Improving the Safety of Oral Immunotherapy for Cow's Milk Allergy

Study Overview
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Brief Summary
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Allergy to cow's milk is the most common food allergy affecting children. There is currently no accepted routine clinical therapy to cure milk allergy. Recently studies have attempted to induce desensitisation using small daily doses of cow's milk, predominantly by the oral route (oral immunotherapy, OIT). Although this therapy works for some people, its effects are not generally long lasting and it is associated with significant side effects during protocol, including potentially life-threatening allergic reactions. Pilot data suggests that sublingual immunotherapy (SLIT, where allergen is held under the tongue, rather than swallowed) can also induce a degree of desensitisation, but with fewer adverse events. However, the degree of desensitisation induced appears to be lower than that with oral immunotherapy. The investigators wish to determine whether a sublingual pretreatment phase can improve the safety of conventional OIT in cow's milk allergy.

Official Title
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Phase 2/3 Clinical Trial to Assess the Effect of a Sublingual Treatment Phase Prior to Oral Immunotherapy in Children With Cow's Milk Allergy

Conditions
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Food Allergy

Intervention / Treatment
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* Other: SLIT to cow's milk
* Other: Low dose OIT
* Other: Conventional OIT to cow's milk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Allergic to 1.44g CM protein (approx. 40ml fresh milk) or less, at DBPCFC prior to randomisation Informed consent of parent/legal guardian, patient assent where possible Exclusion Criteria: Required previous admission to an intensive care unit for management of an allergic reaction. Significant symptoms of non---IgE---mediated CM allergy within the previous 12 months. Children with a past history of CM allergy currently consuming CM-containing products other than extensively--heated milk in baked foods (e.g. biscuits, cakes). Poorly controlled asthma within the previous 3 months (as defined by clinician judgement with reference to the ICON consensus), or asthma requiring treatment with >5 days oral corticosteroids within the previous 3 months. Moderate---severe eczema, defined as requiring more than once daily application of 1% hydrocortisone as maintenance treatment despite appropriate use of emollients (eczema is not otherwise an exclusion criteria) Clinically significant chronic illness (other than asthma, rhinitis or eczema) History of symptoms of eosinophilic oesophagitis, irrespective of cause Undergoing specific immunotherapy to another allergen and within the first year of treatment. Receiving anti--IgE therapy, oral immunosuppressants, beta---blocker or ACE inhibitor. Pregnancy Unwilling or unable to fulfil study requirements

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SLIT followed by Conventional OIT<br>Participants will receive up to 7 months of SLIT followed by 6 months conventional OIT to cow's milk | Other: SLIT to cow's milk<br>* Sublingual immunotherapy<br>Other: Conventional OIT to cow's milk<br>* Oral Immunotherapy<br>|
| Active Comparator: Conventional OIT<br>Participants will receive up to 7 months of low dose OIT, followed by 6 months conventional OIT to cow's milk | Other: Low dose OIT<br>* Oral Immunotherapy (low dose)<br>Other: Conventional OIT to cow's milk<br>* Oral Immunotherapy<br>|
| Placebo Comparator: Delayed start OIT<br>Participants will receive up to 7 months placebo, followed by 6 months conventional OIT to cow's milk | Other: Conventional OIT to cow's milk<br>* Oral Immunotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events in participants | Proportion of participants experiencing adverse events (excluding mild, non-transient symptoms) conventional OIT to cow's milk in phase 2, in those who have received SLIT pretreatment compared to placebo. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Incidence of adverse events experienced (including rate of withdrawals, and anaphylaxis/adrenaline use during updosing) | 1 year | 
| Eliciting dose(mg cow's milk protein) at DBPCFC after each phase of immunotherapy | Efficacy defined at Double-blind, placebo-controlled food challenge (DBPCFC) as the proportion of study participants experiencing: No symptoms (or only mild transient symptoms) to 8 grams CM protein (approx. 250mls fresh milk) (Complete desensitisation) No symptoms (or only mild transient symptoms) to at least 1.4 grams CM protein (approx. 45mls fresh milk) (Partial desensitisation) At least a 10--fold increase in eliciting dose (defined as the lowest dose which elicits objective symptoms or signs at challenge). …at 6 and 12 months in the different treatment groups | 1 year | 
| Change in Health-related quality of life (HRQL) from baseline - assessed using FAQLQ - after each phase of immunotherapy | Change in HRQL measures at 6, 12 and 15 months from baseline, as assessed in study participants and their parent/carer using the following validated questionnaire: - Food Allergy Quality of Life Questionnaires (FAQLQ) | 15 months | 
| Change in Health-related quality of life (HRQL) from baseline - assessed using FAIM - after each phase of immunotherapy | Change in HRQL measures at 6, 12 and 15 months from baseline, as assessed in study participants and their parent/carer using the following validated questionnaire: - Food Allergy Independent Measure (FAIM) | 15 months | 
| Change in Health-related quality of life (HRQL) from baseline - assessed using Change in EQ-5D from baseline - after each phase of immunotherapy | Change in HRQL measures at 6, 12 and 15 months from baseline, as assessed in study participants and their parent/carer using the following validated questionnaire: - EQ-5D - a standardized instrument for use as a measure of health outcome. | 15 months | 
| Change in self-efficacy after each phase of immunotherapy | Change in self-efficacy at 6, 12 and 15 months from baseline, as assessed in study participants and their parent/carer using validated questionnaire. | 15 months | 
| Immunological outcomes | Change in skin prick test wheal (mm), end-point titration skin prick test, allergen-specific IgE (KuA/l) between baseline and post immunotherapy | 12 months | 
| Immunological outcome: skin prick test | Change in skin prick test wheal (mm) and end-point titration skin prick test between baseline and post immunotherapy | 12 months | 
| Immunological outcomes: Allergen-specific IgE | Change in allergen-specific IgE (KuA/l) between baseline and post immunotherapy | 12 months | 
| Peptide microarray | Trend in CM-peptide binding during OIT | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cow's milk allergy, Desensitisation, Safety