{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:50:49Z","timestamp":1792457449408,"version":"4.5.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100030829","name":"Nestl\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100030829","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:p>Hydrolyzed rice formulas (HRF) are a suitable option for the nutritional management of non-breastfed children with cow\u2019s milk allergy (CMA). Human milk oligosaccharides (HMOs) enhance gastrointestinal health, promote the growth of beneficial gut microbiota, and may reduce the incidence of infections and antibiotic use. There is currently no evidence regarding the hypoallergenicity of HRF containing HMOs. The purpose of this study is to demonstrate the hypoallergenicity of a new hydrolyzed rice protein-based formula containing two manufactured HMOs (HRF-HMO). RIGHT-HY is a multi-center randomized controlled study enrolling infants and children (60 days\u20133 years) with documented Immunoglobulin E-mediated CMA. Children will be randomized in a crossover fashion to double-blind placebo-controlled food challenges (DBPCFC) with HRF-HMO and an amino acid-based formula (AAF)-HMO, followed by a 7-days open challenge with HRF-HMO requiring a daily minimum intake of 240 ml. Both formulas contain 2-fucosyllactose and lacto-N-neotetraose (1.5 g\/L). The primary objective is to demonstrate with 95% confidence that 90% of children with CMA do not develop allergic reactions to HRF-HMO under DBPCFC conditions. Up to 67 children will be enrolled to meet the hypoallergenicity criteria. This sample size allows for a 10% drop-out rate and occurrence of one allergic reaction. An interim analysis will be performed after 42 children have completed both food challenges to assess whether hypoallergenicity criteria have been met, in which case, the study will be stopped for success. Secondary endpoints include HRF-HMO intake and gastrointestinal tolerance during the week-long open challenge, and adverse events throughout the study. The RIGHT-HY study was approved by ethical committees of all participating sites. This study will be the first to generate robust evidence on the hypoallergenicity of this rice formula with added HMOs in children with CMA. The results of the study will be disseminated in peer-reviewed publications and presentations at scientific conferences.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Study protocol registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT06633289<\/jats:ext-link>\n                      , identifier NCT06633289.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1798624","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:35:17Z","timestamp":1776832517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoallergenicity of a hydrolyzed rice protein-based formula containing 2-fucosyllactose and lacto-N-neotetraose in children with cow\u2019s milk allergy: protocol for a randomized controlled study. The RIGHT-HY study"],"prefix":"10.3389","volume":"13","author":[{"given":"Boutaina","family":"Zemrani","sequence":"first","affiliation":[{"name":"Scientific Translation and Clinical Strategy Unit, Soci\u00e9t\u00e9 des Produits Nestl\u00e9 S.A.","place":["Vevey, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P.","family":"Hays","sequence":"additional","affiliation":[{"name":"Scientific Translation and Clinical Strategy Unit, Soci\u00e9t\u00e9 des Produits Nestl\u00e9 S.A.","place":["Vevey, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enza","family":"D\u2019Auria","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan","place":["Milan, Italy"]},{"name":"Allergy Unit, Buzzi Children\u2019s Hospital","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mori","sequence":"additional","affiliation":[{"name":"Allergy Unit, Meyer Children\u2019s Hospital IRCCS","place":["Florence, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Kalb","sequence":"additional","affiliation":[{"name":"Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noura","family":"Darwish","sequence":"additional","affiliation":[{"name":"Biostatistics, Clinical Research Unit, Nestl\u00e9 Research, Soci\u00e9t\u00e9 des Produits Nestl\u00e9 S.A.","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University Hospital of Parma","place":["Parma, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Brzozowska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Allergy, Copernicus Memorial Hospital, Medical University of Lodz","place":["Lodz, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urszula","family":"Jedynak-Wasowicz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s