Impact of Infant Formula on Resolution of Cow's Milk Allergy

Study Overview
=================
Brief Summary
-----------------
Primary Endpoint -The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula. Secondary Endpoints Tolerance The transcriptional profile of milk-specific T cells by clinical outcome. Growth and Weight Velocity Stool Consistency and Frequency The estimated frequency of milk-specific T cells by clinical outcome. The TCR diversity of milk-specific T cells by clinical outcome. The milk allergen component-specific IgE, IgG4 and IgA by clinical outcome. Safety The rate of reported adverse events by treatment group.

Detailed Description
-----------------
Cow's Milk Allergy (CMA) is prevalent and most often presents during infancy. Disease manifestations vary through a range of immediate and delayed inflammatory responses to milk protein from anaphylaxis to enterocolitis. The natural history is also highly variable; most children will achieve clinical tolerance early in life, while a minority will have disease persisting to adulthood for reasons that are not known. Most presentations are mild and are managed by restriction or reduction of immunologically intact milk protein with reintroduction sometime after a year of age; however, there are data to suggest that some level of antigenic stimulation may be beneficial. Furthermore, recent data suggest that oral probiotic exposure may also promote tolerance, though the kinetics of tolerance acquisition, the interaction between these two factors (probiotics and milk antigen exposure) and their relationship to regulatory T cell responses are all poorly defined. Therefore, there is an unmet need to identify dietary interventions, along with corresponding immune responses, that favor the promotion of tolerance. A major objective will be to measure the effect probiotics have on the development of tolerance to milk antigen over time. By following these infants during the first year of life, and repeatedly collecting blood and stool samples from them, we will be poised to analyze their stool microbiome signatures, and we will estimate the frequency, phenotype and TCR diversity of milk-specific T cells over time. By repeatedly challenging them with more immunologically intact milk protein, we will better define the kinetics of CMA resolution and its association to these variables. This information is likely to further elucidate CMA disease mechanisms and identify possible biomarkers of disease resolution versus persistence. It will be directly useful for evaluating the efficacy of probiotics and hydrolyzed formula for promoting milk tolerance.

Official Title
-----------------
A Prospective Randomized Controlled Trial to Evaluate the Effect of Infant Formula on the Resolution of Cow's Milk Allergy of Infancy

Conditions
-----------------
Milk Allergy

Intervention / Treatment
-----------------
* Dietary Supplement: Lactobacillus GG
* Dietary Supplement: Extensively Hydrolyzed Casein Formula
* Dietary Supplement: Amino Acid Formula


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (to consent): Infants 0-120 days of age with suspected CMA, as determined by the pediatrician or specialist, will be referred to the study. A Standard Operating Procedures (SOP) document will be provided for the clinicians to help guide their referral to the study. Physician diagnosis of CMA will be based on the following: Physician documented, gross or persistent microscopic blood in stool (3 positive guaiac cards on three separate stools) in the absence of other explanation (e.g., fissure, moderate-to-severe constipation) AND / OR Infant with at least one gastrointestinal, dermatological, or respiratory allergic manifestation suggestive of CMA: Gastrointestinal: Chronic Diarrhea, Constipation or Vomiting/Gastro-esophageal reflux Dermatologic: Atopic Dermatitis or Urticaria Respiratory: Cough, Allergic rhinitis or Recurrent Wheezing General:Colic / Irritability No change in treatment with medications during the 7 days preceding the elimination diet and no expected change in medications during the DBPCFCs (unless otherwise medically necessary) Signed informed consent obtained for infants participation in the study Signed authorization obtained to use and/or disclose Protected Health Information for infant from birth through the length of the study period Willingness to comply with following inclusion criteria if found to have a positive DBPCFC screen: Caregiver(s) agree to comply with the infant elimination diet given to them by the investigator for the duration of the study Mother agrees to follow an elimination diet throughout duration of breast feeding Parent(s) or legally authorized representative agrees not to enroll infant in another interventional clinical study while participating in this study Inclusion Criteria (to randomization): Positive Double Blind Placebo Controlled Food Challenge (DBPCFC). Exclusion Criteria (to consent): History of anaphylaxis to milk Use of probiotics Use in the previous 4 weeks of systemic steroids Use of systemic immunomodulatory treatment, including biologics with an immune target such as Xolair Known eosinophilic GI disorders Episode(s) of severe repetitive vomiting and lethargy prompting an emergency room visit and occurring within 4 hours of ingesting a milk protein (i.e. consistent with FPIES) Co-existing autoimmune or other chronic disease or serious health problem, including celiac disease, inflammatory bowel disease, malignancy, congenital, metabolic or genetic disorders or malformations Intention to exclusively breast feed Infants born at less than 36 weeks gestation (35 weeks + 6 days is considered 35 weeks gestation) Exclusion Criteria (to randomization): Severe reaction to Milk Protein during the DBPCFC

Ages Eligible for Study
-----------------
Maximum Age: 120 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Amino Acid Formula<br> | Dietary Supplement: Amino Acid Formula<br>* Amino Acid Formula<br>|
| Active Comparator: EHCF<br>Extensively Hydrolyzed Casein Formula | Dietary Supplement: Extensively Hydrolyzed Casein Formula<br>* Extensively Hydrolyzed Casein Formula<br>|
| Active Comparator: EHCF + LGG<br>Extensively Hydrolyzed Casein Formula + Lactobacillus GG | Dietary Supplement: Lactobacillus GG<br>* Lactobacillus GG<br>Dietary Supplement: Extensively Hydrolyzed Casein Formula<br>* Extensively Hydrolyzed Casein Formula<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula. |  | 12 months post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by adverse events graded using the NCI-CTCAE scale by treatment group. | The rate of reported adverse events by treatment group. | 36 months | 
| Tolerance as assessed by the transcriptional profile of milk-specific T cells by clinical outcome. |  | 36 months | 
| Tolerance as assessed by weight for age Z-scores. |  | 36 months | 
| Tolerance as assessed by length for age Z-scores. |  | 36 months | 
| Tolerance as assessed by weight for length Z-scores. |  | 36 months | 
| Tolerance as assessed by stool consistency using the Bristol Stool Chart. |  | 36 months | 
| Tolerance as assessed by stool frequency. |  | 36 months | 
| Tolerance as assessed by changes in the stool microbiome. |  | 36 months | 
| Tolerance as assessed by the estimated frequency of milk-specific T cells by clinical outcome. |  | 36 months | 
| Tolerance as assessed by the TCR diversity of milk-specific T cells by clinical outcome. |  | 36 months | 
| Tolerance as assessed by the milk allergen component-specific IgE, IgG4 and IgA by clinical outcome. |  | 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
milk, allergy, tolerance