Gluten Reduction and Risk of Celiac Disease (GRAIN)

• ClinicalTrials.gov Identifier: NCT04593888
• Recruitment Status: Recruiting
• First Posted: October 20, 2020
• Last Update Posted: January 24, 2024
• Sponsor: Lund University
• Information provided by (Responsible Party): Lund University

Study Description

Brief Summary:

Celiac disease shares many features of other autoimmune diseases such as type 1 diabetes. Recently, it was published that higher amounts of gluten intake increased the risk for celiac disease. Optimal amounts of gluten to be introduced during weaning have not yet been established. The aim is to investigate if a gluten-restricted diet (e.g. below 3 gram per day) during the first 3 years of life will reduce the risk of develop CDA and IA in genetically predisposed children by the age of 7 years. Children who screened positive for HLA DQ2/X (X is neither DQ2 nor DQ8) in the GPPAD-02 (ASTR1D [ClinicalTrials.gov Identifier NCT03316261]) screening will be contacted by a study nurse.

Condition or disease	Intervention/treatment	Phase
Celiac Disease in Children; Autoimmune Diseases; type1diabetes	Behavioral: Gluten reduced diet	Not Applicable

Detailed Description:

Gluten is a complex mixture of proteins, mainly gliadin and glutenin, rich in proline and glutamine amino acids which make these proteins resistant to complete degradation by enzymes in the small intestinal. Intolerance to gluten leads to inflammation of the intestinal epithelium and villous atrophy, a disorder called celiac disease. Celiac disease shares many features of other autoimmune diseases such as type 1 diabetes (T1D). First, celiac disease is associated with certain HLA genotypes of whom 95% of all patients with celiac disease carry the haplotypes DQA1*0501-DQB1*0201 (abbreviated DQ2) and the reminder 5% DQA1*0301-DQB1*0302 (abbreviated DQ8). There is a gene dose effect of HLA-DQ on the risk of develop celiac disease; 20% of the children homozygous for HLA-DQ2/DQ2 will develop celiac disease by 10 years of age. Second, celiac disease is also strongly associated with the presence of autoantibodies directed against tissue transglutaminase (tTGA) that occurs in 100% of children with celiac disease. Timing of gluten introduction and breastfeeding duration have previously been proposed to influence risk for celiac disease. However, based on the results from the multinational birth cohort study The Environmental determinants of Diabetes in the Young (TEDDY) study and other observational studies, timing of gluten introduction seems not associated with celiac disease in genetically at-risk children. In an RCT, introduction of small amounts of gluten at the age of 4-6 months did not reduce the risk for celiac disease by the age of 3 years in genetically at-risk children. Current international infant feeding recommendations recommend that gluten is introduced into the infant's diet anytime between 4-12 months of age and that consumption of large quantities of gluten should be avoided during the first month after gluten introduction and during infancy. Recently, the TEDDY study published that higher amounts of gluten intake increased the risk for celiac disease, which have been confirmed in two other observational cohort studies. In the TEDDY study, daily gluten intake was associated with higher increased risk of developing persistently positive tTGA, a definition coined celiac disease autoimmunity (CDA), as well as with celiac disease for every 1-g/day increase in gluten intake. Optimal amounts of gluten to be introduced during weaning have not yet been established. It is well known that an overlap between celiac disease and T1D exists most likely due to shared genetic risks of HLA-DQ2 and/or DQ8 in both disorders. Prospective studies in infants genetically predisposed to T1D and celiac disease showed that antibody positivity to both disorders begins in the first 1-3 years of life. The study aim is to investigate if a gluten-restricted diet during the first 3 years of life will reduce the risk of develop CDA and IA in genetically predisposed children by the age of 7 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: study participants will be randomized to either the "gluten-reduced" or "no intervention" arm on-going after enrolment.
• Primary Purpose: Prevention
• Official Title: Gluten Reduction After Infancy and Risk of Celiac Disease
• Actual Study Start Date: May 5, 2021
• Estimated Primary Completion Date: December 31, 2025
• Estimated Study Completion Date: December 31, 2035

Arms and Interventions

Arm	Intervention/treatment
No Intervention: No intervention; The group will be followed without any intervention, with regular visits at the research clinic.
Experimental: Gluten reduced diet; Subjects will follow a diet that does not exceed a daily intake of 3 gram gluten. The group will be followed with regular visits at the research clinic.	Behavioral: Gluten reduced diet; Dietary advice focusing on reducing gluten intake in children

Outcome Measures

Primary Outcome Measures :

1. Celiac disease autoimmunity (CDA) [ Time Frame: from 6 months of age up until 7 years of age ]
   Children tested positive for tissue transglutaminase autoantibodies (tTGA) in two consecutive serum samples 3-6 months apart.

