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Celiac DiseaseCADER2NCT06500754

Persistent Villous Atrophy in Celiac Disease Patients Following an Intentionally Strict Gluten-free Diet

An observational study of Celiac Disease and Villous Atrophy of Intestine, run by Hospital Mutua de Terrassa at 1 site in Spain.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

Celiac disease (CD) is an immune-mediated disease characterized by small intestinal inflammation from gluten ingestion, a group of proteins present in various cereals, including wheat, rye, barley, spelt, and kamut. Read more about this study

Who is it for?
Ages 20 to 80 years
Conditions the study is for
Celiac Disease, Villous Atrophy of Intestine
What is being tested?
Ultra-strict gluten-free diet
How many people
80 participants
Where
1 siteSpain
Study dates
1 Jan 2022to 1 Jan 2027
Phase
Observational
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Celiac Disease patients from the participating hospitals

Who may be able to join

  • Age at diagnosis 18 years or more.
  • Diagnosis of CD with villous atrophy, positive serology and clinical and serological response to GFD.
  • To be in a GFD for at least 2 years, with good adherence to it.
  • Negative or positive anti-transglutaminase (tTG2) IgA antibodies at low titers (<2 times the normal value) at recruitment.
  • Written informed consent.

Who cannot join

  • Refractory CD (RCD) type 2 and type 1
  • Other associated intestinal diseases (inflammatory bowel disease, microscopic colitis, other types of enteropathies).
  • Need for treatment with corticosteroids or immunosuppressants.
  • Surgeries or other diseases predisposing to bacterial overgrowth in the small intestine.
  • Pregnancy, lactation.
  • Associated chronic diseases (lung, heart, kidney, liver cirrhosis).
  • Alcoholism or drug addiction.
  • Schizophrenia-type psychiatric diseases, other psychoses, bipolar.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Spain1 site, 1 recruiting
  • Hospital Universitari MútuaTerrassa

    Terrassa, Barcelona, 08221

    Yamile Zabana, MD, PhD, yzabana@gmail.com

    Recruiting

Other trials in Spain

About this study

Official title: Study of the Causes and Consequences of Persistent Villous Atrophy Despite an Intentionally Strict Gluten-free Diet in Celiac Disease Patients - Effect of an Ultra-strict Gluten-free Diet on Persistent Villous Atrophy

Celiac disease (CD) is an immune-mediated disease characterized by small intestinal inflammation from gluten ingestion, a group of proteins present in various cereals, including wheat, rye, barley, spelt, and kamut. CD is the most common chronic gastrointestinal disease and one of the most common autoimmune disorders, estimated to affect 0.4-1.7% of the general population. Currently, a strict lifelong gluten-free diet (GFD) is the only available treatment to avoid the inappropriate inflammatory response and prevent the shortening of the villi lining the small intestine (villous atrophy). However, a significant proportion of CD patients, ranging from 4% to 79%, show persistent villous atrophy despite following an intentional GFD. The causative factors and the clinical consequences of persistent villous atrophy in CD patients are not well known yet but might resemble untreated CD long-term complications.

Interestingly, in the precedent study (CADER) persistent villous atrophy was found to be more present in patients diagnosed at an older age (65% of CD patients diagnosed after 30 years of age) than in younger patients. Moreover, unintentional exposure to gluten was found in 70% of the cases. The causative factors of this hypersensitivity to small amounts of gluten present in older patients are unknown. The intestinal microbiota and age-related epigenetic changes may help maintaining the dysregulation of the immune response, causing older patients to be hypersensitive to small amounts of gluten.

Read more

The aim of this study (CADER2) is to identify the immunological and clinical consequences of persistent villous atrophy in CD and study whether changes in the intestinal microbiome and age-related epigenetic modifications may contribute to it. Last, the investigators want to assess if an ultra-strict GFD can be a viable and effective alternative to treat this subset of CD patients. In order to achieve these objectives, the study includes 2 phases: 1) Cross-sectional study to assess the causes and the clinical consequences of persistent villous atrophy in CD patients; and 2) Longitudinal study to evaluate the potential therapeutic effect of an ultra-strict GFD on persistent villous atrophy and its subtle clinical manifestations.

