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

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.

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:

1. Caregiver(s) agree to comply with the infant elimination diet given to them by
the investigator for the duration of the study

2. Mother agrees to follow an elimination diet throughout duration of breast feeding

3. 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