AN-PEP on Gluten Exposure in Celiacs

• ClinicalTrials.gov Identifier: NCT04788797
• Recruitment Status: Recruiting
• First Posted: March 9, 2021
• Last Update Posted: August 20, 2021
• Sponsor: Dr. C. Bonorino Udaondo Gastroenterology Hospital
• Information provided by (Responsible Party): Edgardo Smecuol, Dr. C. Bonorino Udaondo Gastroenterology Hospital

Study Description

Brief Summary:

The AN-PEP, an Aspergillus niger derived endopeptidase, has been developed aiming to produce a complete luminal detoxification of gluten. If AN-PEP is able to produce a complete luminal digestion of gluten in the context of the real life of celiac disease (CeD) patients is unknown. Hypothetically, AN-PEP effect could be detected by the reduction in the excretion of GIP in stool and urine.

The objective of this study is to establish the effect of the daily administration of AN-PEP compared to placebo on GIP excretion in an interventional, prospective, randomized, comparative, double-blind study in conditions mimicking the real-life of CeD treated patients. The study consists in a four-week GFD stabilization period followed by a four-week study period with patients randomized to receive active AN-PEP or placebo in a blindly manner.

Condition or disease	Intervention/treatment	Phase
Celiac Disease	Drug: Prolyl Endopeptidase; Other: Placebo	Phase 4

Detailed Description:

Background: The strict gluten-free diet (GFD) is the only accepted treatment for celiac disease (CeD). However, performing a strict diet is still a non solved problem affecting the future of patients. In a real-life study it was recently shown that 89% of treated CeD patients performing a strict diet have contact with dietary gluten at least one week per 4 weeks of testing and averaging 3 weeks per month. Furthermore, 40% of patients excreted gliadin immunogenic peptides (GIP) (surrogated markers of gluten exposure) in the range for immunological activation and intestinal mucosal damage. Endopeptidases to produce a complete intraluminal proteolysis of gluten avoiding antigenic stimulation were produced to avoid damage of continuous gluten exposure. AN-PEP is an Aspergillus niger derived endopeptidase has been produced aiming to luminal detoxification of gluten have been explored for its clinical effect. However, whether AN-PEP is able to completely destroy gluten in the context of the real life of CeD patients is still unknown. Hypothesis: The investigators estimate that AN-PEP is an effective therapy for proteolysis for gluten exposure in the real-life of CeD patients and that the effect could be detected by the reduction in the excretion of GIP in stool and urine based on a clinical research model that we developed. AIMS: to establish the effect of daily administration of AN-PEP compared to placebo in terms of: (1) frequency of GIP excretion in stool and urine episodes in 4 weeks; (2) concentration of GIP excretion for both arms; and (3) differences in proportion of patients excreting GIP above the threshold for mucosal damage (>2 µg/g of GIP in stool or >12 ng/mL in urine). Study design: Interventional, prospective, randomized, comparative, double-blind study. Components: 1- four-week GFD stabilization period; 2-Randomization. 3- four4-week study period: Patients blinded-receive active AN-PEP (GliadinX®) at a dose of 2 capsules/breakfast, lunch and dinner (study arm), or 2 capsules at same time points of placebo (specially designed and prepared for the study) (Placebo arm).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of the Endopeptidase AN-PEP on Gluten Exposure in Real Life in Celiac Disease Patients Treated With a Long-term Gluten-free Diet. Exploratory, Interventional, Prospective, Controlled and Double Blind Study
• Actual Study Start Date: March 17, 2021
• Estimated Primary Completion Date: August 30, 2022
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Prolyl Endopeptidase; Patients blinded-receive active AN-PEP at a dose of 2 capsules/breakfast, lunch and dinner during 8 weeks (study arm)	Drug: Prolyl Endopeptidase; Two capsules three times a day.; Other Name: GliadinX
Placebo Comparator: Placebo; Patients blinded-receive 2 capsules of a placebo (specially designed and prepared for the study) at breakfast, lunch and dinner during 8 weeks (Placebo arm).	Other: Placebo; Two capsules three times a day

Outcome Measures

Primary Outcome Measures :

