Gluten Sensitivity in Non-Celiac Patients (GS)

Double Blind Randomized Placebo Controlled Multicenter Trial (Gluten vs Placebo) in Gluten Sensitive Subjects

The idea is to evaluate if the so called "Gluten Sensitivity" is a real clinical entity. Gluten sensitive (GS) persons are defined as those patients, being neither celiac or allergic to weat, who develop symptoms following gluten consumption. This will be achieved by evaluating a global symptom score in GS patients receiving gluten compared to those receiving placebo (primary end point). Symptoms to be evaluated: gastrointestinal (Gastrointestinal Symptom Rating Scale, GSRS); not-gastrointestinal (specifically built evaluation scale); VQV scale, built to evaluate quality of life. Gluten or placebo will be administered daily (10 g) for 15 days; for the 15 days before and 15 after all patients will stay on Gluten Free Diet (GFD). Besides clinical evaluation (each week for 6 weeks), intestinal permeability testing and blood sampling will be requested for the identification of possible markers (serological, gut barrier function, immunological and expression of tight junctions constitutive proteins) that may be of help to differentiate the condition of gluten sensitivity (GS) from that of Celiac Disease (CD)(secondary end point). Inclusion and exclusion criteria for patients enrolling are strictly dependant on the given "Gluten sensitivity" definition. We expect to experience a worsening of gastrointestinal and extra-gastrointestinal symptoms, from hours to days, with an increase in the overall symptom score, above the cut off, in at least 45% of GS subjects enrolled and that have received gluten compared to GS who received placebo.

Study Overview

• Status: Completed
• Conditions: Gluten Sensitivity
• Intervention / Treatment: Dietary supplement: gluten; Dietary supplement: rice starch

Detailed Description

Gluten is the most important protein component of some grains, notably wheat, rye, and barley, which are the basis for a variety of flour and wheat derived alimentary products consumed throughout the world (bread, pasta, pizza etc). However the "engineering" of gluten-containing grains created the conditions for human diseases related to gluten exposure. These forms of gluten intolerance represent a heterogeneous set of conditions, including wheat allergy, Gluten Sensitivity and Celiac Disease, that, combined, affect about 10% of the general population. The frequency of not-celiac gluten intolerance is however still unknown, even though it is possible that these conditions have been undiagnosed and under-diagnosed by the physicians for long time. The state of immune responsiveness to wheat antigens, represents a complex process, and its establishment and maintenance are not completely elucidated. The most frequent diseases caused by wheat ingestion are T cell-mediated disorders, IgE-mediated allergic reactions and celiac disease (CD).

However, besides CD and wheat allergy, there are cases of gluten reactions in which neither allergic nor autoimmune mechanisms are involved. These are generally defined as gluten sensitivity (GS). Some individuals, who experience distress when eating gluten-containing products and show improvement when following a gluten-free diet, may have GS instead of CD. GS patients are unable to tolerate gluten and develop an adverse reaction when eating gluten that usually, and differently from CD, does not lead to small intestinal damage. While the gastrointestinal symptoms in GS may resemble those associated with CD, the overall clinical picture is generally less severe and is not accompanied by the concurrence of tTG autoantibodies or autoimmune disease. Typically the diagnosis is made by exclusion, and an elimination diet and "open challenge" (i.e., the monitored reintroduction of gluten-containing foods) are most often used to evaluate whether health improves with the elimination or reduction of gluten from the diet.

