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Anemia in Non-celiac Wheat Sensitivity

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ClinicalTrials.gov Identifier: NCT04377061
Recruitment Status : Recruiting
First Posted : May 6, 2020
Last Update Posted : May 7, 2020
Sponsor:
Information provided by (Responsible Party):
Pasquale Mansueto, University of Palermo

Brief Summary:

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). This is very often a self-reported condition, since patients refer to intestinal [mainly irritable bowel syndrome (IBS)-like] and/or extra-intestinal symptoms (i.e. fatigue, headache, anemia) caused by gluten or wheat ingestion, even though they do not suffer from celiac disease (CD) or wheat allergy (WA).

Among the extra-intestinal symptoms, several studies have shown, in patients with NCWS, the presence of anemia, generally mild, often with iron or folate deficiency characteristics, but no research has ever been planned with the specific intention of analyze this particular aspect of the disease.

Therefore, the aim of the present multicentric research was to analyze, both retrospectively and prospectively, the laboratory data of NCWS patients, compared to CD and IBS controls, to identify: a) the presence, severity and morphologic characteristic of anemia; 2) possible pathogenic mechanisms.


Condition or disease Intervention/treatment
Non-celiac Gluten Sensitivity Anemia Diagnostic Test: Evaluation of anemia

Detailed Description:

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). This is very often a self-reported condition, since patients refer to intestinal [mainly irritable bowel syndrome (IBS)-like] and/or extra-intestinal symptoms (i.e. fatigue, headache, anemia) caused by gluten or wheat ingestion, even though they do not suffer from celiac disease (CD) or wheat allergy (WA).

There are conflicting data about the real mechanisms which induce symptoms in NCGS/NCWS patients after wheat ingestion. Some authors suggested a prevalent role for Fermentable Oligosaccharides-Disaccharides-Monosaccharides and Polyols (FODMAPs), rather than gluten in determining the symptoms. Other studies underlined the activation of mechanisms of both innate and acquired immunity in NCWS patients after wheat ingestion.

Given the lack of a diagnostic biomarker, NCGS/NCWS mostly remains a diagnosis of exclusion, especially respect to CD and WA, so a confirmatory test is required. The "Salerno criteria" suggested the double-blind, placebo-controlled (DBPC), cross-over, gluten/wheat challenge as the gold standard test to discriminate true NCGS/NCWS patients.

By definition, NCGS/NCWS symptoms generally occur after the ingestion of gluten/wheat, disappear within a few days of a gluten-free diet (GFD) and quickly reappear when gluten/wheat is, voluntarily or accidentally, reintroduced. However, GDF is very difficult and onerous from a social (presence of gluten in many industrial food products and "contamination", both domestic and extra-domestic), psychological (e.g. for adolescents, exclusion from the "peer group", with difficulty in accepting the diagnosis) and economic point of view.

Among the extra-intestinal symptoms, several studies have shown, in patients with NCWS, the presence of anemia, generally mild, often with iron or folate deficiency characteristics, but no research has ever been planned with the specific intention of analyze this particular aspect of the disease.

Therefore, the aim of the present multicentric research was to analyze, both retrospectively and prospectively, the laboratory data of NCWS patients, compared to CD and IBS controls, to identify: a) the presence, severity and morphologic characteristic of anemia; 2) possible pathogenic mechanisms, with particular attention to iron, vitamin B12 and folate metabolism, thyroid hormones, and autoimmune gastric involvement.

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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Clinical Characteristics and Pathogenic Mechanisms of Anemia in Non-celiac Wheat Sensitivity Compared to Celiac Disease and Irritable Bowel Syndrome
Actual Study Start Date : January 1, 2020
Estimated Primary Completion Date : January 1, 2021
Estimated Study Completion Date : January 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy Anemia

Group/Cohort Intervention/treatment
NCWS retrospective and prospective patients
The clinical charts of NCWS patients, diagnosed by DBPC gluten/wheat challenge, between January 2001 and December 2019, attending the Department of Internal Medicine at the University Hospital of Palermo, the Department of Internal Medicine of the Hospital of Sciacca, and the Department of Medical and Surgical Sciences of the University of Bologna, will be reviewed retrospectively. The investigators prospectively will also survey patients with functional gastroenterological symptoms according to the Rome III criteria, and a definitive diagnosis of NCWS by DBPC gluten/wheat challenge. The patients will be recruited between January 2019 and January 2022 at the same centers, and at the Internal Medicine Division of the "Cervello-Villa Sofia" Hospital of Palermo, Palermo.
Diagnostic Test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.

CD retrospective and prospective control patients
To compare the presence and characteristics of anemia in NCWS patients, the clinical charts of a control group of CD patients had been randomly chosen by a computer-generated method from patients diagnosed in the same centers, during the same period (2001-2019), and age- and sex-matched with the NCWS patients. The investigators prospectively will also survey a control group of CD patients randomly chosen by a computer-generated method from subjects diagnosed in the same centers, during the same period (2019-2022), and age- and sex-matched with the NCWS patients.
Diagnostic Test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.