The investigators hypothesize that persistent villous atrophy in CD patients despite an intentional GFD is associated with chronic low-grade inflammation and increased circulating cytokines in blood, potentially leading to cognitive deficits, fatigue, anxiety, depression, malnutrition, sarcopenia and osteoporosis. The intestinal microbiota and age-related epigenetic changes may help to maintain the dysregulation of the immune response, causing patients to be hypersensitive to small amounts of gluten. This subset of CD patient could highly benefit from an ultra-strict GFD.

To date, six centers have been recruited: Hospital Universitari Mutua Terrassa (Barcelona), Hospital Clínico San Carlos (Madrid), Hospital Fundación Jiménez Díaz (Madrid), Hospital Universitario de La Princesa (Madrid), Hospital Universitario Ramón y Cajal (Madrid) and Hospital Universitario Virgen Macarena (Sevilla). Digestive, endocrine, nutritional and clinical psychology experts will be involved in the monitoring of the patients. Microbiome analysis will be performed at the Genomics Unit, Microbiota Laboratory (LABMIC) of the IdISSC (Madrid). The methylation studies (age-related epigenetic modifications) will be hired externally.

Overall, the results of this study (CADER2) may help identify new therapeutic strategies as well as improve the management of chronicity and care of CD patients who do not respond to the current treatment. Furthermore, it will contribute to a deeper understanding of the pathophysiological relationships between diet, microbiome, genetics and immunology in CD.

Being tested
Ultra-strict gluten-free diet
Keywords
persistent villous atrophy, ultra-strict gluten-free diet, microbiota, epigenetics
Medical subject headings
Celiac Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ultra-strict gluten-free dietOther

    ultra-strict gluten-free diet (avoiding traces and contamination) under dietitian supervision

Study groups in NCT06500754
Study groupRoleWhat they receive
Celiac Disease patientsNot described
Receives: Other: Ultra-strict gluten-free diet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Persistent villous atrophy frequency

    proportion of patients showing villous atrophy after 2 years of an intentionally strict gluten-free diet

    Measured: at inclusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jul 2024
  2. Study start1 Jan 2022
  3. Primary completion1 Jan 2026 (estimated)
  4. Study completion1 Jan 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Cross-sectional
Enrolment
80 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06500754
Sponsor's protocol ID
P/21-098
Acronym
CADER2
Status last verified
Jul 2024
First submitted
8 Jul 2024
Last updated
19 Jul 2024
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Fernandez-Banares F, Beltran B, Salas A, Comino I, Ballester-Clau R, Ferrer C, Molina-Infante J, Rosinach M, Modolell I, Rodriguez-Moranta F, Arau B, Segura V, Fernandez-Salazar L, Santolaria S, Esteve M, Sousa C; CADER study group. Persistent Villous Atrophy in De Novo Adult Patients With Celiac Disease and Strict Control of Gluten-Free Diet Adherence: A Multicenter Prospective Study (CADER Study). Am J Gastroenterol. 2021 May 1;116(5):1036-1043. doi: 10.14309/ajg.0000000000001139.

    PubMed 33491958
  • Catassi C, Fabiani E, Iacono G, D'Agate C, Francavilla R, Biagi F, Volta U, Accomando S, Picarelli A, De Vitis I, Pianelli G, Gesuita R, Carle F, Mandolesi A, Bearzi I, Fasano A. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007 Jan;85(1):160-6. doi: 10.1093/ajcn/85.1.160.

    PubMed 17209192
  • Collin P, Maki M, Kaukinen K. Safe gluten threshold for patients with celiac disease: some patients are more tolerant than others. Am J Clin Nutr. 2007 Jul;86(1):260; author reply 260-1. doi: 10.1093/ajcn/86.1.260. No abstract available.

    PubMed 17616789
  • Hollon JR, Cureton PA, Martin ML, Puppa EL, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013 Feb 28;13:40. doi: 10.1186/1471-230X-13-40.