This has two major aims:

1. Evaluation of the effective dependence from the gluten of the clinical alterations presented by subjects with gluten sensitivity (GS). The study will be done after a period of gluten-free diet (washout of 15 days), comparing two groups of GS subjects: given gluten or placebo (15 days), followed by a further period (15 days) on gluten free diet .
2. identification of possible markers (serological, gut barrier function, immunological and expression of tight junctions constitutive proteins) that may be of help to differentiate, in humans, the condition of gluten sensitivity (GS) from that of Celiac Disease (CD); these markers might be of help in the early diagnosis of GS versus CD especially in the case of discordant serology.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy
    • Università Politecnica delle Marche
  • Avellino, Italy
    • Gastroenterologia ed Endoscopia digestiva, Ospedale San Giuseppe Moscati
  • Naples, Italy, 80138
    • Gastroenterology, Second University of Naples
  • Palermo, Italy
    • Internal Medicine, Policlinico di Palermo
  • Salerno, Italy
    • Gastroenterology, University of Salerno
  • San Giovanni Rotondo (Foggia), Italy
    • Ospedale "Casa Sollievo della Sofferenza" - IRCCS -
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Center for Celiac Research & Treatment, Yawkey Center for Outpatients Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients with age between 18-65 with signs/symptoms compatible with gluten-triggered disorders
• Patients testing negative for celiac disease either by biopsy Marsh 0-1 or those who are HLA-DQ2 and DQ8 negative, as well as tTG and EMA negative
• Patients that improved on a gluten free diet

Exclusion Criteria:

• Subjects diagnosed with celiac disease (positive TTG and/or EMA, and histology positive with Marsh II or above);
• Subjects diagnosed with wheat allergy
• Subjects with Type 1 Diabetes (T1D)
• Subjects with Inflammatory Bowel Disease (ulcerative colitis or Crohn's disease)
• Pregnancy
• Subjects with Helicobacter Pylori infection and other gastrointestinal infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: gluten; gluten is administered blindly versus placebo for 15 days at 10 g/day	Dietary supplement: gluten; gluten is administered once a day at 10g/day for 15 days
Placebo Comparator: rice starch; placebo (rice starch) will be administered blindly versus gluten for 15 days at 10 g/day	Dietary supplement: rice starch; rice starch is administered once a day at 10 g/day for 15 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptoms evaluation according to 3 scales: score after 2 weeks of gluten ingestion	The evaluation will be made according to the score calculated on the basis of three evaluation scales: "Gastrointestinal Symptom Rating Scale "(GSRS), modified, provides a score ranging MIN=15/MAX=60; Extra-gastrointestinal symptoms evaluation scale, proposed on the basis of the symptoms most frequently observed in GS patients, provides a score ranging MIN=9/MAX=34; VQV scale proposed to evaluate the quality of life, provides a score ranging MIN=16/MAX=64. Total score can be no less than 37 (MIN) and not more than 146 (MAX), with a cut-off of 55.	Change from baseline at 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bio-Markers to differentiate GS and CD	The identification of possible markers (serological, gut barrier function, immunological and expression of tight junctions constitutive proteins) that may be of help to differentiate, in humans, the condition of gluten sensitivity (GS) from that of Celiac Disease (CD); these markers might be of help in the early diagnosis of GS versus CD especially when the serology is discordant.	Change from baseline at 2 weeks
Symptoms evaluation according to 3 scales: scores 2 weeks after completion of intervention	The evaluation will be made according to the score calculated on the basis of three evaluation scales: "Gastrointestinal Symptom Rating Scale "(GSRS), modified, provides a score ranging MIN=15/MAX=60; Extra-gastrointestinal symptoms evaluation scale, proposed on the basis of the symptoms most frequently observed in GS patients, provides a score ranging MIN=9/MAX=34; VQV scale proposed to evaluate the quality of life, provides a score ranging MIN=16/MAX=64. Total score can be no less than 37 (MIN) and not more than 146 (MAX), with a cut-off of 55.	Return to baseline values at 4 weeks

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Investigators: Principal Investigator: Anna Sapone, MD, PhD, University of Campania "Luigi Vanvitelli"

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: November 17, 2011
• First Submitted That Met QC Criteria: December 1, 2011
• First Posted (Estimate): December 5, 2011

Study Record Updates

• Last Update Posted (Estimate): April 13, 2016
• Last Update Submitted That Met QC Criteria: April 12, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: gluten sensitivity
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: 61-2-9-2011