- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03563300
Gluten-related Disorders in Familial Mediterranean Fever Patients
April 16, 2019 updated by: Pasquale Mansueto, University of Palermo
Gluten-related Disorders in Patients Affected With Familial Mediterranean Fever
It is known that the gluten-containing grains can be responsible for human diseases related to gluten exposure.
These forms of gluten intolerance represent a heterogeneous set of conditions, including celiac disease (CD), wheat allergy (WA) and not celiac gluten sensitivity (NCGS), that combined seems to affect about 5-10% of the general population.
NCGS is the most recent gluten-related disease, characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects in whom either celiac disease or wheat allergy previously has been excluded.
However, as it is not known what component of the cereals causes the symptoms in NCGS patients, the investigators prefer the label of "Not-celiac wheat sensitivity" (NCWS).
Typically, the NCWS diagnosis is made by exclusion.
Furthermore, similarly to CD, the investigators had demonstrated that NCWS may be associated with other autoimmune disease (i.e.
Hashimoto's thyroiditis).
Among these autoimmune conditions, in our daily out clinic work, the investigators have observed an association between self-reported NCWS and Familial Mediterranean Fever (FMF).
Our preliminary observational data indicate that some FMF patients relate their symptoms (especially gastrointestinal) to gluten assumption, then excluding it from diet and using gluten-free products, with partial remission of gastrointestinal symptoms.
Therefore, FMF and NCGS share some clinical features, such as abdominal pain, diarrhea, arthralgia and arthritis, and tend to be commonly associated with other inflammatory and autoimmune diseases.
This study has 2 major aims: 1.To evaluate the real relationship between the wheat ingestion and the gastrointestinal manifestations presented by FMF patients, self-reporting a NCWS.
2. To identify possible immunologic markers that may explain the mechanism underling FMF abdominal attack and wheat ingestion.
Study Overview
Status
Completed
Intervention / Treatment
Detailed Description
It is known that the gluten-containing grains can be responsible for human diseases related to gluten exposure.
These forms of gluten intolerance represent a heterogeneous set of conditions, including celiac disease (CD), wheat allergy (WA) and not celiac gluten sensitivity (NCGS), that combined seems to affect about 5-10% of the general population.
NCGS is the most recent gluten-related disease.
It is characterized by intestinal (i.e.
irritable bowel syndrome, bloating, dyspepsia) and extra-intestinal symptoms (i.e.
fatigue, headache, numbness, mental confusion) related to the ingestion of gluten-containing food, in subjects in whom either celiac disease or wheat allergy previously has been excluded.
However, as it is not known what component of the cereals causes the symptoms in NCGS patients, the investigators prefer the label of "Not-celiac wheat sensitivity" (NCWS).
Typically, the NCWS diagnosis is made by exclusion.
In fact, in previous studies the investigators showed that patients self-reporting gastrointestinal symptoms related to wheat ingestion, could suffer not only from CD or WA, but from small intestinal bacterial overgrowth or inflammatory bowel diseases also.
Furthermore, similarly to CD, the investigators had demonstrated that NCWS may be associated with other autoimmune disease (i.e.
Hashimoto's thyroiditis).
Among these autoimmune conditions, in our daily out clinic work, the investigators have observed an association between self-reported NCWS and Familial Mediterranean Fever (FMF).
Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease, characterized by self-limited recurrent attacks of fever and serositis, resulting in pain in the abdomen, chest, joints and muscles.
FMF is caused by mutations in MEFV gene, which encodes pyrin.
Pyrin is implicated in a complex interplay with proteins involved in Toll-like receptor (TLR) signalling, PYD superfamily and procaspase-1 activation, suggesting a controlling role in inflammatory response.
Abdominal pain is the most frequent symptom encountered in FMF; 95% of patients report this as the main symptom during at least some of their fever episodes, while 50% cite such an 'abdominal attack' as the first symptom of their disease.
Presentation of a typical abdominal attack will resemble that of 'acute abdomen'.
Onset is sudden and acute, leading to rapid development of symptoms within 1-2 hours.
The abdominal pain is usually diffuse throughout the entire abdomen, although in some cases it may be localized; it may be very severe in intensity.
This may be accompanied by any bowel activity, ranging from constipation (most often) to diarrhoea.
