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JAMA. 2018 Jan 2;319(1):38-48. doi: 10.1001/jama.2017.19826.

Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Collaborators (646)

Mandrup-Poulsen T, Arjas E, Lernmark Å, Läärä E, Schmidt B, Krischer JP, Åkerblom HK, Hyytinen M, Knip M, Koski K, Koski M, Merentie K, Pajakkala E, Reunanen A, Salonen M, Terhonen T, Virkkunen S, Cuthbertson D, Gainer B, Hadley D, Krischer JP, Malloy J, Nallamshetty L, Shanke L, Bradley B, Dupré J, Mahon JL, Lough G, Fraser W, Lawson ML, Sermer M, Taback SP, Becker D, Franciscus M, Nucci A, Palmer J, Alahuhta K, Bärlund S, Korhonen T, Kovanen L, Lehtonen E, Niinistö S, Pekkala M, Sorkio S, Toivanen L, Vähätalo L, Virtanen SM, Uusitalo U, Öhman T, Bongiorno R, Catteau J, Fraser G, Howard N, Lloyd M, Crock P, Giles M, Siech K, Wong See D, Brown C, Catteau J, Craig M, Johnston A, Bere LJ, Clarson CL, Jenner M, Mahon JL, McManus R, Renato N, Lovell M, Higo D, Kent N, Kwan J, Marshall C, Metzger D, Chanoine JP, Stewart L, Thompson D, Edwards A, Lange I, Mercer J, Pacaud D, Josephine H, Schwarz, Stephure DK, Boer J, Chatur T, Chick C, Couch B, Demianczuk N, Girgis R, Marks S, Ryan E, Thompson M, Dean HJ, Grant L, Hamelin K, LaForte J, Murphy L, Catte D, Schneider C, Sellers EA, Taback SP, Woo V, Boland A, Bradley B, Clark HD, Cooper T, Gruslin A, Karovitch A, Keely E, Lawson ML, Lough G, Malcolm JC, Sauro V, Tawagi GF, Andrighetti S, Arnold G, Barrett J, Blumer I, Daneman D, Donat D, Ehrlich R, Feig D, Gottesman I, Gysler M, Karkanis S, Kenshole A, Knight B, Lackie E, Lewis V, Martin MJ, Maxwell C, Oliver G, Panchum P, Sermer M, Shilletto N, Simone A, Skidmore M, Turrini T, Wong S, Allen C, Bélanger L, Bouchard I, Ferland S, Frenette L, Garrido-Russo M, Leblanc M, Imbeault J, Morin V, Olivier G, Weisnagell J, Costain G, Dornan J, Heath K, MacSween MC, McGibbon A, Ramsay C, Sanderson F, Sanderson S, Benabdesselam L, Fraser W, Gonthier M, Huot C, Thibeault M, Laforte D, Legault L, Perron P, Armson A, Canning P, Cummings EA, Ivanko V, McLeod L, Mokashi A, Scott K, Bridger T, Crane J, Crummell C, Curtis JC, Dawson C, Joyce C, Newhook LA, Newman S, Druken E, Begum-Hasan J, Breen A, Houlden R, Woods M, Carrson G, Kelly S, Martel MJ, Penner M, Sankaran K, Hardy-Brown K, King N, White RA, Park M, Popkin J, Robson L, Coles K, Al Taji E, Cerna M, Cerny M, Francova H, Hainerova I, Kothankova H, Koukalova R, Krakorova V, Mendlova P, Sitova R, Stechova K, Vavrinec J, Vosahlo J, Zlatohlavkova B, Brazdova L, Faksova P, Gregorova D, Kantor L, Malkova K, Venhacova J, Venhacova P, Cipra A, Skvor J, Tomsikova Z, Botkova-Krauseova H, Mockova A, Paterová P, Gogelova P, Kandrnalova J, Einberg Ü, Jakovlev Ü, Posiadlo S, Rannaste E, Raukas R, Riikjärv MA, Valla K, Astover V, Kirss A, Ormisson A, Retpap J, Täht E, Tillmann V, Vahtra S, Åkerblom HK, Heikkilä M, Hirvasniemi M, Luopajärvi K, Johansson S, Kleemola P, Knip M, Laukkanen E, Parkkola A, Pigg HM, Puttonen H, Renlund M, Salonen K, Suomalainen H, Tenkula T, Teramo K, Järvenpää AL, Hämälainen AM, Jussila R, Kiiveri S, Haavisto H, Holopainen S, Kupiainen H, Leeve T, Lumme K, Nironen T, Salonen M, Tenhola S, Tiilikainen T, Keinonen H, Lautala P, Salonen P, Vesanto M, Aspholm AS, Asunta P, Ikävalko H, Jason E, Jäminki S, Kekki P, Koskinen M, Lehtimäki S, Lähde J, Mäkelä M, Peltoniemi S, Poutiainen L, Ranta K, Salonsaari T, Sarviharju-Tujula SL, Selvenius J, Siljander H, Haanpää PL, Holm C, Juutilainen A, Järveläinen V, Kangaskolkka-Keskilohko AM, Laino E, Marjamäki L, Suominen E, Ylitalo S, Hokkanen M, Lounamaa R, Matikainen M, Nuuja A, Paalanen I, Riikka Puupponen A, Salo-Edwards H, Alanne S, Kultti T, Linjama H, Muhonen K, Vääräniemi M, Talvitie T, Backman M, Hanhijärvi R, Koivula P, Lindström K, Martikainen A, Nurmi P, Björk A, Huopio H, Komulainen J, Lehtomäki S, Muikku E, Pesola J, Sankilampi U, Arkkola T, Hekkala A, Jurvakainen S, Koivikko ML, Kähönen M, Leinonen E, Mykkänen T, Pohjola H, Riikonen K, Niittyvuopio A, Stenius A, Tapanainen P, Veijola R, Alar A, Jovio S, Korpela P, Mäkinen E, Hietanen L, Kivistö J, Käär ML, Lehtimäki P, Mustila T, Popov E, Säätelä S, Taittonen L, Ahtiainen K, Laaksonen N, Luoto M, Viitala J, Virransalo R, Nykänen P, Paajanen S, Parkkinen S, Pyrhönen H, Särkkä T, Aschemeier B, Bektas S, Biester T, Danne T, Datz N, Deiss D, Fath M, Kordonouri O, Lüpke K, Müller B, Nestoris C, Rothes S, Sadeghian E, Semler K, Arató A, Krikovszky D, Madácsy L, Nobilis A, Szénási J, Benevento D, Beretta Anguissola G, Biagioni M, Bizzarri C, Cherubini V, Ferrito L, Giordano C, Giorgetti C, Manon Khazrai Y, Kyanvash S, Maddaloni E, Napoli A, Piergiovanni F, Pitocco D, Pozzilli P, Suraci T, Tabacco G, Valente L, Visalli N, Carboni MB, Cavallo R, Cau V, Isola C, Ledda A, Loddo M, Mannu C, Pettinau M, Pisano S, Porceddu M, Putzu C, Rita A, Songini M, de Beaufort C, Peters D, Schierloh U, Bruining J, Bisschoff M, Blonk L, Lappenschaar T, Manai B, Seesink M, Sperling-Conrad M, Verhagen M, Age Zoethout J, Basiak A, Chalas M, Chesiak M, Gramza A, Iwankiewicz J, Sieradzan E, Wasikowa R, Wikiera B, Ciechanowska M, Dziatkowiak H, Futona B, Górska A, Glowacka-Woźny M, Kaim I, Klich B, Starzyk J, Wolanin M, Tokarska L, Chucherco D, Deja G, Firek-Pedras M, Jarosz-Chobot P, Kalina M, Kutrowska-Adamusiak K, Minkina-Pedras M, Muchaka-Bianga M, Bodalski J, Mlynarski W, Szadkowska A, Cieslak A, Cypryk K, Dziatosz K, Jastzebowska J, Krysiak A, Szymanska U, Wilczyński J, Zawodniak-Szalapska M, Aguayo A, Bilbao JR, Castano L, Chueca M, Cortazar A, Echarte G, Gonzalez Frutos T, Jimenez P, Martul P, Moreno A, Oyarzabal M, Rica I, Salgado Y, Serrano-Ríos