University Hospital, Jagiellonian University Medical College","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Beyer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Charit\u00e9 Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hania","family":"Szajewska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Medical University of Warsaw","place":["Warsaw, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Berni","family":"Canani","sequence":"additional","affiliation":[{"name":"Pediatric Allergy Program, Department of Translational Medical Science, University of Naples \u201cFederico II\u201d","place":["Naples, Italy"]},{"name":"ImmunoNutrition Lab, CEINGE Advanced Biotechnologies, University of Naples \u201cFederico II\u201d","place":["Naples, Italy"]},{"name":"NutriTechLab, University of Naples \u201cFederico II\u201d","place":["Naples, Italy"]},{"name":"European Laboratory for the Investigation of Food-Induced Diseases, University of Naples \u201cFederico II\u201d","place":["Naples, Italy"]},{"name":"Task Force for Microbiome Studies, University of Naples \u201cFederico II\u201d","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1097\/MPG.0000000000003897","article-title":"An ESPGHAN position paper on the diagnosis, management, and prevention of cow\u2019s milk allergy.","volume":"78","author":"Vandenplas","year":"2024","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"100888","DOI":"10.1016\/j.waojou.2024.100888","article-title":"World allergy organization (WAO) diagnosis and rationale for action against cow\u2019s milk allergy (DRACMA) guideline update - XII - recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA.","volume":"17","author":"Bognanni","year":"2024","journal-title":"World Allergy Organ J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1111\/all.12630","article-title":"Incidence and natural history of challenge-proven cow\u2019s milk allergy in European children\u2013EuroPrevall birth cohort.","volume":"70","author":"Schoemaker","year":"2015","journal-title":"Allergy."},{"key":"B4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/2045-7022-4-31","article-title":"Dietary elimination of children with food protein induced gastrointestinal allergy - micronutrient adequacy with and without a hypoallergenic formula?","volume":"4","author":"Meyer","year":"2014","journal-title":"Clin Transl Allergy."},{"key":"B5","first-page":"272","article-title":"Nutrient intake among two-year-old children on cows\u2019 milk-restricted diets.","volume":"89","author":"Henriksen","year":"2000","journal-title":"Acta Paediatr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2654","DOI":"10.3390\/nu12092654","article-title":"Hydrolyzed rice protein-based formulas, a vegetal alternative in cow\u2019s milk allergy.","volume":"12","author":"Dupont","year":"2020","journal-title":"Nutrients."},{"key":"B7","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.arcped.2019.03.001","article-title":"Efficacy and safety of hydrolyzed rice-protein formulas for the treatment of cow\u2019s milk protein allergy.","volume":"26","author":"Bocquet","year":"2019","journal-title":"Arch Pediatr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"100687","DOI":"10.1016\/j.waojou.2022.100687","article-title":"Managing food allergy: ga2len guideline 2022.","volume":"15","author":"Muraro","year":"2022","journal-title":"World Allergy Organ J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"926","DOI":"10.3390\/foods11070926","article-title":"Alternatives to Cow\u2019s milk-based infant formulas in the prevention and management of Cow\u2019s milk allergy.","volume":"11","author":"Maryniak","year":"2022","journal-title":"Foods."},{"key":"B10","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S1081-1206(10)62060-1","article-title":"Allergenicity of a hydrolyzed rice infant formula in a guinea pig model.","volume":"91","author":"Piacentini","year":"2003","journal-title":"Ann Allergy Asthma Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.arcped.2012.12.002","article-title":"[Growth and tolerance in infants fed an infant formula based on hydrolyzed rice proteins].","volume":"20","author":"Girardet","year":"2013","journal-title":"Arch Pediatr."},{"key":"B12","volume-title":"Commission Regulation (EU) 2023\/915 of 25 April 2023 on Maximum Levels for Certain Contaminants in Food and Repealing Regulation (EC) No 1881\/2006 (Text with EEA Relevance).","year":"2023"},{"key":"B13","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1111\/pai.12913","article-title":"Low inorganic arsenic in hydrolysed rice formula used for cow\u2019s milk protein allergy.","volume":"29","author":"Meyer","year":"2018","journal-title":"Pediatr Allergy Immunol."