Food Hypersensitivity, Milk Hypersensitivity
Conditions
Keywords
Food Allergy, Milk Allergy
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.
Interventions
BIOLOGICALNon-baked Milk
Those subjects tolerant to rice pudding will undergo oral food challenge with non-baked milk.
BIOLOGICALBaked 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.
Sponsors
Asthma and Allergic Diseases Cooperative Research Centers
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 10 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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, Month 12, Month 24, and Month 36 | This outcome measure was not well defined in the protocol and was not analyzed. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation - Reacted to Pizza At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to pizza and were then randomized to return for re-evaluation every 6 months (dose escalation) to determine whether they might progress to ingesting higher amounts of baked milk protein. Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 16 |
| Dose Escalation - Reacted to Rice Pudding At baseline, participants performed an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to rice pudding and were then randomized to re-try less denatured milk protein food items every 6 months (dose escalation). Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 5 |
| Dose Escalation - Reacted to Non-baked Milk At baseline, participants performed an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to non-baked milk and were then randomized to re-try less denatured milk protein food items every 6 months (dose escalation). Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 20 |
| Maintenance - Reacted to Pizza At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to pizza and were then randomized to return for re-evaluation every 12 months (maintenance) to determine whether they might progress to ingesting higher amounts of baked milk protein. Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 15 |
| Maintenance - Reacted to Rice Pudding At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to rice pudding and were then randomized to continue eating the food at the same level of milk denaturalization and come in for OFCs every 12 months. Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 6 |
| Maintenance- Reacted to Non-baked Milk At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to rice pudding and were then randomized to continue eating the food at the same level of milk denaturalization and come in for OFCs every 12 months. Participants in this group received instructions for intake of baked milk foods at home and were followed up to 46 months. | 23 |
| Not Randomized - Comparison Participants in this group fulfilled inclusion criteria into the study but refused participation. These participants were used as comparison to other groups | 34 |
| Non-Randomized - Reacted to Muffin At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group reacted to muffin and were not randomized. Participants were instructed to avoid milk and return for re-evaluation with laboratory tests at 12 and 24 months and baked milk challenge at 36 months | 41 |
| Non-Randomized - Tolerant to Baked and Non-baked Milk At baseline, participants had an oral food challenge (OFC). They were given food containing milk protein denatured through baking. Participants were given progressively increasing quantities of less denatured milk protein foods until they had an allergic reaction. The food they experienced a reaction to was their baseline group. Participants in this group passed all OFCs without a reaction were not randomized. Participants were instructed to include full milk products to their diet for 3 months, followed by complete dietary milk elimination for 1 month. Participants were then re-challenged to unheated milk. Following successful challenge, participants were placed on an unrestricted milk diet and brought in for re-evaluation at 6 months. If participants were not successful in their challenge to unheated milk, they had baked milk products progressively re-introduced to their diets. | 10 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 0 | 0 | 3 | 2 | 2 | 0 |
| Overall Study | New Contraindication | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Non-compliance | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 2 | 8 | 2 | 0 | 6 | 12 | 12 | 4 |
