Wheat Flour Treatment With Microbial Transglutaminase and Lysine Ethyl Ester: New Frontiers in Celiac Disease Treatment.

NCT02472119 | Unknown Phase 2

• 1 other identifier: 672/10 Rif. 1907 / 22.07.2010
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Celiac disease is one of the most common forms of food intolerance (prevalence 1/200). The disease occurs in genetically predisposed individuals after ingestion of foods containing gluten. Celiac patients can suffer from severe malabsorption syndrome, mainly characterized by diarrhea and weight loss. The only therapeutic approach currently recognized is a life-long gluten-free diet. Specific regions of gluten molecule become recognizable by lymphocytes and activate them, due to changes made by tissue transglutaminase. These changes consist in the conversion of specific residues of glutamine into glutamic acid. The consequence is an increased binding affinity between gluten and histocompatibility molecule (HLA-DQ2), localized on the surface of the "antigen presenting cells" (APC); the exposure of the fragments of modified gluten on the surface of APC is a phenomenon that eventually activates T lymphocytes. Recent studies on modified gluten confirmed the hypothesis that it is possible to block the presentation of gluten to lymphocytes by means of lysine ethyl ester binding exclusively to those gluten regions responsible for lymphocyte activation. The enzymatic treatment is performed directly on flour instead of extracted gluten, maintaining the same anti-inflammatory effectiveness. The procedure uses a food-grade enzyme, the microbial transglutaminase (mTGasi) isolated from Streptoverticillium mobarensis, able to catalyze the formation of intermolecular "cross-links" that modify the functional properties of the products. Objective of the study is to validate the ability of the enzyme treatment of wheat flour with mTGasi and lysine ethyl ester to block the toxic effect of gluten in celiac patients.

Conditions

Celiac Disease

Keywords

Celiac disease; Gluten-free diet; Wheat flour treatment; Microbial transglutaminase; Lysine Ethyl Ester; Celiac Disease Treatment

Outcome Measures

Primary Outcomes (7)

• Change from baseline in IgA anti-tissue transglutaminase (anti-tTG) antibodies at 30 days

  Proof of any positivization of specific serological antibodies for celiac disease. Results quantified by an ELISA reader at 450 nm (A450nm) is expressed in U/mL and the antibody level 10 U/mL was used as a cutoff value to identify anti-tTG positive results.

  After 1 month

• Change from baseline in IgA anti-tissue transglutaminase (anti-tTG) antibodies at 60 days

  Proof of any positivization of specific serological antibodies for celiac disease. Results quantified by an ELISA reader at 450 nm (A450nm) is expressed in U/mL and the antibody level 10 U/mL was used as a cutoff value to identify anti-tTG positive results.

  After 2 months

• Change from baseline in IgA anti-tissue transglutaminase (anti-tTG) antibodies at 90 days

  Proof of any positivization of specific serological antibodies for celiac disease. Results quantified by an ELISA reader at 450 nm (A450nm) is expressed in U/mL and the antibody level 10 U/mL was used as a cutoff value to identify anti-tTG positive results.

  After 3 months

• Change from baseline in IgA anti-endomysium antibodies (EMA) at 30 days

  Test used to confirm serological activation of celiac disease. IgA EMA were searched in sera diluted 1:5 by indirect immunofluorescence analysis on cryostat sections of monkey esophagus. The results are expressed as ''positive/negative''.

  After 1 month

• Change from baseline in IgA anti-endomysium antibodies (EMA) at 60 days

  Test used to confirm serological activation of celiac disease. IgA EMA were searched in sera diluted 1:5 by indirect immunofluorescence analysis on cryostat sections of monkey esophagus. The results are expressed as ''positive/negative''.

  After 2 months

• Change from baseline in IgA anti-endomysium antibodies (EMA) at 90 days

  Test used to confirm serological activation of celiac disease. IgA EMA were searched in sera diluted 1:5 by indirect immunofluorescence analysis on cryostat sections of monkey esophagus. The results are expressed as ''positive/negative''.

  After 3 months

• Pathologic variations in histologic analysis from baseline

  Proof of duodenal mucosa histological alterations induced by celiac disease, consisting in altered (\<3:1) villous height/crypt depth ratio and increased (\>25) intraepithelial lymphocytes per 100 intestinal epithelial cells, according to Marsh-Oberhuber classification.

  After 3 months, or in case of serum anti-tTG IgA/EMA IgA positive results

Secondary Outcomes (16)

• Presence of bloating at baseline

  At baseline

• Presence of abdominal pain at baseline

  At baseline

• Presence of diarrhea at baseline

  At baseline

• Presence of asthenia at baseline

  At baseline

• Variation of bloating from baseline at 30 days

  After 1 month

Study Arms (2)

rusks made with treated flour

EXPERIMENTAL

Gluten-free diet adding rusks (100g / day) produced with commercial wheat flour enzymatically treated with mTGasi and lysine ethyl ester.

