Specific Oral Tolerance Induction in Children Allergic to Cow’s Milk Proteins


Induction of oral tolerance in children allergic to cow's milk proteins is not risk-free. The analysis of factors that may influence the outcome is of utmost importance. The aim of the study is to analyse the efficacy and safety of the induction phase of oral tolerance induction according to specific IgE level, as well as adverse events during the maintenance phase. Patients allergic to cow's milk are to be included in an oral tolerance induction protocol. Patients will be grouped according to specific IgE levels in serum (ImmunoCAP) into group I (sIgE<3.5 kU/L), II (sIgE 3.5-17 kU/L) and III (>17-50kU/L). Allergic children with similar characteristics will included as a control group. Visits are established at 1, 6 and 12 months after the induction phase. Serum specific IgE levels to cow's milk and its proteins will be determined at inclusion, and at 6 and 12 months visits after the induction phase.

Full Title of Study: “Efficacy and Safety of Specific Oral Tolerance Induction in Children Allergic to Cow’s Milk Proteins According to Their Serum Specific IgE Level”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2011

Detailed Description

Children allergic to cow's milk proteins (CMA) will be included. They have to be diagnosed with CMA during the first year of life and have attended periodic follow-up visits to our Allergy Clinic at Hospital La Paz (Madrid, Spain). Clinical data on personal history of asthma, allergy to other foods and positive reactions upon cow's milk ingestion along with their evolution from initial diagnosis will be recorded. Prior to inclusion in the SOTI protocol, determination of serum specific IgE to cow's milk (CM), ALA, BLG and casein (ImmunoCAP, Phadia, Uppsala, Sweden) will be performed and current clinical status will be confirmed by oral food challenge (OFC) with cow's milk. An open OFC with CM (3 g of proteins per 100 mL) will be performed following a modified protocol according to the level of allergic sensitisation. Group I will start at a dose of 2 mL, and those in groups II and III started at a dose of 0.005 mL. In both protocols doses will be doubled until objective clinical reactivity is achieved. Determination of serum specific IgE to cow's milk and its proteins will be performed in the follow-up at 6 and 12 months visits. In order to evaluate the influence of the level of sensitisation in the result of SOTI, patients will be classified into three groups according to the level of sIgE for CM and/or its proteins: group I (0.35-3.5 kU/L, CAP Class I and II); group II (>3.5-17 kU/L, CAP Class III); group III (>17-50kU/L, CAP Class IV). The highest sIgE level against any of the CM or its proteins will determine the group of inclusion. A control group of cow's milk allergic children, with similar levels of sIgE, will be included in order to evaluate the natural evolution to tolerance in CMA. They will be followed for one year, after which, clinical reactivity with OFC will be again confirmed. These control patients will selected among those who, after the initial OFC, refuse to undergo SOTI. Specific Oral Tolerance Induction: The initial dose for SOTI will be the previous dose that elicited symptoms in the OFC. Group I doses will be upped weekly in the hospital setting, and patients will maintain that dose twice daily at home. Groups II and III also will start with the previous dose that elicited symptoms in the OFC, but will receive incremental doses daily in the hospital setting until they reach a dose of 1 mL. Achieving an intake of 200 mL of milk (6 g of proteins) twice a day, which is the usual amount for patients of that age, will be considered complete tolerance. Reactions occurring during the induction phase at the hospital will be treated according to the severity of symptoms. If patients present with mild non-objective symptoms, the same dose will be repeated. If the reaction is objective and limited to local symptoms, the previous dose will be given after the resolution of symptoms. If the reaction is generalised, involving two organ systems, SOTI will be continued with a dose which is two doses previous to the one that elicited symptoms. If the reaction involves three organ systems, the next dose administered will be reduced three steps in the dosage protocol. Written instructions will be given to parents regarding how to treat possible adverse reactions at home. After the induction phase, patients will continue to consume 200 mL milk twice daily and dairy products were allowed freely. In the maintenance phase, follow-up visits are scheduled at one month, six months and one year after finishing the induction phase. Data on tolerance of cow's milk and dairy products will be recorded. Adverse events upon ingestion will also be recorded.


  • Other: Cow’s milk
    • Group I: Increase 2 mL until 10 mL, 10 mL until 50 mL, 20 mL until 100 mL and 50 mL until 200 mL was reached. Groups II and III: Doubling dose until 1 mL, increase 2 mL until 20 mL, 5 mL until 50 mL, 10 mL until 100 mL and 20 mL until 200 mL was reached.

Arms, Groups and Cohorts

  • Active Comparator: Cow’s milk
  • No Intervention: Control group

Clinical Trial Outcome Measures

Primary Measures

  • Tolerance to cow’s milk
    • Time Frame: 12 months
    • After administration of 250ml of milk, the patient is evaluated to determined if the milk is tolerated or not.

Secondary Measures

  • Adverse events
    • Time Frame: 12 months

Participating in This Clinical Trial

Inclusion Criteria

-Patients diagnosed with cow's milk allergy meeting the following criteria: Immediate-type clinical manifestations, skin (urticaria, angioedema and/or erythema), digestive (acute vomiting and/or diarrhea) or respiratory (bronchospasm and/or rhinitis) involvement in the first two hours after cow's milk ingestion. Skin test readings ≥ 3 mm and specific IgE titers > 0.35 kU/l for whole cow's milk or someone of isolated CMPs (casein, alpha-lactalbumin, beta-lactoglobulin )

  • Age 4 years old or older – Specific IgE (measured by ImmunoCAP) lower than 50 KU/L for cow's milk or its proteins – Positive oral food challenge with a dose higher than 2 mL – Written informed consent signed by parents or legal representatives Exclusion Criteria:

  • Age younger than 4 y.o. – Specific IgE higher than 50 kU/L – Patients in whom oral food challenges is contraindicated, because of having a positive accidental reaction with moderate or severe symptoms in the previous 12 months prior to the inclusion.

Gender Eligibility: All

Minimum Age: 4 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Instituto de Investigación Hospital Universitario La Paz
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Carmen García-Ara, MD, PhD, Principal Investigator, Instituto de Investigación Sanitaria Hospital Universitario La Paz


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