Stepwise Heat-Denaturated Protein Introduction for Tolerance Induction in Food Allergy

NCT ID: NCT06380673

Last Updated: 2024-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-22
• Study Completion Date: 2029-12-30

Brief 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. 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.

Conditions

Food Allergy; Cow Milk Allergy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Stepwise introduction using gradually shorter heating of cow's milk proteins

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.

Group Type: OTHER

Implementation of cow's milk in decreasingly heated forms

Intervention Type: OTHER

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.

Stepwise introduction using the Flemish Milk Ladder

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.

Group Type: OTHER

Implementation of cow's milk in decreasingly heated forms

Intervention Type: OTHER

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.

Control arm with introduction of 20' cooked cow's milk

Step 1: open introduction of 20' cooked cow's milk (at least 10 mL per portion, 2-3X a week) for 12 months.

Group Type: OTHER

Implementation of heated cow's milk

Intervention Type: OTHER

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 age-matched subjects

For work package 2, 15 healthy age-matched subjects are included to compare immunological mechanisms with.

Group Type: OTHER

No intervention

Intervention Type: OTHER

Healthy subjects undergo no intervention.

Interventions

Implementation of cow's milk in decreasingly heated forms

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.

Intervention Type: OTHER

Implementation of heated cow's milk

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.

Intervention Type: OTHER

No intervention

Healthy subjects undergo no intervention.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: lead

Responsible Party

Dominque Bullens

Clinic Head in Pediatrics-Allergy at UZ Leuven, Head of the Allergy and Clinical Immunology Research group at KU Leuven (prof., dr.)

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jasmine Leus, MD

Role: PRINCIPAL_INVESTIGATOR

Maria Middelares Hospital, Gent

Katrien Coppens, MD

Role: PRINCIPAL_INVESTIGATOR

Imelda Hospital, Bonheiden

Sophie Verelst, MD

Role: PRINCIPAL_INVESTIGATOR

KU Leuven and Jessa Hospital, Hasselt

Kate Sauer, MD

Role: PRINCIPAL_INVESTIGATOR

AZ Sint-Jan AV

Locations

Imelda Hospital Bonheiden

Bonheiden, , Belgium

Site Status: RECRUITING

AZ Sint-Jan

Bruges, , Belgium

Site Status: RECRUITING

AZ Maria Middelares

Ghent, , Belgium

Site Status: RECRUITING

Jessa Hospital

Hasselt, , Belgium

Site Status: RECRUITING

UZ Leuven Gasthuisberg

Leuven, , Belgium

Site Status: RECRUITING

Countries

Belgium

Central Contacts

Dominique MA Bullens, Prof. MD

Role: CONTACT

dominique.bullens@kuleuven.be

+32016343801

Marleen Jannis

Role: CONTACT

marleen.jannis@uzleuven.be

+32016343801

Facility Contacts

Katrien Coppens, MD

Role: primary

Kate Sauer, MD

Role: primary

Jasmine Leus, MD

Role: primary

Sophie Verelst, MD

Role: primary

Dominique MA Bullens, Prof. Dr.

Role: primary

dominique.bullens@kuleuven.be

+32016343801

Other Identifiers

s68299

Identifier Type: -

Identifier Source: org_study_id