Dietary Supplement: rusks made of wheat flour enzymatically treated; Dietary Supplement: Gluten-free diet

rusks made with not-treated flour

ACTIVE COMPARATOR

Gluten-free diet adding rusks (100g / day) produced with untreated wheat flour.

Dietary Supplement: rusks made of wheat flour not enzimatically modified; Dietary Supplement: Gluten-free diet

Interventions

rusks made of wheat flour enzymatically treated DIETARY_SUPPLEMENT

100 g of rusks obtained from commercial wheat flour enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

rusks made with treated flour

rusks made of wheat flour not enzimatically modified DIETARY_SUPPLEMENT

100 g of rusks obtained from commercial wheat flour NOT enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

rusks made with not-treated flour

Gluten-free diet DIETARY_SUPPLEMENT

gluten-free diet

rusks made with not-treated flour; rusks made with treated flour

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• diagnosis of celiac disease according to ESPGHAN criteria: class III according to Marsh-Oberhuber classification, clear response to gluten-free diet, serological antiendomysium and antitransglutaminase antibodies positive results before GFD;
• HLA DQ2-DQ8 positive results;
• gluten-free diet from at least one year;
• negative serology from at least 1 year;

You may not qualify if:

• inflammatory bowel diseases;
• tumors;
• infectious liver disease;
• renal impairment.

Sponsors & Collaborators

• University of Roma La Sapienza: lead

Study Sites (1)

Sapienza University - Policlinico Umberto I

Rome, Italy, 00186, Italy

RECRUITING

Related Publications (10)

• Branski D, Fasano A, Troncone R. Latest developments in the pathogenesis and treatment of celiac disease. J Pediatr. 2006 Sep;149(3):295-300. doi: 10.1016/j.jpeds.2006.06.003. No abstract available.

  PMID: 16939736 BACKGROUND

• Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998 Sep;115(3):551-63. doi: 10.1016/s0016-5085(98)70134-9.

  PMID: 9721152 BACKGROUND

• Molberg O, Mcadam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998 Jun;4(6):713-7. doi: 10.1038/nm0698-713.

  PMID: 9623982 BACKGROUND

• Gianfrani C, Siciliano RA, Facchiano AM, Camarca A, Mazzeo MF, Costantini S, Salvati VM, Maurano F, Mazzarella G, Iaquinto G, Bergamo P, Rossi M. Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology. 2007 Sep;133(3):780-9. doi: 10.1053/j.gastro.2007.06.023. Epub 2007 Jun 20.

  PMID: 17678925 BACKGROUND

• Yokoyama K, Nio N, Kikuchi Y. Properties and applications of microbial transglutaminase. Appl Microbiol Biotechnol. 2004 May;64(4):447-54. doi: 10.1007/s00253-003-1539-5. Epub 2004 Jan 22.

  PMID: 14740191 BACKGROUND

• Fink ML, Chung SI, Folk JE. gamma-Glutamylamine cyclotransferase: specificity toward epsilon-(L-gamma-glutamyl)-L-lysine and related compounds. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4564-8. doi: 10.1073/pnas.77.8.4564.

  PMID: 6107907 BACKGROUND

• 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.

  PMID: 17209192 BACKGROUND

• Picarelli A, Di Tola M, Sabbatella L, Anania MC, Calabro A, Renzi D, Bai JC, Sugai E, Carroccio A, Di Prima L, Bardella MT, Barisani D, Ribes-Koninckx C, Aliaga ED, Gasparin M, Bravi E; Multicentre Organ Culture System Study Group. Usefulness of the organ culture system in the in vitro diagnosis of coeliac disease: a multicentre study. Scand J Gastroenterol. 2006 Feb;41(2):186-90. doi: 10.1080/00365520510024151.

  PMID: 16509042 BACKGROUND

• Picarelli A, Maiuri L, Frate A, Greco M, Auricchio S, Londei M. Production of antiendomysial antibodies after in-vitro gliadin challenge of small intestine biopsy samples from patients with coeliac disease. Lancet. 1996 Oct 19;348(9034):1065-7. doi: 10.1016/S0140-6736(96)03060-7.

  PMID: 8874458 BACKGROUND

• Marino M, Casale R, Borghini R, Di Nardi S, Donato G, Angeloni A, Moscaritolo S, Grasso L, Mazzarella G, Di Tola M, Rossi M, Picarelli A. The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. Int Immunopharmacol. 2017 Jun;47:1-8. doi: 10.1016/j.intimp.2017.03.012. Epub 2017 Mar 23.

  PMID: 28343108 DERIVED

MeSH Terms

Conditions

Celiac Disease

Interventions

Diet, Gluten-Free

Condition Hierarchy (Ancestors)

Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Central Study Contacts

Antonio Picarelli, medicine

CONTACT

+39 06 49978370; antonio.picarelli@uniroma1.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor

Study Record Dates

• First Submitted: June 3, 2015
• First Posted: June 15, 2015
• Study Start: June 1, 2015
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: June 15, 2015

Record last verified: 2015-06

Locations

IT (1)