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
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
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.
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
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
Learn more about this trial
Lymphocytic Enteritis and Suspected Coeliac Disease: Gluten vs Placebo
We'll reach out to this number within 24 hrs