Clinical Trial: Study of Milk Allergy and Tolerance in Children

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Dietary Intervention in Milk Allergy and Tolerance Development

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 Summary:

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.


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

Current Primary Outcome: 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 [ Time Frame: 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.


Original Primary Outcome: Ratio for progression in tolerance of baked milk and ultimately unheated milk in Dose escalation sub-arm compared to Maintenance sub-arm 2 [ Time Frame: Throughout study ]

Current Secondary Outcome:

  • Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months [ Time Frame: 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.
  • Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months [ Time Frame: 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 [ Time Frame: 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 Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity [ Time Frame: 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.
  • Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity [ Time Frame: 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 [ Time Frame: 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.
  • Odds ratio for progression in tolerating more allergenic forms of milk [ Time Frame: At Months 12 and 24 ]
  • Percent of participants becoming tolerant to unheated cow's milk [ Time Frame: At Months 12, 24, and 36 ]
  • Percent of participants who develop tolerance to unheated cow's milk [ Time Frame: Through 36 Months ]
  • Correlation of baseline mechanistic studies [humoral, T cell and basophil] and stool CD23 and IgE with the outcome of the baseline OFC to identify the biomarkers of clinical reactivity and persistence of milk allergy [ Time Frame: Throughout study ]
  • Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance [ Time Frame: Throughout study ]
  • Relationship between reactivity to casein versus whey fractions and time to complete tolerance [ Time Frame: Throughout study ]
  • Relationship between dose of baked-milk protein and reactivity to casein versus whey and type of symptoms elicited during OFC [ Time Frame: Throughout study ]
  • Comparison of percent of participants tolerant to non-heated milk protein between the participants in Arms 1 and 2 [ Time Frame: At Months 12, 24, and 36 ]
  • 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 [ Time Frame: Throughout the study ]


Information By: National Institute of Allergy and Infectious Diseases (NIAID)

Dates:
Date Received: October 21, 2008
Date Started: August 2008
Date Completion:
Last Updated: March 29, 2016
Last Verified: March 2016