IBS retrospective and prospective control patients
To compare the presence and characteristics of anemia in NCWS patients, the clinical charts of another control group of IBS patients had been randomly chosen by a computer-generated method from patients diagnosed in the same centers, during the same period (2001-2019), and age- and sex-matched with the NCWS patients. The investigators prospectively will also survey a control group of IBS patients randomly chosen by a computer-generated method from subjects diagnosed in the same centers, during the same period (2019-2022), and age- and sex-matched with the NCWS patients.
Diagnostic Test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.




Primary Outcome Measures :
  1. Presence, severity and morphologic characteristic of anemia [ Time Frame: At baseline and at 24 months ]
    red blood cells (adults references ranges, RR, 4.5-5.9 million cells/mcL, men, 4.1-5.1 million cells/mcL, women), hemoglobin (RR 13-17 g/dL, men, 12-15 g/dL, women), hematocrit (RR 40%-52%, men, 36%-47%, women), mean corpuscular volume (RR 80-100 fL), mean corpuscular hemoglobin (RR 0.4-0.5 fmol/cell), mean corpuscular hemoglobin concentration (RR 30-35 g/dL), red cell distribution width (RR 11.5%-14.5%)


Secondary Outcome Measures :
  1. Possible pathogenic mechanisms [ Time Frame: At baseline and at 24 months ]
    reticulocytes count (RR 0.5%-1.5%), total serum iron (RR 65-180 µg/dL, men, 30-170 µg/dL, women), ferritin (RR 12-300 ng/mL, men, 12-150 ng/mL, women), transferrin (200-350 mg/dL), total iron-binding capacity (RR 45-85 µmol/L), vitamin B12 (RR 130-700 ng/L), folic acid (RR 7-36 nmol/L), thyroid-stimulating hormone (TSH, RR 2-10 μU/mL), anti-nuclear antibodies (ANA), anti-intrinsic factor (IFA) and/or parietal cell (APCA) antibodies



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Probability Sample
Study Population
We will enroll NCWS patients, both with retrospective and prospective methods. As controls groups, we will enroll CD and IBS patients, both with retrospective and prospective methods.
Criteria

Inclusion Criteria:

  1. To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:

    - negative serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) immunoglobulin (Ig)A and IgG antibodies, absence of intestinal villous atrophy, negative IgE-mediated immune-allergy tests to wheat (skin prick tests and/or serum specific IgE detection), resolution of the IBS symptoms on standard elimination diet, excluding wheat, cow's milk, egg, tomato, chocolate, and other self-reported food(s) causing symptoms, symptom reappearance on double-blind placebo-controlled (DBPC) wheat challenge. As the investigators previously described in other studies, DBPC cow's milk protein challenge and other "open" food challenges will be performed too.

  2. To diagnose CD the standard criteria will be adopted. All the patients will meet the following criteria:

    - positive serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) immunoglobulin (Ig)A and IgG antibodies presence of intestinal villous atrophy.

  3. To diagnose IBS the standard Rome II (for retrospective patients) and Rome III (for prospective patients) Criteria will be adopted. None of these subjects improved on an elimination diet without wheat, cow's milk, egg, tomato, or chocolate.

Exclusion Criteria:

For NCWS diagnosis it will be evaluated the following exclusion criteria:

- positive EmA in the culture medium of the duodenal biopsies, also in the case of normal villi/crypts ratio in the duodenal mucosa, self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study, other previously diagnosed gastrointestinal disorders, other previously diagnosed gynaecological disorders, nervous system disease and/or major psychiatric disorder, physical impairment limiting physical activity.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04377061


Contacts
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Contact: Antonio Carroccio, PhD +393395665437 acarroccio@gmail.com

Locations
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Italy
Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca Completed
Sciacca, Agrigento, Italy, 92019
Internal Medicine Division of the "Cervello-Villa Sofia" Hospital Recruiting
Palermo, PA, Italy, 90129
Contact: Antonio Carroccio, PHD    +390916552884    acarroccio@hotmail.com   
Department of Internal Medicine, University Hospital of Palermo Recruiting
Palermo, Italy, 90129
Contact: Pasquale Mansueto, MD    +390916552884    pasquale.mansueto@unipa.it   
Sponsors and Collaborators
University of Palermo
Investigators
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Principal Investigator: Pasquale Mansueto, MD University of Palermo
Publications of Results:

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Responsible Party: Pasquale Mansueto, Principal Investigator, University of Palermo
ClinicalTrials.gov Identifier: NCT04377061    
Other Study ID Numbers: ACPM25
First Posted: May 6, 2020    Key Record Dates
Last Update Posted: May 7, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pasquale Mansueto, University of Palermo:
Non-celiac Gluten Sensitivity
Anemia
Additional relevant MeSH terms:
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Anemia
Hypersensitivity
Hematologic Diseases
Immune System Diseases