Table 2.

Main trials evaluating safety and efficacy of different hydrolysed formulas in the treatment of CMA.

References	Type of Study	Subjects	Type of Formula	Intervention/ Follow-Up Duration	Outcomes	Results
Niggemann 2001 [33]	Multicentric RCT	N = 73 infants (median age, 5.7 months) with atopic dermatitis and CMA	EHWF vs. AAF	6 months	Severity of eczema (SCORAD) and growth (length, weight-for-length) measured as median at 3 and 6 months in each group	Both AAF and eHF resulted in a significant clinical improvement; AAF resulted in improved growth compared with eHF
Niggemann 2008 [34]	Multicentric RCT	N = 77 infants aged <12 months with suspected CMA	EHWF vs. AAF	6 months	Severity of eczema (SCORAD), allergic manifestation, growth (z-score for length, body weight, and head circumference at 28, 60, 90, and 180 days), adverse effects	No significant differences in growth measurements or allergy symptoms; SCORAD decrease in AAF group
Berni Canani 2017 [35]	Multicentric RCT	N = 65 infants aged 5–12 months, with strongly suspected CMA, or healthy controls	EHWF vs. AAF vs. healthy controls	12 months	Growth (z-score for body weight, length/height and head circumference at 3, 6 and 12 months	At 12 months, no significant difference in weight z-scores
Isolauri 1995 [36]	RCT	N = 45 infants (mean age: 6 months) with atopic dermatitis and CMA	EHWF vs. AAF	9 months	Growth (body weight and length), severity of eczema (mean SCORAD)	In both groups, atopic eczema improved significantly. Growth was adequate in both groups, though promoted only in AAF infants
Lasekan 2006 [31]	Randomized, blinded, prospective trial	N = 65 healthy infants	Partially hydrolysed rice protein-based formula fortified with lysine and threonine vs. standard intact cow’s milk protein-based formula	16 weeks	Growth, tolerance and plasma biochemistries	The two study groups had comparable growth, tolerance, and plasma biochemistry, despite some differences in amino acid profiles
Agostoni 2007 [32]	Randomized, prospective, comparative, unblinded trial	N = 160 infants fully breast- fed during the first 4 months of life and diagnosed with CMA within 6 months of age	Soy formula, eHF, hydrolysed rice-based formula vs. breastfed infants	6–12 months of age	growth indices	Infants fed hydrolysed products showed a trend toward higher weight-for-age z-score increments in the 6- to 12-month period
Reche 2010 [43]	Prospective open, randomized clinical study	N = 92 infants with IgE-mediated CMA	hydrolysed rice-based formula vs. EHF	24 months	Clinical tolerance	Both formulas were well tolerated. Growth parameters were similar between the two study groups
Vandenplas 2014 [44]	Prospective trial	N = 40 infants with CMA	Extensively hydrolysed rice-based formula	6 months	hypoallergenicity and safety	Symptoms significantly decreased in the first month of intervention; catch-up to normal weight gain as of the first month as well as a normalization of the weight-for-age, weight-for length, and BMI z-scores within the 6-month study period
Vandenplas 2014 [45]	Prospective trial	N = 39 infants with a confirmed CMA	Extensively hydrolysed rice-based formula	One month	Tolerance and growth	Extensively hydrolysed rice-based formula was tolerated by more than 90% of children with proven CMPA; and weight and length gains were normal
Rzehak 2011 [46]	Prospective, randomized, double-blind trial	N = 1840 full-term neonates with atopic heredity	pHF-W, eHF-W, eHF-C, CMF, breastfed	16 weeks and 10 years	differences in body mass index (BMI) over the first 10 years of life	No significant differences in BMI trajectories were shown between the study groups at 10 years of age