Secondary Outcome Measures :

1. Celiac disease (CD) [ Time Frame: from 6 months of age up until 7 years of age ]
   celiac disease diagnosed, defined by intestinal biopsy showing a Marsh score of >2 or by high levels of tTGA with symptoms.

Other Outcome Measures:

1. Islet autoimmunity [ Time Frame: from 6 months of age up until 7 years of age ]
   Children tested positive for typ1 1 diabetes related autoantibodies (IAA, GADA, IA2A) in two consecutive serum samples 3-6 months apart.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 6 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• children screened positive for HLA DQ2/X (X is neither DQ2 or DQ8)
• children who refused enrolment to the on-going study PreSiCe (ClinicalTrials.gov Identifier NCT03562221)

Exclusion Criteria:

• congenital chronic disorder where intervention with diet may be affected
• written informed consent from both caregivers are missing

Contacts and Locations

Contacts

Contact: Carin Andrén Aronsson, PhD; +46 40391113; carin.andren_aronsson@med.lu.se

Locations

Sweden

Clinical Research Center (CRC), Bldng 60:11; Recruiting

Malmö, Sweden, 20502

Contact: Carin Andrén Aronsson, PhD +46 40391113 carin.andren_aronsson@med.lu.se

Sponsors and Collaborators

Lund University

Investigators

• Principal Investigator: Daniel Agardh, MD, PhD; Lund University

More Information

Publications of Results:

Andren Aronsson C, Lee HS, Hard Af Segerstad EM, Uusitalo U, Yang J, Koletzko S, Liu E, Kurppa K, Bingley PJ, Toppari J, Ziegler AG, She JX, Hagopian WA, Rewers M, Akolkar B, Krischer JP, Virtanen SM, Norris JM, Agardh D; TEDDY Study Group. Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk. JAMA. 2019 Aug 13;322(6):514-523. doi: 10.1001/jama.2019.10329.

Marild K, Dong F, Lund-Blix NA, Seifert J, Baron AE, Waugh KC, Taki I, Stordal K, Tapia G, Stene LC, Johnson RK, Liu E, Rewers MJ, Norris JM. Gluten Intake and Risk of Celiac Disease: Long-Term Follow-up of an At-Risk Birth Cohort. Am J Gastroenterol. 2019 Aug;114(8):1307-1314. doi: 10.14309/ajg.0000000000000255.

Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, Kolacek S, Koletzko S, Korponay-Szabo IR, Mummert E, Polanco I, Putter H, Ribes-Koninckx C, Shamir R, Szajewska H, Werkstetter K, Greco L, Gyimesi J, Hartman C, Hogen Esch C, Hopman E, Ivarsson A, Koltai T, Koning F, Martinez-Ojinaga E, te Marvelde C, Pavic A, Romanos J, Stoopman E, Villanacci V, Wijmenga C, Troncone R, Mearin ML. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014 Oct 2;371(14):1304-15. doi: 10.1056/NEJMoa1404172.

Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri S, Barbato M, Barbera C, Barera G, Bellantoni A, Castellano E, Guariso G, Limongelli MG, Pellegrino S, Polloni C, Ughi C, Zuin G, Fasano A, Catassi C; SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition) Working Group on Weaning and CD Risk. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014 Oct 2;371(14):1295-303. doi: 10.1056/NEJMoa1400697.

Andren Aronsson C, Lee HS, Koletzko S, Uusitalo U, Yang J, Virtanen SM, Liu E, Lernmark A, Norris JM, Agardh D; TEDDY Study Group. Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort. Clin Gastroenterol Hepatol. 2016 Mar;14(3):403-409.e3. doi: 10.1016/j.cgh.2015.09.030. Epub 2015 Nov 25.

• Responsible Party: Lund University
• ClinicalTrials.gov Identifier: NCT04593888
• Other Study ID Numbers: 2020-00446
• First Posted: October 20, 2020
• Last Update Posted: January 24, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lund University:

gluten; diet

Additional relevant MeSH terms:

Celiac Disease; Autoimmune Diseases; Metabolic Diseases; Immune System Diseases; Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases