Study of Milk Allergy and Tolerance in Children

Phase 2

Completed

Conditions: Food Hypersensitivity
Milk Hypersensitivity

Interventions: Biological: Baked Milk
Biological: Non-baked Milk

Registration Number: NCT00778258

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The purpose of this study is to determine if children who are allergic to milk can increase tolerance through frequent dose-escalation every 6 months versus 12 months leading to eventual tolerance of less heated milk and ultimately unheated milk.

Detailed Description: Milk is among the most common food allergens in infants and children. The majority of children outgrow their milk allergies; however, the exact mechanisms by which food tolerance is achieved are unknown. Strict avoidance of the offending food is currently the only known therapy. However, some have been known to tolerate milk products cooked at high heat such as when baked in foods.

This clinical trial involves a diet containing extensively baked milk protein to investigate the effects of ingestion of heat-denatured milk on development of oral tolerance to non-baked milk.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 170

Inclusion Criteria

One or more of the following inclusion criteria for enrollment in the study have to be met:

Convincing history of an allergic reaction to milk or a positive double blind placebo controlled milk challenge (DBPCMC) within the past 2 years and either detectable milk immunoglobulin E (IgE) or positive prick skin test to milk OR
Serum milk-IgE of high predictive value >14 kUa/L or prick skin test to milk > 10mm wheal within the past 6 months regardless of past clinical history of reactions OR
Convincing history of an allergic reaction to milk or a positive DBPCMC more than 2 years ago and either a positive serum milk-IgE < 14 kUA/L or positive prick skin test to milk < 10 mm wheal within the past 6 months (eligible only for the active arm of the study and will undergo a reversed sequence of initial baked-milk challenges)

Exclusion Criteria

Inability or unwillingness of a participant to give written informed consent or to comply with study protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Reacted to Non-baked Milk	Baked Milk	Subjects will be assigned to this arm, if they can tolerate ingesting a muffin, pizza and rice pudding but react to a standardized dose of non-baked milk. Within the arm, subjects will be randomized in 1:1 ratio to either return for re-evaluation at 6 months (Dose Escalation sub-arm) or 12 months (Maintenance sub-arm) to determine whether they might progress to ingesting higher amounts of baked milk protein.
Milk-allergic; Non-consumption	Baked Milk	Subjects in this arm reacted to the lowest baseline dose of baked milk (muffin) and will continue strict milk avoidance, returning for re-evaluation with laboratory tests at 12 and 24 months and baked milk challenge at 36 months. Individual participants may be challenged at 12 and or 24 months.
Tolerated Muffin, Reacted to Pizza	Baked Milk	Subjects will be assigned to this arm, if they can tolerate ingesting a muffin but react to ingesting the amount of baked milk in a standardized portion of pizza. Within the arm, subjects will be randomized in 1:1 ratio to either return for re-evaluation at 6 months (Dose Escalation sub-arm) or 12 months (Maintenance sub-arm) to determine whether they might progress to ingesting higher amounts of baked milk protein.
Reacted to Rice Pudding	Baked Milk	Subjects will be assigned to this arm, if they can tolerate ingesting a muffin and a standardized portion of pizza but react to a standardized dose of baked milk in rice pudding. Within the arm, subjects will be randomized in 1:1 ratio to either return for re-evaluation at 6 months (Dose Escalation sub-arm) or 12 months (Maintenance sub-arm) to determine whether they might progress to ingesting higher amounts of baked milk protein.
Tolerant to Baked and Non-baked Milk	Non-baked Milk	Biological/Vaccine: Baked Milk At baseline, each subject will undergo sequential oral food challenges with the products that contain increasing amounts of milk protein that are baked: Stage 1 (muffin), Stage 2 (pizza), and Stage 3 (rice pudding) doses of baked milk to determine the extent to which they tolerate various baked milk proteins. Based on the outcomes of the baseline oral food challenges, subjects will be assigned to one of the 5 study arms. Biological/Vaccine: Non-baked Milk Those subjects tolerant to rice pudding will undergo oral food challenge with non-baked milk.
Reacted to Non-baked Milk	Non-baked Milk	Subjects will be assigned to this arm, if they can tolerate ingesting a muffin, pizza and rice pudding but react to a standardized dose of non-baked milk. Within the arm, subjects will be randomized in 1:1 ratio to either return for re-evaluation at 6 months (Dose Escalation sub-arm) or 12 months (Maintenance sub-arm) to determine whether they might progress to ingesting higher amounts of baked milk protein.
Tolerant to Baked and Non-baked Milk	Baked Milk	Biological/Vaccine: Baked Milk At baseline, each subject will undergo sequential oral food challenges with the products that contain increasing amounts of milk protein that are baked: Stage 1 (muffin), Stage 2 (pizza), and Stage 3 (rice pudding) doses of baked milk to determine the extent to which they tolerate various baked milk proteins. Based on the outcomes of the baseline oral food challenges, subjects will be assigned to one of the 5 study arms. Biological/Vaccine: Non-baked Milk Those subjects tolerant to rice pudding will undergo oral food challenge with non-baked milk.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Positive Progression in Tolerance of Baked Milk and Ultimately Unheated Milk in Dose Escalation Sub-arm Compared to Maintenance Sub-arm	Randomization through end of study (up to 36 months)	Participants were grouped based on the food to which they experienced a reaction at the baseline Oral Food Challenge (OFC). Group 1=reacted to muffin; Group 2=reacted to pizza; Group 3=reacted to rice pudding; Group 4=reacted to non-baked milk; Group 5=did not react. Groups 2, 3, and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, participants performed an OFC where they were given food products containing milk protein denatured through baking. Participants were given progressively less denatured milk protein food items until they had an allergic reaction. Participants were considered to have a positive progression in tolerance of baked milk if they experienced a reaction to a less denatured milk protein food item at any post randomization visits than the one to which they reacted at their baseline visit.

