Dose-finding Gluten Challenge Trial in Nonceliac Gluten-sensitivity (RAPLAGE)

Randomized, Dose-finding, Double-blind, Placebo-controlled, Crossover Gluten Challenge Trial in Subjects With Nonceliac Gluten-sensitivity

An emerging problem in clinical practice is how to manage the growing number of patients who experience symptoms related to the ingestion of gluten-containing foods gluten and in whom celiac disease has been ruled out. These patients most frequently report gastrointestinal symptoms such as diarrhea, abdominal discomfort or pain, bloating, flatulence, but also extraintestinal symptoms, including headache, lethargy, attention-deficit/hyperactivity disorder, ataxia, or recurrent oral ulceration. This heterogeneous syndrome, which has been reported to improve or even disappear after gluten withdrawal and to relapse after gluten challenge, is called non-celiac gluten sensitivity.1 The concept of nonceliac gluten sensitivity is not completely new. Besides several sporadic single cases reported, more than 30 years ago an oral, double-blind, placebo-controlled, cross-over gluten challenge trial showed that six out of eight adult non-celiac patients, who suffered from intestinal symptoms caused by the ingestion of gluten-containing food, were affected by gluten-sensitive diarrhea. Over the last few years, an intense debate about the existence and the prevalence of nonceliac gluten sensitivity has emerged, as shown by the considerable increase in internet forums of discussion on this topic and in availability of gluten-free food. A definition of nonceliac gluten sensitivity based on definitive scientific evidence does not still exist, and the clinical trials conducted so far in order to fill this knowledge gap are burdened by a number of biases. In a cross-over trial of subjects with suspected NCGS, the severity of overall (intestinal plus extraintestinal) symptoms increased significantly during 1 week of intake of small amounts of gluten (daily 4.375 grams), compared with placebo. Among the 59 participants in this trial, the Investigatotors identified only three true gluten-sensitive patients, defined as having a delta overall score -calculated by subtracting the weekly overall score under placebo from that under gluten- higher than the mean delta overall score plus 2 standard deviations. However, these results should be cautiously interpreted due to the lack of a control group of non-gluten-sensitive subjects.

On this basis, the Investigators will conduct a randomized, dose-finding, double-blind, placebo-controlled, cross-over gluten challenge trial aimed at comparing the effects of a daily dose of 8.4 grams of gluten with those of a daily dose of 6.0 or 4.2 grams of gluten on a cohort of subjects with nonceliac gluten sensitivity versus healthy volunteers.

Study Overview

• Status: Unknown
• Conditions: Nonceliac Gluten Sensitivity
• Intervention / Treatment: Diagnostic test: Gluten or placebo capsules

Detailed Description

The Investigators will consecutively enroll adult patients referred to outpatients' Clinics of 21 Centres because of persistence of relevant intestinal and extraintestinal symptoms believed by them to be caused by the ingestion of food containing even low doses of gluten. In their clinical management patients in gluten-containing diet since at least two months will undergo ad hoc tests including serum determination of IgA anti-tissue transglutaminase and anti-endomysial antibodies, IgG anti-gliadin antibodies (AGA), total IgA and IgE, wheat-specific IgE, upper endoscopy with collection of multiple duodenal biopsies, HLA genotyping, fecal calprotectin and lactose breath test. The Investigators will investigate serum AGA IgG since they have been detected in some patients with "suspected" nonceliac gluten sensitivity. Patients with celiac disease, wheat allergy, intolerance to further food source of fermentable oligo- and disaccharides, monosaccharides and polyols, lactose intolerance, Helicobacter pylori infection, giardiasis, inflammatory bowel disease, cirrhosis, excessive alcohol intake, intake of nonsteroidal anti-inflammatory agents, use of systemic immunosuppressant medication, poorly controlled psychiatric disease, pregnancy and those unable to give written informed consent will be excluded. The Investigators will also recruit as control group 420 age- and sex-matched healthy volunteers, undergoing IgG AGA and all negative for anti-tissue transglutaminase antibodies. Healthy volunteers will not be affected by any comorbidity and food intolerance.

Each Centre will enroll 20 patients with suspected nonceliac gluten sensitivity and 20 healthy volunteers. Recruitment of patients and, at greater extent, healthy volunteers should not be an issue as the 21 Centres involved in this trial are well-known for diagnosis and treatment of gluten-related disorders. The Investigators will consider drop-outs from the study all the patients who will fail to attend even a single appointment or test in the trial. Moreover, compliance with the study treatment will be assessed by unused capsule counts at T2 and T4. Compliance with the gluten-free diet at each time point will be assessed through a validated questionnaire. To exclude the possibility of patients being able to discriminate between gluten capsules and placebo capsules, we preliminarily tested capsule recognition in a group of 20 healthy volunteers. On two different days, healthy volunteers were asked to take capsules and then clearly state if the capsules contained gluten or not. Healthy volunteers were not able to differentiate the appearance and taste of gluten capsules from those of placebo capsules. Assuming a within-patient comparison and a SD of the overall score of 40, 70 subjects per arm would be needed in order to achieve a power of 80%, at a 2-sided 5% significance level, if the true difference is 15.

• Study Type: Interventional
• Enrollment (Anticipated): 840
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antonio Di Sabatino, MD; Phone Number: +39 0382 501596; Email: a.disabatino@smatteo.pv.it

Study Locations

• Italy
  • Pv
    • Pavia, Pv, Italy, 27100
      • Recruiting
      • Fondazione IRCCS Policlinico San Matteo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• persistence of relevant intestinal and extraintestinal symptoms believed by them to be caused by the ingestion of food containing even low doses of gluten

Exclusion Criteria:

• celiac disease
• wheat allergy
• intolerance to further food source of fermentable oligo- and disaccharides, monosaccharides and polyols
• lactose intolerance
• Helicobacter pylori infection
• giardiasis
• inflammatory bowel disease
• cirrhosis
• excessive alcohol intake
• intake of nonsteroidal anti-inflammatory agents
• use of systemic immunosuppressant medication
• poorly controlled psychiatric disease
• pregnancy
• patients unable to give written informed consent will be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1A - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 14 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 8.4 grams for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
ACTIVE_COMPARATOR: 1B - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 10 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 6.0 grams for five days. In order to maintain the double-blind, patients will be also given 4 capsules of placebo (rice starch) per day. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
ACTIVE_COMPARATOR: 1C - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 7 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 4.2 grams for five days. In order to maintain the double-blind, patients will be also given 7 capsules of placebo (rice starch) per day. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2C - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 7 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 4.2 grams for five days. In order to maintain the double-blind, patients will be also given 7 capsules of placebo (rice starch) per day. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2B - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 10 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 6.0 grams for five days. In order to maintain the double-blind, patients will be also given 4 capsules of placebo (rice starch) per day. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2A - NCGS; Seventy subjects with nonceliac gluten sensitivity will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 8.4 grams for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
ACTIVE_COMPARATOR: 1A - HV; Seventy healthy volunteers will be given 14 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 8.4 grams for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
ACTIVE_COMPARATOR: 1B - HV; Seventy healthy volunteers will be given 10 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 6.0 grams for five days. In order to maintain the double-blind, patients will be also given 4 capsules of placebo (rice starch) per day. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
ACTIVE_COMPARATOR: 1C - HV; Seventy healthy volunteers will be given 7 gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 4.2 grams for five days. In order to maintain the double-blind, patients will be also given 7 capsules of placebo (rice starch) per day. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2C- HV; Seventy healthy volunteers will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 7 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 4.2 grams for five days. In order to maintain the double-blind, patients will be also given 7 capsules of placebo (rice starch) per day. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2B - HV; Seventy healthy volunteers will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 7 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 4.2 grams for five days. In order to maintain the double-blind, patients will be also given 7 capsules of placebo (rice starch) per day. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules
PLACEBO_COMPARATOR: 2A - HV; Seventy healthy volunteers will be given 14 daily gastrosoluble capsules containing placebo (rice starch) for five days. At the end of the first five day-long treatment, subjects will continue only their wash-out from gluten for two weeks, without taking any capsule. At T3, individuals will be given 14 daily gastrosoluble capsules containing purified wheat gluten corresponding to a daily gluten intake of 8.4 grams for five days. In both first and second five day-long treatment the 14 capsules will be ingested in no more than two times using a glass of water over the day.	Diagnostic test: Gluten or placebo capsules; Administration of gluten or placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in delta overall (intestinal plus extraintestinal) score in nonceliac gluten sensitivity	The change in delta overall (intestinal plus extraintestinal) score, calculated by subtracting the 5-day overall score under placebo from the 5-day overall score under gluten, between the highest daily intake of gluten (8.4 grams) and the lowest ones (either 6.0 or 4.2 grams) in nonceliac gluten sensitivity.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in individual symptom scores between the 5-day treatment with gluten and the 5-day treatment with placebo		18 months
The identification of patients with true nonceliac gluten sensitivity	True nonceliac gluten-sensitive patients will be defined as having at the end of the trial a delta overall score higher than the mean delta overall score plus two standard deviations of healthy volunteers taking the same daily gluten dose.	18 months
Laboratory parameters as predictors of true nonceliac gluten sensitivity	To verify whether laboratory parameters (erum IgG AGA, HLA genotyping and intraepithelial lymphocyte density) at baseline might be predictive of true nonceliac gluten sensitivity	24 months
Change in delta overall (intestinal plus extraintestinal) score between the highest daily intake of gluten (8.4 grams) and the lowest ones (either 6.0 or 4.2 grams) in healthy volunteers		24 months

Collaborators and Investigators

• Sponsor: Antonio Di Sabatino

Publications and helpful links

General Publications

• Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, Corazza GR. Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1604-12.e3. doi: 10.1016/j.cgh.2015.01.029. Epub 2015 Feb 19.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 13, 2017
• Primary Completion (ANTICIPATED): June 13, 2019
• Study Completion (ANTICIPATED): December 13, 2020

Study Registration Dates

• First Submitted: June 13, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (ACTUAL): June 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 10, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: placebo; gluten; dose-finding; extraintestinal symptoms; intestinal symptoms
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: 20150017440

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No