Baseline characteristics
| Characteristic | Dose Escalation - Reacted to Rice Pudding | Total | Non-Randomized - Tolerant to Baked and Non-baked Milk | Non-Randomized - Reacted to Muffin | Not Randomized - Comparison | Maintenance- Reacted to Non-baked Milk | Dose Escalation - Reacted to Pizza | Maintenance - Reacted to Rice Pudding | Maintenance - Reacted to Pizza | Dose Escalation - Reacted to Non-baked Milk |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 6.2 years STANDARD_DEVIATION 1.6 | 6.9 years STANDARD_DEVIATION 2.2 | 6.5 years STANDARD_DEVIATION 2.2 | 7.5 years STANDARD_DEVIATION 1.9 | 6.5 years STANDARD_DEVIATION 2.3 | 6.3 years STANDARD_DEVIATION 2.1 | 6.6 years STANDARD_DEVIATION 2.3 | 6.7 years STANDARD_DEVIATION 2.7 | 7.3 years STANDARD_DEVIATION 2.2 | 7.7 years STANDARD_DEVIATION 2.1 |
| Baseline Boiled Milk Wheal | 6.1 Mm STANDARD_DEVIATION 3.5 | 6.9 Mm STANDARD_DEVIATION 3.2 | 3.4 Mm STANDARD_DEVIATION 2.5 | 7.9 Mm STANDARD_DEVIATION 2.6 | 7.7 Mm STANDARD_DEVIATION 4.5 | 5.5 Mm STANDARD_DEVIATION 3.2 | 7.3 Mm STANDARD_DEVIATION 2.4 | 7.6 Mm STANDARD_DEVIATION 2 | 7.6 Mm STANDARD_DEVIATION 1.9 | 6.6 Mm STANDARD_DEVIATION 2.8 |
| Baseline Cow's Milk IgE | 10.5 kUa/L STANDARD_DEVIATION 7.8 | 10.6 kUa/L STANDARD_DEVIATION 13.6 | 4.9 kUa/L STANDARD_DEVIATION 8.1 | 15.1 kUa/L STANDARD_DEVIATION 12.7 | 14.7 kUa/L STANDARD_DEVIATION 21.3 | 4.1 kUa/L STANDARD_DEVIATION 4.5 | 10.3 kUa/L STANDARD_DEVIATION 11.5 | 13.7 kUa/L STANDARD_DEVIATION 13.1 | 7.8 kUa/L STANDARD_DEVIATION 9.7 | 5.3 kUa/L STANDARD_DEVIATION 5.4 |
| Baseline Milk Extract Wheal | 8.6 Mm STANDARD_DEVIATION 1.2 | 8.9 Mm STANDARD_DEVIATION 3.4 | 5.0 Mm STANDARD_DEVIATION 2.6 | 10.5 Mm STANDARD_DEVIATION 3.7 | 9.0 Mm STANDARD_DEVIATION 3.8 | 8.5 Mm STANDARD_DEVIATION 3.4 | 8.9 Mm STANDARD_DEVIATION 2.4 | 8.1 Mm STANDARD_DEVIATION 2.7 | 8.9 Mm STANDARD_DEVIATION 2.8 | 9.1 Mm STANDARD_DEVIATION 3.4 |
| Baseline Unheated Milk Wheal | 11.6 Mm STANDARD_DEVIATION 4.2 | 9.3 Mm STANDARD_DEVIATION 3.4 | 5.6 Mm STANDARD_DEVIATION 2.8 | 10.1 Mm STANDARD_DEVIATION 2.6 | 9.6 Mm STANDARD_DEVIATION 4.3 | 9.7 Mm STANDARD_DEVIATION 4 | 10.4 Mm STANDARD_DEVIATION 4.2 | 10.0 Mm STANDARD_DEVIATION 2.7 | 8.8 Mm STANDARD_DEVIATION 2.3 | 8.3 Mm STANDARD_DEVIATION 2.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 159 Participants | 10 Participants | 38 Participants | 28 Participants | 21 Participants | 16 Participants | 6 Participants | 15 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 11 Participants | 0 Participants | 3 Participants | 6 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 15 Participants | 1 Participants | 5 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 11 Participants | 0 Participants | 3 Participants | 6 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 141 Participants | 9 Participants | 31 Participants | 28 Participants | 18 Participants | 14 Participants | 6 Participants | 13 Participants | 18 Participants |
| Region of Enrollment United States | 5 participants | 170 participants | 10 participants | 41 participants | 34 participants | 23 participants | 16 participants | 6 participants | 15 participants | 20 participants |
| Sex: Female, Male Female | 1 Participants | 52 Participants | 5 Participants | 12 Participants | 11 Participants | 6 Participants | 4 Participants | 3 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 118 Participants | 5 Participants | 29 Participants | 23 Participants | 17 Participants | 12 Participants | 3 Participants | 12 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 5 / 5 | 20 / 20 | 15 / 15 | 6 / 6 | 23 / 23 | 20 / 34 | 40 / 41 | 4 / 10 |
| serious Total, serious adverse events | 1 / 16 | 0 / 5 | 0 / 20 | 0 / 15 | 1 / 6 | 0 / 23 | 0 / 34 | 0 / 41 | 0 / 10 |
Outcome results
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.
Time frame: Randomization through end of study (up to 36 months)
Population: Randomized intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose-Escalation Group | 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 | 26 participants |
| Maintenance Group | 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 | 31 participants |
p-value: 0.5895% CI: [0.31, 1.93]Regression, Logistic
Secondary
Changes in Mechanistic Values [Humoral, T Cell and Basophil]
This outcome measure was not well defined in the protocol and was not analyzed.