Secondary Outcome Measures

Name	Time	Method
Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months	12 months, 24 months, and 36 months	Participants were grouped based on the food to which they experienced a reaction at the baseline Oral Food Challenge (OFC). Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Groups 2, 3 and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, participants performed an OFC where they were given food products containing milk protein denatured through baking. Participants were given progressively less denatured milk protein food items until they had an allergic reaction. Participants were considered to become tolerant to unheated cow's milk if at the specified visit, they did not react to any of the foods given in the OFC.
Percent of Participants Becoming Tolerant to Unheated Cow's Milk	Randomization through end of study (up to 36 months)	Participants were grouped based on the food to which they experienced a reaction at the baseline Oral Food Challenge (OFC). Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Groups 2, 3 and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, participants performed an OFC where they were given food products containing milk protein denatured through baking. Participants were given progressively less denatured milk protein food items until they had an allergic reaction. Participants were considered to become tolerant to unheated cow's milk if at any post-randomization visit up through 36 months, they did not react to any of the food given in the OFC.
Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	Baseline	This endpoint evaluates the correlation between the mechanistic biomarker of IgE to milk proteins and allergic reaction at baseline. Participants were grouped according to food at which participants experienced a reaction during their baseline oral food challenge: Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Quantitative IgE to milk proteins was done using FEIA (UniCAP) on serum from blood drawn at baseline.
Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	Baseline	This endpoint evaluates the correlation between the mechanistic biomarker of the number of basophils and T regulatory cells reactive to milk proteins and the food to which participants reacted at baseline. Participants were grouped according to food at which participants experienced a reaction during their baseline oral food challenge: Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Quantitative IgE to milk proteins was done using FEIA (UniCAP) on serum from blood drawn at baseline.
Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance	Randomization through end of study (up to 36 months)	Participants were grouped based on the food to which they experienced a reaction at the baseline Oral Food Challenge (OFC). Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Groups 2, 3 and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, participants performed an OFC where they were given food products containing milk protein denatured through baking. Participants were given progressively less denatured milk protein food items until they had an allergic reaction. Participants were considered to become tolerant to unheated cow's milk if at any post-randomization visit up through 36 months, they did not react to any food, including unheated whole milk.
Comparison of Percent of Participants Tolerant to Non-heated Milk Between the Participants Who Ingested Baked-milk Products and Participants Who Continued to Avoid All Forms of Milk	Month 36	Participants were grouped based on the food they reacted to, at the baseline Oral Food Challenge (OFC). Group 1= reacted to muffin; Group 2= reacted to pizza; Group 3= reacted to rice pudding; Group 4= reacted to non-baked milk; Group 5= did not react. Groups 2- 4 were randomized to dose escalation or maintenance, and Group 1, and a Control group that chose not to participate in the study, continued to avoid milk. Randomized participants performed an OFC at each visit during which they were given progressively less denatured/ baked milk protein food items until they had an allergic reaction. Participants were considered tolerant to unheated cow's milk if at any post-randomization visit up through 36 months, they did not react to any food, including unheated whole milk. Tolerance of non-heated milk was assessed by report among those who continued to avoid milk.
Changes in Mechanistic Values [Humoral, T Cell and Basophil]	Baseline to the time complete milk tolerance was established	This outcome measure was not well defined in the protocol and was not analyzed.
Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months	12 months, 24 months	Participants were grouped based on the food they experienced a reaction to at the baseline Oral Food Challenge (OFC). Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Groups 2, 3 and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, performed an OFC where food products containing milk protein denatured through baking were given. Participants were given progressively less denatured milk protein food items until an allergic reaction occurred. A positive progression in tolerance of baked milk was defined as a reaction to a less denatured milk protein food at 12 months than at baseline. Positive progression at 24 months was defined as experiencing a reaction to a less denatured milk protein food at 24 months than at 12 months.
Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	Baseline	This endpoint evaluates the correlation between the mechanistic biomarkers of basophil reactivity and the food to which participants reacted at baseline. Participants were grouped according to food at which participants experienced a reaction during their baseline oral food challenge: Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Basophils come from blood drawn at baseline. Basophils counts were done using whole blood specimens. Basophil reactivity as measured as maximal degranulation percentage after stimulation with titrated dilutions of milk powder (from 1x103 to 1x10-1 µg/mL total protein) and was correlated to group assignment using Spearman correlation coefficients.
Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey	Baseline, Month 12, Month 24, Month 36	Participants were grouped based on the food to which they experienced a reaction at the baseline Oral Food Challenge (OFC). Group 1 = reacted to muffin; Group 2 = reacted to pizza; Group 3 = reacted to rice pudding; Group 4 = reacted to non-baked milk; Group 5 = did not react. Groups 2, 3 and 4 were randomized to dose escalation or maintenance, and at each visit following randomization, participants performed an OFC where they were given food products containing milk protein denatured through baking. Participants were given progressively less denatured milk protein food items until they had an allergic reaction. The relationship between serum IgE to betalactoglobulin and casein, and the food level at which the participant reacted, were evaluated at each post randomization OFC visit. It is expected that those who reacted to muffin would have a higher ratio of casein to betalactoglobulin than those who reacted to less heated forms of milk.