Oral Immunotherapy in Cow's Milk Allergy (CMA) in Children : Petit Lait Study

Study Overview
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Brief Summary
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Prospective study Main objective: to evaluate the efficiency and the security of two protocols of immunotherapy (raw milk versus heated milk) in a cohort of children with persistent Immunoglobulin E (IgE) mediated CMA (IgE-CMA). Secondary objectives: to determinate if the enumeration of casein-specific IL-4- and IL-13-secreting T cells could be a valuable biomarker of successful immunotherapy.

Detailed Description
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The study prospectively included children aged older than 3 years, with an IgE-CMA. Children were part of the  Petit Lait  Study, led from June 2012 in the Allergology Department of Armand Trousseau Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), France Inclusion criteria All the children presenting with a diagnosis of IgE- CMA(defined as a history of reaction to the ingestion of cow's milk product and positive skin prick test (wheal ≥3 mm to cow's milk with no reaction to the negative control and specific IgE to casein >0.35 (kiloUnit) kU/l) and referred to one of the Allergology Department were offered to enter the study. Double-blind, placebo-controlled (DBPCFC) oral food challenge The DBPCFC was performed outside of episodes of exacerbation of acute illness. Children were admitted to the allergy clinic on two separate days, and food challenges were performed under the supervision of an experienced allergist. A peripheral intravenous line was inserted in each patient before starting the challenge, according to recommendations.Increasing doses of cow's milk were administered 20 min apart. Two protocols were available, one called  standard protocol  and one called hyperallergic protocol. Type of protocol was chosen before inclusion through a multidisciplinar and collegial manner. Challenge was stopped in case of a clinical reaction compatible with an allergic reaction. Antihistamine, methylprednisolone, bronchodilator or epinephrine was administered if necessary. Cumulative dose of cow's milk tolerated defined the reactive threshold in CMA children. Exclusion criteria Children who have presented an anaphylactic reaction during the previously year, who reacted with placebo during the DBPCFC or those with lacking consent or parents having difficulties to understand the protocol were excluded from the study. Oral Immunotherapy Phase Children were assigned by randomization to raw milk immunotherapy or heated milk immunotherapy. Prospective follow-up A monthly call was performed by a medical staff trained to allergology and families were asked on milk dose daily ingested at home and on eventual adverse side effects. A final DBPCFC using the standard protocol was planned once the daily dose attained 80 mL of raw milk. Biological markers Measurement of IgE and Immunoglobulin G4 (IgG4) against casein Measurement of Interleukin 4 (IL4) and Interleukin 13 (IL13) secreting lymphocyts by an Enzym Link ImmunoSpot (ELISpot) assay to cow's milk protein

Official Title
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Oral Immunotherapy in Cow's Milk Allergy (CMA) in Children : Petit Lait Study

Conditions
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Cow's Milk Allergy

Intervention / Treatment
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* Other: raw milk
* Other: Heated milk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All the children presenting with a diagnosis of IgE- CMA(defined as a history of reaction to the ingestion of cow's milk product and positive skin prick test (wheal ≥3 mm to cow's milk with no reaction to the negative control and specific IgE to casein >0.35 kU/l) Exclusion Criteria: Children who have presented an anaphylactic reaction during the previously year, who reacted with placebo during the DBPCFC or those with lacking consent or parents having difficulties to understand the protocol

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Raw milk<br>For raw milk immunotherapy (RMI), fixed dose of raw milk was daily administered at home, determined using tolerated threshold dose during the DBPCFC. Augmentation was made every 5 weeks in the allergy clinic. | Other: raw milk<br> <br> |
| Active Comparator: Heated milk<br>For heated milk immunotherapy (HMI), families were asked to weekly increase the daily dose of milk at home using industrial preparations. Milk included in the preparation was less and less heated among time. Passage from heated-milk to half-heated milk and then raw milk was performed in the allergy clinic. | Other: Heated milk<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Outcome: increased tolerance to cow's milk | daily unit dose in milliliters of milk ingested | 12 months | 
| Clinical Outcome: occurrence of allergic reaction to cow's milk | Number of patients with occurrence of allergic reaction; if yes, severity of allergic reaction evaluated using: Astier score; number of use of rescue medications such as: bronchodilator, anti-histaminics, systemic corticosteroids, epinephrin | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological Outcome: kinetics of specific IgE against casein | changes in blood level of specific IgE against casein | 12 months | 
| Biological Outcome: kinetics of specific IgG4 against casein | changes in blood level of specific IgG4 against casein | 12 months | 
| Biological Outcome: kinetics of IL4 secreting lymphocytes against casein | ELISPOT assay | 12 months | 
| Biological Outcome: kinetics of IL13 secreting lymphocytes against casein | ELISPOT assay | 12 months |