Gluten Reduction and Risk of Celiac Disease

Autoimmune Diseases Clinical Trial

— GRAIN  

Official title:

Gluten Reduction After Infancy and Risk of Celiac Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04593888
• Other study ID #: 2020-00446
• Status: Active, not recruiting
• Phase: N/A
• Start date: May 5, 2021
• Est. completion date: December 31, 2035

Study information

• Verified date: May 2024
• Source: Lund University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1000
• Est. completion date: December 31, 2035
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 6 Months

Eligibility

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

Related Conditions & MeSH terms

• Autoimmune Diseases
• Celiac Disease
• Celiac Disease in Children
• type1diabetes

Intervention

Behavioral:
• Gluten reduced diet
Dietary advice focusing on reducing gluten intake in children

Locations

Country	Name	City	State
Sweden	Clinical Research Center (CRC), Bldng 60:11	Malmö

Sponsors (1)

Lead Sponsor	Collaborator
Lund University

Country where clinical trial is conducted

Sweden, 

References & Publications (5)

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 — View Citation

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 Hepat — View Citation

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 Pe — View Citation

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. 201 — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Islet autoimmunity	Children tested positive for typ1 1 diabetes related autoantibodies (IAA, GADA, IA2A) in two consecutive serum samples 3-6 months apart.	from 6 months of age up until 7 years of age
Primary	Celiac disease autoimmunity (CDA)	Children tested positive for tissue transglutaminase autoantibodies (tTGA) in two consecutive serum samples 3-6 months apart.	from 6 months of age up until 7 years of age
Secondary	Celiac disease (CD)	celiac disease diagnosed, defined by intestinal biopsy showing a Marsh score of >2 or by high levels of tTGA with symptoms.	from 6 months of age up until 7 years of age