M, Martínez-Larrad MT, Hawkins FG, Hernández R, Herranz L, Pallardo LF, Saez de Ibarra L, Huidobro Fernandez B, Leon Luis J, Ortíz-Quintana L, Pintado Recarte P, Rodriguez Arnau D, Aronsson L, Bodén S, Fredriksson J, Isacsson E, Johansson I, Karlsson E, Lock C, Ludvigsson J, Sandström AM, Smolinska Konefal M, Andreasson C, Dahlström U, Hanas R, Lundqvist K, Windell L, Jansson I, Karlsson AK, Lindbladh B, Odenman I, Pettersson C, Sundberg F, Sundqvist M, Aronsson S, Bellman I, Bengtsson AB, Lydén GB, Nilsson NÖ, Söderblom M, Unt C, Augustsson M, Bengtsson M, Fors H, Helmrich A, Osland Johansson T, Andersson AC, Boiard-Stömlid A, Hellgren G, Källsholm H, Lindqvist J, Nilsson M, Nordwall M, Strömstedt C, Åhsberg C, Lindh A, Lindhe C, Samuelsson C, Wiik A, Edenwall H, Ljumgcrantz M, Persson IB, Strigard E, Svensson BL, Åman J, Breivik GE, Detlofsson IL, Kroon M, Särnblad S, Johansson C, Ilvered R, Lundberg A, Åkesson K, Beccarelli A, Gadient M, Konrad D, Rappold-Amrein C, Schoenle E, Becker D, Daftary A, Damagro-Elias ME, Franciscus M, Gilmour C, Klein MB, Lain C, Nucci A, Salerno D, Smith ME, Vats K, Jones Pfaff D, Malone P, Mansfield P, Munns M, Nickel K, Palmer J, Pompilio K, Siemion W, Taculad R, Van Horn K, Zdanadewic M, Chambliss C, Jones J, Sadler M, Tanner-Blasiar M, White N, Bell C, Camper N, Devaskar S, Devaskar U, Horowitz H, Rogers L, Shannahan R, Silk K, Bermudez Z, Colon R, Frazer T, Martinez-Nieves B, Torres J, Vega J, Chan M, Cook S, Goland R, Greenberg E, Jules N, Montes J, Nelson M, Parra-Valencia Z, Schachner H, Softness B, Ilonen J, Kiviniemi M, Suomenin R, Alexander A, Hyrckowian E, Nichol L, Trucco M, Karjalainen E, Louhio T, Sarnesto A, Savilahti E, Valtonen E, Davydova B, Helander S, Hämäläinen J, Härkönen T, Joutsjoki L, Kararic M, Knip M, Latva-Koivisto M, Lönn E, Nurmi T, Ollila I, Rinkinen J, Ronkainen M, Tukiainen H, Cederlöf A, Kiikeri M, Luopajärvi K, Tsupari S, Vaarala O, Cheng R, Bryant K, Chan Y, Dosch HM, Maezawa Y, Paltser G, Rasavi R, Tsui H, Winer S, Wu P, Yantha J.

Abstract

Importance:

Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas.

Objective:

To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children.

Design, Setting, and Participants:

An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017.

Interventions:

The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age.

Main Outcomes and Measures:

Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events).

Results:

Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group).

Conclusions and Relevance:

Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes.

Trial Registration:

clinicaltrials.gov Identifier: NCT00179777.

PMID:
29297078
PMCID:
PMC5833549
DOI:
10.1001/jama.2017.19826
[Indexed for MEDLINE]
Free PMC Article

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