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Lymphocytic Enteritis and Suspected Coeliac Disease: Gluten vs Placebo

Primary Purpose

Celiac Disease, Non-celiac Gluten Sensitivity

Status
Completed
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Gluten challenge
Placebo challenge
Sponsored by
Hospital Mutua de Terrassa
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Celiac Disease focused on measuring celiac disease, lymphocytic enteritis, non-celiac gluten sensitivity, double-blind gluten rechallenge

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Giving written informed consent
  2. Patients with age ≥18 years
  3. Histological diagnosis confirmed of lymphocytic enteritis (LE)
  4. Celiac genetic study (HLA-DQ2 and /or HLA-DQ8 positive)
  5. Negative serology of celiac disease
  6. Previous complete clinical and histological response to gluten-free diet
  7. Initial (at diagnosis) GI symptoms with or without extraintestinal manifestations.
  8. No previous studies on both IEL cytometric pattern and anti-TG2 IgA subepithelial deposits.

Exclusion Criteria:

  1. Patients who are unable to adhere to the study visit schedule and other protocol requirements according to the investigator.
  2. Participation in a clinical trial in the last 30 days, simultaneous participation in a trial or prior participation in this study.
  3. Previous diagnosis with gluten-sensitive enteropathy with villous atrophy and positive serology.
  4. Patients with LE and initial response to gluten free diet but that at the time of inclusion are on a normal gluten-containing diet.
  5. Severe co-morbidities.
  6. Drug or alcohol abuse.
  7. Pregnancy or breast-feeding.

At the initial diagnosis, other LE aetiologies, like non-steroidal anti-inflammatory drugs intake, parasitic infection, and Helicobacter pylori infection, were appropriately ruled out.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    Gluten challenge

    Placebo challenge

    Arm Description

    Gluten powder (10 g every 12 hours), 24 weeks

    Placebo (maltodextrin; 10 g every 12 hours), 24 weeks

    Outcomes

    Primary Outcome Measures

    Clinical relapse
    Visual analogue scale on clinical symptoms at each visit (Baseline, 4 weeks, 12 weeks, 24 weeks)

    Secondary Outcome Measures

    Changes in health related quality of life
    GI quality of life index (GIQLI) at basal and 24 week visits
    Histological evolution (Changes in intraepithelial lymphocyte count)
    Changes in intraepithelial lymphocyte count
    Changes in gamma/delta cells
    Changes in cytometric count of gamma/delta cells
    Changes in transglutaminase deposits
    Presence of tTG deposits (IF)

    Full Information

    First Posted
    June 9, 2015
    Last Updated
    June 15, 2015
    Sponsor
    Hospital Mutua de Terrassa
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02472704
    Brief Title
    Lymphocytic Enteritis and Suspected Coeliac Disease: Gluten vs Placebo
    Official Title
    Lymphocytic Enteritis and Suspected Coeliac Disease: Double-blind Gluten vs Placebo Rechallenge
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    September 2011 (undefined)
    Primary Completion Date
    April 2014 (Actual)
    Study Completion Date
    May 2014 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Hospital Mutua de Terrassa

