AN-PEP on Gluten Exposure in Celiacs

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: Prolyl Endopeptidase
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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,).

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prolyl Endopeptidase<br>Patients blinded-receive active AN-PEP at a dose of 2 capsules/breakfast, lunch and dinner during 8 weeks (study arm) | Drug: Prolyl Endopeptidase<br>* Two capsules three times a day.<br>* Other names: GliadinX;|
| Placebo Comparator: Placebo<br>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<br>* Two capsules three times a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of GIP excretion in stool | 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. | 4 weeks | 
| Weekly concentration of GIP excretion in stool | To determine weekly concentration of GIP excretion in stool (µg/g of GIP) for both patients randomized to AN-PEP or placebo. | 4 weeks | 
| Proportion of patients excreting GIP | 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 weeks | 
| Frequency of GIP excretion in urine | 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 | 4 weeks | 
| Weekly concentration of GIP excretion in urine | To determine weekly concentration of GIP excretion in urine (ng/mL) for both patients randomized to AN-PEP or placebo. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical effect of AN-PEP vs placebo | 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 | 4 weeks | 
| Differences in quality of life scores | 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. | 4 weeks | 
| Major symptoms | 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 weeks | 
| Biochemical effect of AN-PEP vs. placebo | 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. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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celiac disease, endopeptidases, gliadin immunogenic peptides