Clinical Versus Home Introduction of Milk in Children with Non-IgE-mediated Cow's Milk Allergy (ENIGMA)

Evaluation of the Outcome of Clinical or Home Introduction of Milk in Children with Non-IgE-mediated Cow's Milk Allergy (ENIGMA Trial)

There are a lot of parents who believe that their child may not tolerate cow's milk because they develop symptoms such as redness of the skin or they may vomit. It is not always easy to find out if these infants should indeed avoid drinking cow's milk or that the symptoms are caused by something else, for instance because they have a viral illness. The goal of the investigators is to find out if cow's milk should be introduced in the hospital or if it can also be advised to perform the introduction at home to determine if an infant can drink cow's milk without developing symptoms. Half of the participants will drink cow's milk in the hospital. This test is performed on two days. On one of the days cow's milk will be offered. On the other day a look-alike substance is offered. The other half of the participants will drink cow's milk at home by starting to drink a little bit of milk and in a few steps drink a normal bottle of cow's milk. The main question is whether both tests can be used to find out if an infant can drink cow's milk without developing symptoms.

Study Overview

• Status: Recruiting
• Conditions: Cow Milk Allergy; Food Allergy
• Intervention / Treatment: Diagnostic test: Cow's milk; Diagnostic test: Placebo; Diagnostic test: Home introduction

Detailed Description

Cow's milk allergy (CMA) is the most common food allergy among infants. CMA can be divided into immunoglobin E (IgE) and non-IgE-mediated allergy. In case of IgE-mediated allergy, symptoms occur within two hours after ingestion, and are potentially life-threatening. In patients without sensitisation, symptoms may occur up to 48 hours after ingestion and predominantly affect the gastrointestinal tract and skin. The gold standard to diagnose a cow's milk allergy is to perform a double-blind placebo controlled food challenge (DBPCFC). Determination of DBPCFC outcome for non-IgE-mediated allergy can be challenging due to delayed presentation of symptoms after the DBPCFC has been performed. Furthermore, in the majority of infants with non-IgE-mediated cow's milk allergy, symptoms are mild and therefore introduction under medical supervision is superfluous. To date, there is no validated diagnostic to confirm a diagnosis of non-IgE-mediated cow's milk allergy and potential over diagnosis is due to the overlap of symptoms with other common diseases in infants.

The aim of this study is to compare the outcome of an adjusted DBPCFC and introduction at home of cow's milk for children with a suspected non-IgE-mediated cow's milk allergy

Patients with a suspected cow's milk allergy will be randomized to a DBPCFC or home introduction of cow's milk after sensitisation for cow's milk has been excluded and parents have not reported severe symptoms during introduction of cow's milk. Outcome of both introduction methods will be based on predefined criteria. For patients with a negative outcome of the test unrestricted exposure to cow's milk is recommended. In case of a positive outcome, parents are recommended to gradually increase the amount of cow's milk in their child's diet by means of the "milk ladder". During regular follow-up visits the investigators will inquire whether introduction of cow's milk is successful and if needed motivate parents to continue further introduction. Number of all consultations will be registered.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kamps, MD,PhD; Phone Number: 31505246900; Email: a.kamps@mzh.nl
• Study Contact Backup: Name: van der Pluijm, RN; Phone Number: 31505245984; Email: F.vanderPluijm@mzh.nl

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Recruiting
    • Martini Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• maximum age of eighteen months;
• suspected to be allergic for cow's milk (based on medical history);

Exclusion Criteria:

• children older than the age of eighteen months;
• sensitised for cow's milk (i.e. SPT >3mm (in combination with positive control ≥3mm) or specific IgE >0.35 kU/L)
• patient suffers from acute (i.e. within one hour after cow's milk had been eaten) and moderate-severe IgE-mediated symptoms after ingestion of cow's milk
• patient suffers from symptoms according to the FPIES criteria after ingestion of cow's milk
• patient uses beta blockers and/or prednisolone;
• patient suffers from uncontrolled respiratory symptoms or severe eczema or a chronic condition because of which the patients cannot be included as judged by the treating physician;
• parents are unable to adequately report the occurrence of possible symptoms (e.g. insufficient language proficiency).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Double blind placebo controlled challenge test; Introduction of cow's milk by means of an adjusted double blind placebo controlled challenge test	Diagnostic test: Cow's milk; clinical introduction of cow's milk; Other Names: Oral food challenge test; Diagnostic test: Placebo; clinical introduction of placebo; Other Names: Oral food challenge test
Active Comparator: Home introduction test; Introduction of cow's milk by means of a standardized schedule	Diagnostic test: Home introduction; home introduction of cow's milk

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with a positive or negative test	Positive (intolerant) or negative (tolerant) outcome of the introduction test	Determined 1 week after start of the test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regular milk consumption	Milk consumption is based on normal daily intake for age	Determined 6 weeks after completion of the test
Percentage and type of reported symptoms	Reported symptoms are classified according to predefined criteria	Determined 6 weeks after completion of the test
Healthcare utilisation during the study period	Healthcare utilisation is determined by evaluation of the number of physical and telephone consultations	Determined 6 weeks after completion of the test

Collaborators and Investigators

• Sponsor: Martini Hospital Groningen
• Investigators: Principal Investigator: Kamps, MD, PhD, Martini Ziekenhuis Groningen

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: February 24, 2023
• First Submitted That Met QC Criteria: March 24, 2023
• First Posted (Actual): March 27, 2023

Study Record Updates

• Last Update Posted (Estimated): November 25, 2024
• Last Update Submitted That Met QC Criteria: November 21, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Food Hypersensitivity; Milk Hypersensitivity
• Other Study ID Numbers: ABR 83741

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol and data will be shared upon request
• IPD Sharing Time Frame: Data will be analysed after all patients have ended the study period.
• IPD Sharing Access Criteria: Request by mailing principal investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No