1. Frequency of GIP excretion in stool [ Time Frame: 4 weeks ]
   To establish the effect of daily administration of AN-PEP compared to placebo in terms of frequency of GIP excretion in stool episodes in 4 weeks.
2. Weekly concentration of GIP excretion in stool [ Time Frame: 4 weeks ]
   To determine weekly concentration of GIP excretion in stool (µg/g of GIP) for both patients randomized to AN-PEP or placebo.
3. Proportion of patients excreting GIP [ Time Frame: 4 weeks ]
   To establish the proportion of patients excreting GIP above the theoretical threshold for mucosal damage (>1.6 µg/g of GIP in stool or >12 ng/mL in urine)
4. Frequency of GIP excretion in urine [ Time Frame: 4 weeks ]
   To establish the effect of daily administration of AN-PEP compared to placebo in terms of frequency of GIP excretion in urine epidodes in 4 weeks
5. Weekly concentration of GIP excretion in urine [ Time Frame: 4 weeks ]
   To determine weekly concentration of GIP excretion in urine (ng/mL) for both patients randomized to AN-PEP or placebo.

Secondary Outcome Measures :

1. Clinical effect of AN-PEP vs placebo [ Time Frame: 4 weeks ]
   2.1- To establish differences in the clinical effect of AN-PEP vs. placebo in symptomatic celiac patients in terms of the Celiac Clinical Score comparing baseline scores vs. those from the end of the study period. Celiac Clinical Score is made up of sixteen items, 11 of which evaluate "specific symptoms" and 5 evaluate "general health". Each question is answered on a Likert scale from 1 to 5. Overall symptom scores were calculated through simple addition, with higher scores denoting more severe symptoms. Scores of 45 or higher are associated with a relatively poor quality of life and worse GFD adherence. Score less than 45 are associated with better quality of life and gluten adherence
2. Differences in quality of life scores [ Time Frame: 4 weeks ]
   To determine differences in quality of life according to the Short Form 36 questionnaire in the study period in symptomatic and asymptomatic patients. To score this questionnaire scales are standardized with a scoring algorithm to obtain a score ranging from 0 to 100. Higher scores indicate better health status, and a mean score of 50 has been articulated as a normative value for all scales.
3. Major symptoms [ Time Frame: 4 weeks ]
   To explore changes in the daily report of major symptoms (abdominal pain, discomfort, borborygmi, distension, diarrhea) (Likert scale of seven points) in symptomatic patients by using a daily report in a telephonic APP.
4. Biochemical effect of AN-PEP vs. placebo [ Time Frame: 4 weeks ]
   to evaluate changes that occur during the study period in concentrations of CD-specific antibodies (IgA TG2 and DGP antibodies -AU/mL-) comparing consumption of AN-PEP vs. placebo.

Eligibility Criteria

• Ages Eligible for Study: 17 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Over 18 years
• Diagnosis of celiac disease
• Completion of Gluten-free Diet for at least two years without evidence of voluntary violations.
• Patients who do not report symptoms of constipation or illnesses or medications (cathartics, antidiarrheals, etc.) that alter the bowel movement rhythm (accepted rhythm: between 2 times / day to 1 every other day) and diuresis (diuretics). Proton-pump inhibitor.
• Signature of the informed consent

Exclusion Criteria:

• Patients not interested or unable to collaborate with the questionnaires and collection of fecal matter.
• Place of residence of the participant more than 4 hours from the hospital, which interferes with the viability of the sample.
• Complicated CD (refractory CD type II, ulcerative jejunoileitis, lymphoma).
• Concomitant pathologies that are decompensated or untreated at study entry (type I or II diabetes mellitus; hyperthyroidism; hypothyroidism; kidney failure,).

Contacts and Locations

Contacts

Contact: Edgardo G Smecuol, MD; +541144911975; esmecuol@intramed.net

Locations

Argentina

Dr. C. Bonorino Udaondo Gastroenterology Hospital; Recruiting

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, 1602

Contact: Edgardo G Smecuol, MD +5491144911975 esmecuol@intramed.net

Sponsors and Collaborators

Dr. C. Bonorino Udaondo Gastroenterology Hospital

Investigators

• Study Chair: Edgardo G Smecuol; Dr. C. Bonorino Udaondo Gastroenterology Hospital

More Information

Publications:

Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017 Aug;153(2):448-459.e8. doi: 10.1053/j.gastro.2017.05.003. Epub 2017 May 5.

