Study of Milk Allergy and Tolerance in Children

Food Hypersensitivity Clinical Trial

Official title:

Dietary Intervention in Milk Allergy and Tolerance Development

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00778258
• Other study ID #: DAIT AADCRC-MSSM-02
• Status: Completed
• Phase: Phase 2
• First received: October 21, 2008
• Last updated: March 29, 2016
• Start date: August 2008
• Est. completion date: November 2014

Study information

• Verified date: March 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: November 2014
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 4 Years to 10 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Food Hypersensitivity
• Hypersensitivity
• Milk Hypersensitivity

Intervention

Biological:
• 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.
• Non-baked Milk
Those subjects tolerant to rice pudding will undergo oral food challenge with non-baked milk.

Locations

Country	Name	City	State
United States	Mount Sinai School of Medicine	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Asthma and Allergic Diseases Cooperative Research Centers

Country where clinical trial is conducted

United States, 

References & Publications (4)

Nowak-Wegrzyn A, Bloom KA, Sicherer SH, Shreffler WG, Noone S, Wanich N, Sampson HA. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol. 2008 Aug;122(2):342-7, 347.e1-2. doi: 10.1016/j.jaci.2008.05.043. Epub 2008 Jul 11. — View Citation

Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007 Nov;120(5):1172-7. Epub 2007 Nov 1. — View Citation

Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy. 2007 Nov;62(11):1261-9. — View Citation

Vandenplas Y, Koletzko S, Isolauri E, Hill D, Oranje AP, Brueton M, Staiano A, Dupont C. Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child. 2007 Oct;92(10):902-8. Review. Erratum in: Arch Dis Child. 2008 Jan;93(1):93. Arch Dis Child. 2007 Oct;92(10):following 908. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Randomization through end of study (up to 36 months)	No
Secondary	Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 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.	12 months, 24 months	No
Secondary	Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, 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.	12 months, 24 months, and 36 months	No
Secondary	Percent of Participants Becoming Tolerant to Unheated Cow's Milk	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.	Randomization through end of study (up to 36 months)	No
Secondary	Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	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.	Baseline	No
Secondary	Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	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.	Baseline	No
Secondary	Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity	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.	Baseline	No
Secondary	Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance	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.	Randomization through end of study (up to 36 months)	No
Secondary	Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey	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.	Baseline, Month 12, Month 24, Month 36	No
Secondary	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	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.	Month 36	No
Secondary	Changes in Mechanistic Values [Humoral, T Cell and Basophil]	This outcome measure was not well defined in the protocol and was not analyzed.	Baseline, Month 12, Month 24, and Month 36	No
Secondary	Changes in Mechanistic Values [Humoral, T Cell and Basophil]	This outcome measure was not well defined in the protocol and was not analyzed.	Baseline to the time complete milk tolerance was established	No

External Links

•   Description of NIAID Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) Program