New Combination Treatment Promoted Milk Tolerance After Switching from Amino Acid-Based Formula


IgE-mediated children with cow’s milk allergies switching from amino acid-based formula to a new formula showed strong tolerance and better acquisition of immune tolerance, suggesting other studies combining treatments may be useful.

Roberto Berni Canani, MD, PhD


Roberto Berni Canani, MD, PhD


Switching from amino acid-based formula (AAF) to an extensively hydrolyzed casein formula (EHCF) supplemented with the probiotic ‘L.rhamnosus GG (EHCF+LGG) in immunoglobulin E (IgE)-mediated children with allergy to cow’s milk protein (CMA) promotes faster immune tolerance acquisition, according to new findings.1

The findings were the results of the Step-Down Approach for Cow's Milk Allergy (SDACMA) trial and the research was authored by Roberto Berni Canani, MD, PhD, from the Department of Translational Medical Science at the University of Naples Federico II in Italy.

The study “was designed to evaluate in a prospective clinical trial the rate of tolerability of EHCF+LGG in children with IgE-mediated CMA treated with AAF, and to investigate the potential effect on immune tolerance acquisition of switching to EHCF+LGG in CMA pediatric patients previously treated with AAF,” Canani and colleagues wrote.

The team noted that prior studies had found that CMA children may have a reaction to residual allergens in EHCF, but they added that data remained conflicted before SDACMA.2

Background and Findings

The investigators conducted the SDACMA study as a randomized, double-blind, parallel-arm trial. They carried out the study at a tertiary center for pediatric allergy between February of 2018 and December of 2020.

The study evaluated the efficacy and safety of an EHCF+LGG in infants with IgE-mediated CMA who were specifically not breastfed and previously placed on an AAF by their physicians.

The investigators’ exclusion criteria included various medical conditions, participation in other studies, and uncertainty about the subject's ability or willingness to comply with the protocol requirements. They used 3 parallel teams for the trial: the Multidisciplinary Pediatric Allergy Team, the Research Team, and the Statistical Team.

The investigators used procedures such as skin prick tests (SPT) to cow's milk proteins, raw cow's milk, and EHCF+LGG, followed later by a double-blind, placebo-controlled food challenge with EHCF+LGG or the AAF previously used.

The investigators observed the infants for 2 hours following the final dose and then they were discharged. They gathered data on the infants' symptoms, total amount of formula ingested, types of foods eaten, and other related information.

The investigators recruited participants that had negative oral food challenges (OFC) to EHCF+LGG. These study participants were randomized into 2 groups: The first group remained on the AAF while the second group switched to EHCF+LGG.

The study was blinded and the participants’ families were instructed on how to implement a cow milk protein-free diet with both oral and written instructions. Compliance was judged to be acceptable by the investigators in the presence of >80% recommended formula intake.

Anthropometric measurements were gathered, and a new double-blind placebo-controlled food challenge with cow’s milk protein was performed after 12 months of dietary treatment to evaluate the acquisition of immune tolerance to cow’s milk proteins. Unscheduled visits were conducted if required due to allergic symptoms or other morbidities.

Overall, the investigators had enrolled 60 children with IgE-mediated CMA, and among those treated with AAF, 98% were found to have tolerated the first exposure of EHCF+LGG. The rate of immune tolerance acquisition to cow milk proteins following 12 total months of treatment was also found to be higher in the EHCF+LGG arm (48%) compared to the AAF arm (3%).

Additionally, the investigators noted that the EHCF+LGG arm showed an absolute benefit increase of about 45% (corresponding to a number needed to treat of 2) for tolerance rate versus the AAF arm. Both study groups showed a normal body growth pattern.

“This discrepancy could be due to several factors including the study design, the simultaneous evaluation of different extensively hydrolysed cow’s milk proteins formulas, the patients feature, and the evaluation procedures adopted in these studies,” they wrote.


  1. Nocerino R, Coppola S, Carucci L, Severina AFGDS, Oglio F, De Michele R, Di Sessa I, Masino A, Bedogni G, Berni Canani R. The Step-Down approach in children with Cow's Milk Allergy: results of a randomized controlled trial. Allergy. 2023 Apr 23. doi: 10.1111/all.15750. Epub ahead of print. PMID: 37087638.
  2. Dupont C, Chouraqui JP, Linglart A, Bocquet A, Darmaun D, Feillet F, et al. Committee on Nutrition of the French Society of Pediatrics. Nutritional management of cow's milk allergy in children: An update. Arch Pediatr. 2018;25:236-243.
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