementation of heated cow's milk in cow's milk allergic subjects, tolerant to heated cow's milk, to assess the influence on tolerance induction. | Other | Control arm with introduction of 20' cooked cow's milk |
| No interventionHealthy subjects undergo no intervention. | Other | Healthy age-matched subjects |
Primary outcome
Complete cow's milk tolerance after 12 months of stepwise heated cow's milk introduction
Time frame: 12 months
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).
6 secondary outcomes
Time to complete tolerance in all three arms
Time frame: 12 months
Quality of life in all three arms
Time frame: 12 months
Clinical reactions
Time frame: 12 months
Side effects
Time frame: 12 months
IL-10-producing cow's milk specific regulatory T and B cells
Time frame: Three times in 12 months
BATs to mimic the outcome of cow's milk provocation tests
Time frame: Three times in 12 months
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 8 May 2026.
- Individual participant dataSharing planned: No
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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.
Jasmine Leus, MD principal investigator
Maria Middelares Hospital, Gent
Katrien Coppens, MD principal investigator
Imelda Hospital, Bonheiden
Sophie Verelst, MD principal investigator
KU Leuven and Jessa Hospital, Hasselt
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Implementation of cow's milk in decreasingly heated forms and Implementation of heated cow's milk in people with Food Allergy and Cow Milk Allergy, run by Universitaire Ziekenhuizen KU Leuven at 5 sites in Belgium.
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 4 inclusion and 5 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 8 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Belgium. 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 Dominique MA Bullens, Prof. MD (+32016343801, dominique.bullens@kuleuven.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Complete cow's milk tolerance after 12 months of stepwise heated cow's milk introduction (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 8 May 2026.