},{"key":"B14","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1542\/peds.106.2.346","article-title":"Committee on nutrition. hypoallergenic infant formulas.","volume":"106","year":"2000","journal-title":"Pediatrics."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1111\/all.12429","article-title":"EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.","volume":"69","author":"Muraro","year":"2014","journal-title":"Allergy."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1046\/j.1365-2222.2003.01781.x","article-title":"Tolerance to a rice hydrolysate formula in children allergic to cow\u2019s milk and soy.","volume":"33","author":"Fiocchi","year":"2003","journal-title":"Clin Exp Allergy."},{"key":"B17","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1111\/j.1365-2222.2006.02428.x","article-title":"A hydrolysed rice-based formula is tolerated by children with cow\u2019s milk allergy: a multi-centre study.","volume":"36","author":"Fiocchi","year":"2006","journal-title":"Clin Exp Allergy."},{"key":"B18","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1080\/07315724.2006.10719509","article-title":"Growth, tolerance and biochemical measures in healthy infants fed a partially hydrolyzed rice protein-based formula: a randomized, blinded, prospective trial.","volume":"25","author":"Lasekan","year":"2006","journal-title":"J Am Coll Nutr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1002\/jpn3.12161","article-title":"Growth pattern of paediatric patients affected by cow milk protein allergy fed with rice hydrolyzed formula.","volume":"78","author":"Nocerino","year":"2024","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1177\/147323000303100308","article-title":"Nutritional value of a rice-hydrolysate formula in infants with cows\u2019 milk protein allergy: a randomized pilot study.","volume":"31","author":"D\u2019Auria","year":"2003","journal-title":"J Int Med Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1007\/s00431-014-2308-4","article-title":"Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow\u2019s milk protein allergy.","volume":"173","author":"Vandenplas","year":"2014","journal-title":"Eur J Pediatr."},{"key":"B22","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1111\/j.1399-3038.2010.00991.x","article-title":"The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow\u2019s milk protein allergy.","volume":"21","author":"Reche","year":"2010","journal-title":"Pediatr Allergy Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1111\/j.1399-3038.2007.00566.x","article-title":"Growth of infants with IgE-mediated cow\u2019s milk allergy fed different formulas in the complementary feeding period.","volume":"18","author":"Agostoni","year":"2007","journal-title":"Pediatr Allergy Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1111\/apa.17159","article-title":"Rapid effectiveness of hydrolysed rice protein formulas on most digestive symptoms of infants.","volume":"113","author":"Jung","year":"2024","journal-title":"Acta Paediatr."},{"key":"B25","doi-asserted-by":"publisher","first-page":"162","DOI":"10.3390\/nu17010162","article-title":"Growth, safety and tolerance in infants fed rice protein hydrolysate formula: the GRITO randomised controlled trial.","volume":"17","author":"Lemoine","year":"2024","journal-title":"Nutrients."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.3390\/nu16121863","article-title":"Tolerance of infants fed a hydrolyzed rice infant formula with 2\u2019-Fucosyllactose (2\u2019-FL) Human milk oligosaccharide (HMO).","volume":"16","author":"Ramirez-Farias","year":"2024","journal-title":"Nutrients."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1093\/glycob\/cws074","article-title":"Human milk oligosaccharides: every baby needs a sugar mama.","volume":"22","author":"Bode","year":"2012","journal-title":"Glycobiology."},{"key":"B28","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1111\/jhn.12990","article-title":"Biology of human milk oligosaccharides: from basic science to clinical evidence.","volume":"35","author":"Sprenger","year":"2022","journal-title":"J Hum Nutr Diet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.3390\/nu13082737","article-title":"The mean of milk: a review of human milk oligosaccharide concentrations throughout lactation.","volume":"13","author":"Soyy\u0131lmaz","year":"2021","journal-title":"Nutrients."