Castellano E, Attanasio R, Gianotti L, Cesario F, Tassone F, Borretta G. Forearm DXA Increases the Rate of Patients With Asymptomatic Primary Hyperparathyroidism Meeting Surgical Criteria. J Clin Endocrinol Metab. 2016 Jul;101(7):2728-32. doi: 10.1210/jc.2016-1513. Epub 2016 Apr 12.

Ricaño-Ponce I, Gutierrez-Achury J, Costa AF, Deelen P, Kurilshikov A, Zorro MM, Platteel M, van der Graaf A; Consortium for the study of genetic associations of celiac disease in Latin-America, Sanna S, Daffra O, Zhernakova A, Fu J, Trynka G, Smecuol E, Niveloni SI, Bai JC, Kumar V, Wijmenga C. Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease. Eur J Hum Genet. 2020 Mar;28(3):313-323. doi: 10.1038/s41431-019-0520-4. Epub 2019 Oct 7.

Pinto-Sanchez MI, Bai JC. Toward New Paradigms in the Follow Up of Adult Patients With Celiac Disease on a Gluten-Free Diet. Front Nutr. 2019 Oct 1;6:153. doi: 10.3389/fnut.2019.00153. eCollection 2019. Review.

Penny HA, Raju SA, Lau MS, Marks LJ, Baggus EM, Bai JC, Bassotti G, Bontkes HJ, Carroccio A, Danciu M, Derakhshan MH, Ensari A, Ganji A, Green PHR, Johnson MW, Ishaq S, Lebwohl B, Levene A, Maxim R, Mohaghegh Shalmani H, Rostami-Nejad M, Rowlands D, Spiridon IA, Srivastava A, Volta U, Villanacci V, Wild G, Cross SS, Rostami K, Sanders DS. Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut. 2021 May;70(5):876-883. doi: 10.1136/gutjnl-2020-320913. Epub 2020 Nov 2.

Seiler CL, Kiflen M, Stefanolo JP, Bai JC, Bercik P, Kelly CP, Verdu EF, Moayyedi P, Pinto-Sanchez MI. Probiotics for Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Am J Gastroenterol. 2020 Oct;115(10):1584-1595. doi: 10.14309/ajg.0000000000000749. Erratum in: Am J Gastroenterol. 2021 Sep 1;116(9):1968.

Stefanolo JP, Tálamo M, Dodds S, de la Paz Temprano M, Costa AF, Moreno ML, Pinto-Sánchez MI, Smecuol E, Vázquez H, Gonzalez A, Niveloni SI, Mauriño E, Verdu EF, Bai JC. Real-World Gluten Exposure in Patients With Celiac Disease on Gluten-Free Diets, Determined From Gliadin Immunogenic Peptides in Urine and Fecal Samples. Clin Gastroenterol Hepatol. 2021 Mar;19(3):484-491.e1. doi: 10.1016/j.cgh.2020.03.038. Epub 2020 Mar 23.

Smecuol E, Constante M, Temprano MP, Costa AF, Moreno ML, Pinto-Sanchez MI, Vázquez H, Stefanolo JP, Gonzalez AF, D'Adamo CR, Niveloni SI, Mauriño E, Verdu EF, Bai JC. Effect of Bifidobacterium infantis NLS super strain in symptomatic coeliac disease patients on long-term gluten-free diet - an exploratory study. Benef Microbes. 2020 Oct 12;11(6):527-534. doi: 10.3920/BM2020.0016. Epub 2020 Oct 9.

• Responsible Party: Edgardo Smecuol, Principal Investigator, Dr. C. Bonorino Udaondo Gastroenterology Hospital
• ClinicalTrials.gov Identifier: NCT04788797
• Other Study ID Numbers: DrUdaondo
• First Posted: March 9, 2021
• Last Update Posted: August 20, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Edgardo Smecuol, Dr. C. Bonorino Udaondo Gastroenterology Hospital:

celiac disease; endopeptidases; gliadin immunogenic peptides

Additional relevant MeSH terms:

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