    PubMed 23448408
  • Sharkey LM, Corbett G, Currie E, Lee J, Sweeney N, Woodward JM. Optimising delivery of care in coeliac disease - comparison of the benefits of repeat biopsy and serological follow-up. Aliment Pharmacol Ther. 2013 Nov;38(10):1278-91. doi: 10.1111/apt.12510. Epub 2013 Oct 5.

    PubMed 24117503
  • Lebwohl B, Michaelsson K, Green PH, Ludvigsson JF. Persistent mucosal damage and risk of fracture in celiac disease. J Clin Endocrinol Metab. 2014 Feb;99(2):609-16. doi: 10.1210/jc.2013-3164. Epub 2014 Jan 16.

    PubMed 24432993
  • Lebwohl B, Granath F, Ekbom A, Smedby KE, Murray JA, Neugut AI, Green PH, Ludvigsson JF. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med. 2013 Aug 6;159(3):169-75. doi: 10.7326/0003-4819-159-3-201308060-00006.

    PubMed 23922062
  • Kaukinen K, Peraaho M, Lindfors K, Partanen J, Woolley N, Pikkarainen P, Karvonen AL, Laasanen T, Sievanen H, Maki M, Collin P. Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment Pharmacol Ther. 2007 May 15;25(10):1237-45. doi: 10.1111/j.1365-2036.2007.03311.x.

    PubMed 17451570
  • Manavalan JS, Hernandez L, Shah JG, Konikkara J, Naiyer AJ, Lee AR, Ciaccio E, Minaya MT, Green PH, Bhagat G. Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol. 2010 Jan;71(1):50-7. doi: 10.1016/j.humimm.2009.09.351.

    PubMed 19735687
  • Heydari F, Rostami-Nejad M, Moheb-Alian A, Mollahoseini MH, Rostami K, Pourhoseingholi MA, Aghamohammadi E, Zali MR. Serum cytokines profile in treated celiac disease compared with non-celiac gluten sensitivity and control: a marker for differentiation. J Gastrointestin Liver Dis. 2018 Sep;27(3):241-247. doi: 10.15403/jgld.2014.1121.273.hey.

    PubMed 30240467
  • Dunne MR, Byrne G, Chirdo FG, Feighery C. Coeliac Disease Pathogenesis: The Uncertainties of a Well-Known Immune Mediated Disorder. Front Immunol. 2020 Jul 8;11:1374. doi: 10.3389/fimmu.2020.01374. eCollection 2020.

    PubMed 32733456
  • Olano C, Lopez V, Freire T, Rodriguez X, Pontet Y, Aleman A, Rodriguez N, Rovira L, Trucco E, Osinaga E, Cohen H, Quigley EM. Irritable bowel syndrome in celiac disease - relationships to celiac disease antibodies and levels of pro-inflammatory cytokines. Rev Gastroenterol Peru. 2020 Apr-Jun;40(2):127-135.

    PubMed 32876628
  • Yelland GW. Gluten-induced cognitive impairment ("brain fog") in coeliac disease. J Gastroenterol Hepatol. 2017 Mar;32 Suppl 1:90-93. doi: 10.1111/jgh.13706.

    PubMed 28244662
  • Makhlouf S, Messelmani M, Zaouali J, Mrissa R. Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet. Acta Neurol Belg. 2018 Mar;118(1):21-27. doi: 10.1007/s13760-017-0870-z. Epub 2017 Dec 15.

    PubMed 29247390
  • Croall ID, Tooth C, Venneri A, Poyser C, Sanders DS, Hoggard N, Hadjivassiliou M. Cognitive Impairment in Coeliac Disease with Respect to Disease Duration and Gluten-Free Diet Adherence: A Pilot Study. Nutrients. 2020 Jul 8;12(7):2028. doi: 10.3390/nu12072028.

    PubMed 32650524

Questions about this trial

What is this clinical trial studying?

An observational study of Celiac Disease and Villous Atrophy of Intestine, run by Hospital Mutua de Terrassa at 1 site in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 19 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Persistent villous atrophy frequency (time frame: at inclusion). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06500754, which also lists 20 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jul 2024.

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