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Study of Milk Allergy and Tolerance in Children

This study has been completed.
Sponsor:
Collaborator:
Asthma and Allergic Diseases Cooperative Research Centers
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00778258
First received: October 21, 2008
Last updated: March 29, 2016
Last verified: March 2016
Results First Received: December 17, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Food Hypersensitivity
Milk Hypersensitivity
Interventions: Biological: Baked Milk
Biological: Non-baked Milk

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
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.
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 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.
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.
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.
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.
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.
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
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
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.

Participant Flow:   Overall Study
    Dose Escalation - Reacted to Pizza     Dose Escalation - Reacted to Rice Pudding     Dose Escalation - Reacted to Non-baked Milk     Maintenance - Reacted to Pizza     Maintenance - Reacted to Rice Pudding     Maintenance- Reacted to Non-baked Milk     Not Randomized – Comparison     Non-Randomized – Reacted to Muffin     Non-Randomized – Tolerant to Baked and Non-baked Milk  
STARTED     16     5     20     15     6     23     34     41     10  
COMPLETED     9     3     10     12     6     13     19     26     6  
NOT COMPLETED     7     2     10     3     0     10     15     15     4  
Adverse Event                 1                 0                 0                 0                 0                 1                 0                 0                 0  
Lost to Follow-up                 0                 0                 2                 0                 0                 3                 2                 2                 0  
Withdrawal by Subject                 6                 2                 8                 2                 0                 6                 12                 12                 4  
New Contraindication                 0                 0                 0                 0                 0                 0                 0                 1                 0  
Non-compliance                 0                 0                 0                 1                 0                 0                 0                 0                 0  
Unspecified                 0                 0                 0                 0                 0                 0                 1                 0                 0  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Enrolled

Reporting Groups
  Description
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.
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.
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.
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.
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.
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.
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
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
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.
Total Total of all reporting groups

Baseline Measures
    Dose Escalation - Reacted to Pizza     Dose Escalation - Reacted to Rice Pudding     Dose Escalation - Reacted to Non-baked Milk     Maintenance - Reacted to Pizza     Maintenance - Reacted to Rice Pudding     Maintenance- Reacted to Non-baked Milk     Not Randomized – Comparison     Non-Randomized – Reacted to Muffin     Non-Randomized – Tolerant to Baked and Non-baked Milk     Total  
Number of Participants  
[units: participants]
  16     5     20     15     6     23     34     41     10     170  
Age  
[units: years]
Mean (Standard Deviation)
  6.6  (2.3)     6.2  (1.6)     7.7  (2.1)     7.3  (2.2)     6.7  (2.7)     6.3  (2.1)     6.5  (2.3)     7.5  (1.9)     6.5  (2.2)     6.9  (2.2)  
Gender  
[units: participants]
                   
Female     4     1     7     3     3     6     11     12     5     52  
Male     12     4     13     12     3     17     23     29     5     118  
Ethnicity (NIH/OMB)  
[units: participants]
                   
Hispanic or Latino     0     0     0     0     0     0     0     0     0     0  
Not Hispanic or Latino     16     5     20     15     6     21     28     38     10     159  
Unknown or Not Reported     0     0     0     0     0     2     6     3     0     11  
Race (NIH/OMB)  
[units: participants]
                   
American Indian or Alaska Native     0     0     0     0     0     0     0     0     0     0  
Asian     2     1     1     2     0     3     0     5     1     15  
Native Hawaiian or Other Pacific Islander     0     0     0     0     0     0     0     0     0     0  
Black or African American     0     0     1     0     0     0     0     1     0     2  
White     14     4     18     13     6     18     28     31     9     141  
More than one race     0     0     0     0     0     0     0     1     0     1  
Unknown or Not Reported     0     0     0     0     0     2     6     3     0     11  
Region of Enrollment  
[units: participants]
                   
United States     16     5     20     15     6     23     34     41     10     170  
Baseline Boiled Milk Wheal [1]
[units: Mm]
Mean (Standard Deviation)
  7.3  (2.4)     6.1  (3.5)     6.6  (2.8)     7.6  (1.9)     7.6  (2.0)     5.5  (3.2)     7.7  (4.5)     7.9  (2.6)     3.4  (2.5)     6.9  (3.2)  
Baseline Milk Extract Wheal [1]
[units: Mm]
Mean (Standard Deviation)
  8.9  (2.4)     8.6  (1.2)     9.1  (3.4)     8.9  (2.8)     8.1  (2.7)     8.5  (3.4)     9.0  (3.8)     10.5  (3.7)     5.0  (2.6)     8.9  (3.4)  
Baseline Unheated Milk Wheal [1]
[units: Mm]
Mean (Standard Deviation)
  10.4  (4.2)     11.6  (4.2)     8.3  (2.5)     8.8  (2.3)     10.0  (2.7)     9.7  (4.0)     9.6  (4.3)     10.1  (2.6)     5.6  (2.8)     9.3  (3.4)  
Baseline Cow’s Milk IgE [2]
[units: kUa/L]
Mean (Standard Deviation)
  10.3  (11.5)     10.5  (7.8)     5.3  (5.4)     7.8  (9.7)     13.7  (13.1)     4.1  (4.5)     14.7  (21.3)     15.1  (12.7)     4.9  (8.1)     10.6  (13.6)  
[1] A skin prick test (SPT) measured the presence of immunoglobulin E (IgE) antibodies for the food tested. During the SPT, a drop of solution containing the food allergen was placed on the forearm. Using a small plastic needle, the skin was gently pricked or scratched to allow a tiny amount of the solution to enter just below the surface. After 15 minutes, positive results were indicated by a wheal, a raised white bump surrounded by a small circle of red skin. The wheal was measured in millimeters. Larger sizes indicated a greater chance of experiencing an allergic reaction to the food tested.
[2] When cow’s milk immunoglobulin E (IgE) antibodies are present in serum samples, this is indicative of a potential for an allergic reaction to cow’s milk. The greater the concentration of IgE antibodies present, the more likely an allergic reaction to cow’s milk is to occur.



  Outcome Measures
  Show All Outcome Measures

1.  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   [ Time Frame: Randomization through end of study (up to 36 months) ]

2.  Secondary:   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 ]

3.  Secondary:   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 ]

4.  Secondary:   Percent of Participants Becoming Tolerant to Unheated Cow's Milk   [ Time Frame: Randomization through end of study (up to 36 months) ]

5.  Secondary:   Comparison of Baseline Basophil Percent Maximal Degranulation With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity   [ Time Frame: Baseline ]

6.  Secondary:   Comparison of Baseline IgE With the Outcome of the Baseline OFC to Identify the Biomarkers of Clinical Reactivity   [ Time Frame: Baseline ]

7.  Secondary:   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 ]

8.  Secondary:   Relationship Between Initial Dose of Tolerated Baked-milk Protein and Time to Complete Tolerance   [ Time Frame: Randomization through end of study (up to 36 months) ]

9.  Secondary:   Relationship Between Dose of Baked-milk Protein and Reactivity to Casein Versus Whey   [ Time Frame: Baseline, Month 12, Month 24, Month 36 ]

10.  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   [ Time Frame: Month 36 ]

11.  Secondary:   Changes in Mechanistic Values [Humoral, T Cell and Basophil]   [ Time Frame: Baseline, Month 12, Month 24, and Month 36 ]

12.  Secondary:   Changes in Mechanistic Values [Humoral, T Cell and Basophil]   [ Time Frame: Baseline to the time complete milk tolerance was established ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Director, Clinical Research Operations Program
Organization: DAIT/NIAID
phone: 301-594-7669
e-mail: DAITClinicalTrialsGov@niaid.nih.gov


Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00778258     History of Changes
Other Study ID Numbers: DAIT AADCRC-MSSM-02
Study First Received: October 21, 2008
Results First Received: December 17, 2015
Last Updated: March 29, 2016
Health Authority: United States: Federal Government