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Patients with lymphocytic enteritis (LE), HLA-DQ2/8+, negative celiac serology and clinical and histological response to a gluten-free diet (GFD) do not fulfil the diagnostic criteria of coeliac disease (CoD). At present it remains unclear whether they suffer from coeliac gluten sensitivity (CGS) or non-coeliac gluten sensitivity (NCGS). There are specific tissue markers of CoD such as anti-transglutaminase deposits (tTG) and intraepithelial lymphocytes expressing T-cell receptor (TCR) gamma/delta+. Aim: To demonstrate the existence of CGS in these patients despite having negative celiac serology. Methods: Double-blind randomized clinical trial of gluten vs placebo rechallenge for 6 months in patients with LE on a GFD. Inclusion criteria: >18 years, initial presentation with GI symptoms, HLA-DQ2/8+, negative celiac serology, good clinical and histological response to GFD. Patients were randomised to gluten (20 g/day) and placebo (maltrodextrin) (identical powder sachets mixed with meals). Clinical symptoms were analysed using visual analogue scales. Quality of life (GIQLI), adherence to diet, serology, and histological changes including gamma/delta+ IEL and tTG deposits were evaluated.
    Detailed Description
    Duodenal intraepithelial lymphocytosis (lymphocytic enteritis, LE) is defined by normal villous architecture and intraepithelial lymphocytes (IEL) >25/100 enterocytes. It is a frequent finding present in 2% to 5,4% of duodenal biopsies. LE is secondary to coeliac disease (CoD) in only a minority of patients, since it may be a response to other inflammatory processes in the gut. Other possible aetiologies of LE include infections (Helicobacter Pylori), drugs (nonsteroidal anti-inflammatory or acetylsalicylic acid) and autoimmune disease. Observational studies have established CoD to account for 10% to 43% of cases with LD and positive HLA-DQ2/8 after undertaking an exhaustive diagnostic work-up. These 'minor' forms of CoD may have similar clinical manifestations to those with villous atrophy. However, these patients with 'minor' CoD have often negative celiac serology, and then do not fulfil the present criteria to diagnose CoD. In fact, using the present diagnostic criteria they should be included in the definition of non-celiac gluten sensitivity (NCGS). For diagnosing NCGS it is necessary to rule out CoD by means of negative serology -endomysial and tissue transglutaminase IgA antibodies- and a duodenal biopsy with absence of villous atrophy on a gluten-containing diet. As such it is accepted that NCGS patients might have LE. A recent systematic review on NCGS revealed that 44% of patients presented HLA-DQ2/8 haplotypes, suggesting that a subgroup of patients with NCGS may actually belong in the spectrum of CoD, which some authors have so-called 'coeliac lite' disease. The gold-standard assay for confirming NCGS requires dietary elimination, followed by double-blind, randomized, placebo-controlled food challenge. This procedure is difficult to adopt routinely in clinical practice. To date two double-blind placebo-controlled dietary interventions in patients with presumptive NCGS have been published. The first gluten vs placebo rechallenge trial showed that patients who received gluten had significantly more abdominal symptoms than those on placebo (68% vs 40%). The second study that investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (FODMAPs) in subjects believed to have NCGS, showed no symptomatic worsening after gluten challenge as compared to placebo. Thus, there was no evidence of specific or dose dependent effect of gluten on NCGS patients placed on a diet low in FODMAPs. It is worth mentioning that patients included in these trials were HLA-DQ2/8 negative, and if positive they had a normal duodenal biopsy (Marsh 0) while on a gluten containing diet. Besides, a GFD has been shown to be more effective in IBS-D patients with negative CoD serology but HLA-DQ2/8+ than in those with a negative genetic study. The recent ESPGHAN guidelines for CoD diagnosis suggest that in cases with low-grade enteropathy (including LE) both a high γδ IEL count and the presence of Ig A anti-tissue transglutaminase (anti-TG2) deposits in the mucosa increase the likelihood of CoD. In contrast to CoD, there is stated that in NCGS there is not an increase of T-cell receptor γδ IELs. However, these parameters have only been scarcely used to rule out CoD in patients with NCGS in literature. The aim of study was demonstrate the existence of gluten sensitivity in patients with HLA-DQ2/8+, LE and negative celiac serology, who had presented a clinical and histological response to a gluten-free diet (GFD), using a gluten vs placebo-controlled challenge. In addition, to assess the presence of tissue markers of CoD before and after gluten challenge, thus confirming the existence of a 'coeliac-lite' disease.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Celiac Disease, Non-celiac Gluten Sensitivity
    Keywords
    celiac disease, lymphocytic enteritis, non-celiac gluten sensitivity, double-blind gluten rechallenge