The intensity of symptoms and signs of an inflammatory attack in FMF will decrease spontaneously after 12-24 hours, and usually, the attack resolves over the following 48 hours.
Thus, after about 3 days the patient will be symptom-free again.
Furthermore, so-called "incomplete" abdominal attacks may occur in FMF patients.
These differ from 'typical' abdominal attacks in 1 or 2 features, which may include absence of fever, absence of 'true' peritonitis and/or localisation of the abdominal pain to a single specific abdominal area, minimal change in acute phase parameters.
It may be difficult to differentiate an 'incomplete' abdominal attack from other causes of abdominal pain, mainly because of its atypical presentation.
Our preliminary observational data indicate that some FMF patients relate their symptoms (especially gastrointestinal) to gluten assumption, then excluding it from diet and using gluten-free products, with partial remission of gastrointestinal symptoms.
Therefore, FMF and NCGS share some clinical features, such as abdominal pain, diarrhea, arthralgia and arthritis, and tend to be commonly associated with other inflammatory and autoimmune diseases.
However, to our knowledge, a relationship between FMF and NCGS has not been previously investigated.
This study has 2 major aims: 1.To evaluate the real relationship between the wheat ingestion and the gastrointestinal manifestations presented by FMF patients, self-reporting a NCWS.
The study will be done after a period of gluten-free diet, administering wheat flour or placebo for 15 days.
2. To identify possible immunologic markers (histological features, expression of cytokines and other constitutive mucosal proteins from peripheral blood mononuclear cells and mucosal lymphocytes) that may explain the mechanism underling FMF abdominal attack and wheat ingestion.
Study Type
Interventional
Enrollment (Actual)
8
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
-
Palermo, Italy, 90129
- Department of Internal Medicine, University Hospital of Palermo
-
-
Agrigento
-
Sciacca, Agrigento, Italy, 92019
- Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
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, both genders, with age between 18-65 years, affected with FMF, diagnosed according to clinical criteria designed by Livneh et al ("Tel-Hashomer" criteria), self-reporting a relationship between their symptoms (especially gastrointestinal) and gluten assumption, improving on a gluten-free diet and worsen on a gluten containing diet
- Patients testing negative for celiac disease (anti-tTG and EMA negative, and with biopsy Marsh 0-1) and wheat allergy (serum specific IgE for wheat negative)
Exclusion Criteria:
- Subjects diagnosed with celiac disease (positive anti-tTG and/or EMA, and positive histology, with Marsh 2 or above);
- Subjects diagnosed with wheat allergy (positive serum specific IgE for wheat)
- Subjects with Inflammatory Bowel Diseases (Crohn's disease or ulcerative colitis)
- Subjects with Helicobacter pylori infection and other gastrointestinal infection
- Pregnancy
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Wheat flour
Wheat flour will be administered blindly versus placebo for 7 days
|
Wheat flour will be administered once daily for 7 days
Other Names:
|
Placebo Comparator: Rice flour
Placebo will be administered blindly versus wheat flour for 7 days
|
Placebo will be administered blindly versus wheat flour for 7 days
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Fibromyalgia symptoms evaluation
Time Frame: Change from baseline at 1 week
|
Fibromyalgia symptoms of patients, evaluated by the International Severity Scoring System for Familial Mediterranean Fever (ISSF), will be scored before and after 1 week of wheat (or placebo) ingestion
|
Change from baseline at 1 week
|
Gastrointestinal symptoms evaluation
Time Frame: Change from baseline at 1 week
|
Gastrointestinal symptoms of patients, evaluated by the Gastrointestinal Symptom Rating Scale (GSRS), will be scored before and after 1 week of wheat (or placebo) ingestion
|
Change from baseline at 1 week
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Leukocytes cell surface antigens expression
Time Frame: Change from baseline at 1 week
|
There will be evaluated some leukocytes cell surface antigens expression, i.e.
CD45, CD56, CD117, NKp44, CD3, CD19, and CD14, from peripheral blood mononuclear cells and rectal mucosal lymphocytes before and after 1 week of wheat (or placebo) ingestion
|
Change from baseline at 1 week
|
Cytokines production
Time Frame: Change from baseline at 1 week
|
There will be evaluated some cytokines production, i.e.
IFN-γ, TNF-α, IL-22, IL-17, and T-bet, from peripheral blood mononuclear cells and rectal mucosal lymphocytes before and after 1 week of wheat (or placebo) ingestion
|
Change from baseline at 1 week
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Antonio Carroccio, PHD, University of Palermo
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996.
- Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
- Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. No abstract available.
- Carroccio A, Mansueto P, D'Alcamo A, Iacono G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am J Gastroenterol. 2013 Dec;108(12):1845-52; quiz 1853. doi: 10.1038/ajg.2013.353. Epub 2013 Nov 5.
- Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988 Feb;33(2):129-34. doi: 10.1007/BF01535722.
- Carroccio A, D'Alcamo A, Cavataio F, Soresi M, Seidita A, Sciume C, Geraci G, Iacono G, Mansueto P. High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies. Gastroenterology. 2015 Sep;149(3):596-603.e1. doi: 10.1053/j.gastro.2015.05.040. Epub 2015 May 27.
- Di Liberto D, Mansueto P, D'Alcamo A, Lo Pizzo M, Lo Presti E, Geraci G, Fayer F, Guggino G, Iacono G, Dieli F, Carroccio A. Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet. Clin Transl Gastroenterol. 2016 Jul 7;7(7):e178. doi: 10.1038/ctg.2016.35.
- Demirkaya E, Acikel C, Hashkes P, Gattorno M, Gul A, Ozdogan H, Turker T, Karadag O, Livneh A, Ben-Chetrit E, Ozen S; FMF Arthritis Vasculitis and Orphan disease Research in pediatric rheumatology (FAVOR). Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis. 2016 Jun;75(6):1051-6. doi: 10.1136/annrheumdis-2015-208671. Epub 2016 Jan 28.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
September 1, 2018
Primary Completion (Actual)
March 1, 2019
Study Completion (Actual)
April 1, 2019
Study Registration Dates
First Submitted
May 24, 2018
First Submitted That Met QC Criteria
June 19, 2018
First Posted (Actual)
June 20, 2018
Study Record Updates
Last Update Posted (Actual)
April 17, 2019
Last Update Submitted That Met QC Criteria
April 16, 2019
Last Verified
April 1, 2019
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- ACPM21
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Familial Mediterranean Fever (FMF)
-
Rambam Health Care CampusWithdrawnFamilial Mediterranean Fever (FMF )
-
National Human Genome Research Institute (NHGRI)Merck Sharp & Dohme LLC; Duke University; University of Massachusetts, WorcesterRecruitingFever | Genetic Diseases | Familial Mediterranean Fever (FMF) | Autoinflammation | Periodic Fever | ROSAH | ALPK1United States
-
R-Pharm International, LLCAtlant Clinical LLC; Center for Pharmaceutical Analytics LLC; Unimed Laboratories... and other collaboratorsRecruitingFamilial Mediterranean Fever | FMFArmenia, Georgia, Russian Federation
-
R-Pharm International, LLCR-Pharm; Atlant Clinical LLC; Unimed Laboratories CJSC; Data Management 365; Center...RecruitingFamilial Mediterranean Fever | FMFArmenia, Georgia, Russian Federation
-
Assistance Publique - Hôpitaux de ParisNot yet recruiting
-
Istanbul University - Cerrahpasa (IUC)Recruiting
-
Novartis PharmaceuticalsCompletedColchicine Resistant/Intolerant Familial Mediterranean FeverIsrael
-
University Hospital, MontpellierNot yet recruitingFamilial Mediterranean FeverFrance
-
Sohag UniversityNot yet recruitingFamilial Mediterranean FeverEgypt
Clinical Trials on Wheat flour
-
Purdue UniversityCompletedObesity | Diabetes Mellitus, Type 2 | Appetitive BehaviorUnited States
-
University of Maryland, BaltimoreCompletedSchizophreniaUnited States
-
University of PalermoRecruitingNon-celiac Wheat SensitivityItaly
-
University of PalermoRecruiting
-
Peking UniversityCompleted
-
Peking UniversityNot yet recruitingChronic Disease PreventionChina
-
Aga Khan UniversityThe Hospital for Sick Children; University of California; Bahauddin Zakariya...RecruitingInflammation | Diabetes | Malnutrition | ConjunctivitisPakistan
-
Yale UniversitySilver Palate Kitchens Inc.CompletedDiabetes Type 2United States
-
University of ManitobaPulse CanadaCompletedCardiovascular DiseaseCanada