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e3196","DOI":"10.1128\/mBio.03196-19","article-title":"Linking human milk oligosaccharides, infant fecal community types, and later risk to require antibiotics.","volume":"11","author":"Berger","year":"2020","journal-title":"mBio."},{"key":"B31","doi-asserted-by":"publisher","first-page":"11422","DOI":"10.3390\/ijms241411422","article-title":"An extensively hydrolyzed formula supplemented with two human milk oligosaccharides modifies the fecal microbiome and metabolome in infants with Cow\u2019s milk protein allergy.","volume":"24","author":"Boulang\u00e9","year":"2023","journal-title":"Int J Mol Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1097\/MPG.0000000000001520","article-title":"Effects of infant formula with human milk oligosaccharides on growth and morbidity: a randomized multicenter trial.","volume":"64","author":"Puccio","year":"2017","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3390\/nu14030530","article-title":"Effects of an extensively hydrolyzed formula supplemented with two human milk oligosaccharides on growth, tolerability, safety and infection risk in infants with Cow\u2019s milk protein allergy: a randomized, multi-center trial.","volume":"14","author":"Vandenplas","year":"2022","journal-title":"Nutrients."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1016\/j.jaci.2012.10.017","article-title":"Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology-European academy of allergy and clinical immunology PRACTALL consensus report.","volume":"130","author":"Sampson","year":"2012","journal-title":"J Allergy Clin Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e8488","DOI":"10.2903\/j.efsa.2024.8488","article-title":"Update of the risk assessment of inorganic arsenic in food.","volume":"22","author":"EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk","year":"2024","journal-title":"EFSA J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1177\/0009922814557785","article-title":"Evaluation of hypoallergenicity of a new, amino acid-based formula.","volume":"54","author":"Nowak-W\u0119grzyn","year":"2015","journal-title":"Clin Pediatr."},{"key":"B37","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jaip.2019.09.029","article-title":"Conducting an oral food challenge: an update to the 2009 adverse reactions to foods committee work group report.","volume":"8","author":"Bird","year":"2020","journal-title":"J Allergy Clin Immunol Pract."},{"key":"B38","doi-asserted-by":"publisher","first-page":"S365","DOI":"10.1016\/j.jaci.2009.03.042","article-title":"Work group report: oral food challenge testing.","volume":"123","author":"Nowak-Wegrzyn","year":"2009","journal-title":"J Allergy Clin Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1097\/MPG.0000000000002153","article-title":"The Brussels infant and toddler stool scale: a study on interobserver reliability.","volume":"68","author":"Huysentruyt","year":"2019","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.1001\/jama.2022.21022","article-title":"Guidelines for reporting outcomes in trial reports: the CONSORT-outcomes 2022 extension.","volume":"328","author":"Butcher","year":"2022","journal-title":"JAMA."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1111\/all.12650","article-title":"Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model.","volume":"70","author":"Castillo-Courtade","year":"2015","journal-title":"Allergy."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1002\/eji.201847971","article-title":"Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells.","volume":"49","author":"Xiao","year":"2019","journal-title":"Eur J Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1159\/000323893","article-title":"Faecal microbiota and short-chain fatty acid levels in faeces from infants with cow\u2019s milk protein allergy.","volume":"156","author":"Thompson-Chagoyan","year":"2011","journal-title":"Int Arch Allergy Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"12500","DOI":"10.1038\/s41598-018-30428-3","article-title":"Gut microbiota composition and butyrate production in children affected by non-IgE-mediated cow\u2019s milk allergy.","volume":"8","author":"Berni Canani","year":"2018","journal-title":"Sci Rep."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1798624\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:35:28Z","timestamp":1776832528000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1798624\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":44,"alternative-id":["10.3389\/fnut.2026.1798624"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1798624","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]},"article-number":"1798624"}}