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    18 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Gluten challenge
    Arm Type
    Active Comparator
    Arm Description
    Gluten powder (10 g every 12 hours), 24 weeks
    Arm Title
    Placebo challenge
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo (maltodextrin; 10 g every 12 hours), 24 weeks
    Intervention Type
    Dietary Supplement
    Intervention Name(s)
    Gluten challenge
    Intervention Description
    gluten (20 g/day) (identical powder sachets than placebo, mixed with meals) rechallenge while on a gluten-free diet
    Intervention Type
    Dietary Supplement
    Intervention Name(s)
    Placebo challenge
    Intervention Description
    placebo (maltrodextrin) (identical powder sachets than gluten, mixed with meals) rechallenge while on a gluten-free diet
    Primary Outcome Measure Information:
    Title
    Clinical relapse
    Description
    Visual analogue scale on clinical symptoms at each visit (Baseline, 4 weeks, 12 weeks, 24 weeks)
    Time Frame
    6 months
    Secondary Outcome Measure Information:
    Title
    Changes in health related quality of life
    Description
    GI quality of life index (GIQLI) at basal and 24 week visits
    Time Frame
    Change from baseline at 6 months (or premature withdrawn)
    Title
    Histological evolution (Changes in intraepithelial lymphocyte count)
    Description
    Changes in intraepithelial lymphocyte count
    Time Frame
    Changes from baseline at 6 months (or premature withdrawn)
    Title
    Changes in gamma/delta cells
    Description
    Changes in cytometric count of gamma/delta cells
    Time Frame
    Changes from baseline at 6 months (or premature withdrawn)
    Title
    Changes in transglutaminase deposits
    Description
    Presence of tTG deposits (IF)
    Time Frame
    Changes from baseline at 6 months (or premature withdrawn)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Giving written informed consent Patients with age ≥18 years Histological diagnosis confirmed of lymphocytic enteritis (LE) Celiac genetic study (HLA-DQ2 and /or HLA-DQ8 positive) Negative serology of celiac disease Previous complete clinical and histological response to gluten-free diet Initial (at diagnosis) GI symptoms with or without extraintestinal manifestations. No previous studies on both IEL cytometric pattern and anti-TG2 IgA subepithelial deposits. Exclusion Criteria: Patients who are unable to adhere to the study visit schedule and other protocol requirements according to the investigator. Participation in a clinical trial in the last 30 days, simultaneous participation in a trial or prior participation in this study. Previous diagnosis with gluten-sensitive enteropathy with villous atrophy and positive serology. Patients with LE and initial response to gluten free diet but that at the time of inclusion are on a normal gluten-containing diet. Severe co-morbidities. Drug or alcohol abuse. Pregnancy or breast-feeding. At the initial diagnosis, other LE aetiologies, like non-steroidal anti-inflammatory drugs intake, parasitic infection, and Helicobacter pylori infection, were appropriately ruled out.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Fernando Fernández-Bañares, MD
    Organizational Affiliation
    Hospital Mutua Terrassa
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    25753138
    Citation
    Molina-Infante J, Santolaria S, Sanders DS, Fernandez-Banares F. Systematic review: noncoeliac gluten sensitivity. Aliment Pharmacol Ther. 2015 May;41(9):807-20. doi: 10.1111/apt.13155. Epub 2015 Mar 6.
    Results Reference
    background
    PubMed Identifier
    25010214
    Citation
    Fernandez-Banares F, Carrasco A, Garcia-Puig R, Rosinach M, Gonzalez C, Alsina M, Loras C, Salas A, Viver JM, Esteve M. Intestinal intraepithelial lymphocyte cytometric pattern is more accurate than subepithelial deposits of anti-tissue transglutaminase IgA for the diagnosis of celiac disease in lymphocytic enteritis. PLoS One. 2014 Jul 10;9(7):e101249. doi: 10.1371/journal.pone.0101249. eCollection 2014.
    Results Reference
    background
    PubMed Identifier
    22497904
    Citation
    Rosinach M, Esteve M, Gonzalez C, Temino R, Marine M, Monzon H, Sainz E, Loras C, Espinos JC, Forne M, Viver JM, Salas A, Fernandez-Banares F. Lymphocytic duodenosis: aetiology and long-term response to specific treatment. Dig Liver Dis. 2012 Aug;44(8):643-8. doi: 10.1016/j.dld.2012.03.006. Epub 2012 Apr 11.
    Results Reference
    background
    PubMed Identifier
    27392045
    Citation
    Rosinach M, Fernandez-Banares F, Carrasco A, Ibarra M, Temino R, Salas A, Esteve M. Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease. PLoS One. 2016 Jul 8;11(7):e0157879. doi: 10.1371/journal.pone.0157879. eCollection 2016.
    Results Reference
    derived

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    Lymphocytic Enteritis and Suspected Coeliac Disease: Gluten vs Placebo

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