Time frame: Baseline to the time complete milk tolerance was established
Population: Data were not collected and therefore no analyses could be performed.
Secondary
Changes in Mechanistic Values [Humoral, T Cell and Basophil]
This outcome measure was not well defined in the protocol and was not analyzed.
Time frame: Baseline, Month 12, Month 24, and Month 36
Population: Data were not collected and therefore no analyses could be performed.
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.
Time frame: Baseline
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose-Escalation Group | Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | 41.0 percentage of max basophil degranulation |
| Maintenance Group | Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | 29.3 percentage of max basophil degranulation |
| Group 4 - Milk | Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | 45.6 percentage of max basophil degranulation |
| Group 4 = Milk | Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | 20.3 percentage of max basophil degranulation |
| Group 5 = Passed All | Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | 8.9 percentage of max basophil degranulation |
p-value: 0.09Kruskal-Wallis
p-value: 0.01Spearman's Correlation
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.
Time frame: Baseline
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose-Escalation Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Beta-lactoglobulin IgE | 1.9 kUa/L |
| Dose-Escalation Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Cow's Milk IgE | 12.1 kUa/L |
| Dose-Escalation Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Casein IgE | 12.3 kUa/L |
| Maintenance Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Casein IgE | 4.1 kUa/L |
| Maintenance Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Beta-lactoglobulin IgE | 0.6 kUa/L |
| Maintenance Group | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Cow's Milk IgE | 5.4 kUa/L |
| Group 4 - Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Casein IgE | 5.6 kUa/L |
| Group 4 - Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Beta-lactoglobulin IgE | 1.3 kUa/L |
| Group 4 - Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Cow's Milk IgE | 7.7 kUa/L |
| Group 4 = Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Beta-lactoglobulin IgE | 0.4 kUa/L |
| Group 4 = Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Cow's Milk IgE | 3.5 kUa/L |
| Group 4 = Milk | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Casein IgE | 1.6 kUa/L |
| Group 5 = Passed All | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Casein IgE | 0.8 kUa/L |
| Group 5 = Passed All | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Beta-lactoglobulin IgE | 0.2 kUa/L |
| Group 5 = Passed All | Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Cow's Milk IgE | 0.9 kUa/L |
Comparison: Analysis on Betalactoglobulinp-value: <0.01Kruskal-Wallis
Comparison: Analysis on Betalactoglobulin IgEp-value: <0.01Spearman Correlation
Comparison: Analysis on Casein IgEp-value: <0.01Kruskal-Wallis
Comparison: Analysis on Casein IgEp-value: <0.01Spearman Correlation
Comparison: Analysis on Cow's Milk IgEp-value: <0.01Kruskal-Wallis
Comparison: Analysis on Cow's Milk IgEp-value: <0.01Spearman Correlation
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.
Time frame: Baseline
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose-Escalation Group | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Max Basophil Assessment | 1160.0 cells/µL |
| Dose-Escalation Group | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Tregs | 4.2 cells/µL |
| Maintenance Group | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Max Basophil Assessment | 717.0 cells/µL |
| Maintenance Group | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Tregs | 6.2 cells/µL |
| Group 4 - Milk | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Max Basophil Assessment | 1589.5 cells/µL |
| Group 4 - Milk | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Tregs | 7.5 cells/µL |
| Group 4 = Milk | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Tregs | 5.2 cells/µL |
| Group 4 = Milk | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Max Basophil Assessment | 934.0 cells/µL |
| Group 5 = Passed All | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Max Basophil Assessment | 524.0 cells/µL |
| Group 5 = Passed All | Comparison of Baseline Mechanistic Studies [Treg and Basophil] With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity | Tregs | 4.2 cells/µL |
Comparison: Analysis on Max Basophil Assessmentp-value: 0.01Kruskal-Wallis
Comparison: Analysis on Max Basophil Assessmentp-value: 0.22Spearman Correlation
Comparison: Analysis on Tregsp-value: 0.59Kruskal-Wallis
Comparison: Analysis on Tregsp-value: 0.32Spearman Correlation
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.
Time frame: Month 36
Population: Randomized and comparison participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose-Escalation Group | 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 | 48.2 percent participants |
| Maintenance Group | 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 | 0.0 percent participants |
| Group 4 - 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 | 0.0 percent participants |
Comparison: 36 Month Comparisonp-value: <0.01Chi-squared
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.
Time frame: 12 months, 24 months
Population: Randomized intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose-Escalation Group | Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months | Progressed at 12 Months | 18 participants |
| Dose-Escalation Group | Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months | Progressed at 24 Months | 23 participants |
| Maintenance Group | Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months | Progressed at 12 Months | 18 participants |
| Maintenance Group | Number of Participants With a Positive Progression in Tolerating More Allergenic Forms of Milk at 12 and 24 Months | Progressed at 24 Months | 27 participants |
Comparison: Progression comparison at 12 Monthsp-value: 0.7895% CI: [0.48, 2.68]Chi-squared
Comparison: Progression comparison at 24 Monthsp-value: 0.6295% CI: [0.34, 1.91]Chi-squared
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.
Time frame: Randomization through end of study (up to 36 months)
Population: Randomized intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose-Escalation Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk | 38.7 percentage of participants |
| Maintenance Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk | 54.5 percentage of participants |
| Group 4 - Milk | Percent of Participants Becoming Tolerant to Unheated Cow's Milk | 53.5 percentage of participants |
p-value: 0.41Chi-squared
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.
Time frame: 12 months, 24 months, and 36 months
Population: Randomized intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose-Escalation Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 12 Month | 29.3 percentage of participants |
| Dose-Escalation Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 24 Months | 43.9 percentage of participants |
| Dose-Escalation Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 36 Months | 53.7 percentage of participants |
| Maintenance Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 12 Month | 15.9 percentage of participants |
| Maintenance Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 24 Months | 29.5 percentage of participants |
| Maintenance Group | Percent of Participants Becoming Tolerant to Unheated Cow's Milk at 12, 24, and 36 Months | Tolerant at 36 Months | 43.2 percentage of participants |
Comparison: Comparison at 12 Monthsp-value: 0.14Chi-squared
Comparison: Comparison at 24 Monthsp-value: 0.17Chi-squared
Comparison: Comparison at 36 Monthsp-value: 0.33Chi-squared
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.
Time frame: Baseline, Month 12, Month 24, Month 36
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose-Escalation Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 24 Visit | 3.7 Ratio |
| Dose-Escalation Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Baseline | 4.6 Ratio |
| Dose-Escalation Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 12 Visit | 7.7 Ratio |
| Dose-Escalation Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 36 Visit | 4.6 Ratio |
| Maintenance Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 12 Visit | 3.0 Ratio |
| Maintenance Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Baseline | 4.6 Ratio |
| Maintenance Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 24 Visit | 3.3 Ratio |
| Maintenance Group | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 36 Visit | 2.5 Ratio |
| Group 4 - Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Baseline | 5.5 Ratio |
| Group 4 - Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 36 Visit | 5.1 Ratio |
| Group 4 - Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 12 Visit | 4.5 Ratio |
| Group 4 - Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 24 Visit | 4.8 Ratio |
| Group 4 = Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Baseline | 2.1 Ratio |
| Group 4 = Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 36 Visit | 1.1 Ratio |
| Group 4 = Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 24 Visit | 1.0 Ratio |
| Group 4 = Milk | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 12 Visit | 2.3 Ratio |
| Group 5 = Passed All | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 36 Visit | 2.3 Ratio |
| Group 5 = Passed All | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Baseline | 1.6 Ratio |
| Group 5 = Passed All | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 12 Visit | 2.2 Ratio |
| Group 5 = Passed All | Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey | Month 24 Visit | 2.6 Ratio |
Comparison: Baseline Comparisonp-value: 0.033Spearman Correlation
Comparison: Month 12 Comparisonp-value: 0.002Spearman Correlation
Comparison: Month 24 Comparisonp-value: 0.156Spearman Correlation
Comparison: Month 36 Comparisonp-value: 0.077Spearman Correlation
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.
Time frame: Randomization through end of study (up to 36 months)
Population: Randomized intent-to-treat participants who achieved tolerance
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-Escalation Group | Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance | 24.0 months | Standard Deviation 12.6 |
| Maintenance Group | Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance | 17.8 months | Standard Deviation 12.7 |
| Group 4 - Milk | Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance | 19.6 months | Standard Deviation 10.7 |
p-value: 0.5Kruskal-Wallis