Non-celiac Wheat SensitivityNCT03027492

Gynaecological Disorders in Not-celiac Wheat Sensitivity

A study testing Gluten free diet and NCWS open challenge with wheat in people with Non-celiac Wheat Sensitivity, run by University of Palermo at 3 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years, women only
Conditions the study is for: Non-celiac Wheat Sensitivity
What is being tested?: Gluten free diet and NCWS open challenge with wheat
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 500 participants
Where: 3 sitesItaly
Study dates: 1 Jan 2001to 31 Jul 2025
Phase: Interventional
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:
age ≥18 years and ≤65 years;
negative serum assays for celiac disease: anti-deamidated gliadin peptide (anti-DGP) Ig (Immunoglobulin)A and IgG antibodies, anti-tissue transglutaminase (anti-tTG) IgA and IgG antibodies, and anti-endomysium (anti-EMA) IgA antibodies;
absence of duodenal villous atrophy, documented in all the patients carrying the DQ2 and/or DQ8 Human Leukocyte Antigens (HLA) haplotypes, evaluated during the ingestion of at least 100g of bread and/or pasta every day for at least 45 days;
exclusion of IgE-mediated wheat allergy, documented by a negative skin prick-test and/or serum dosage of IgE specific for wheat, gluten and gliadin;
complete resolution of symptoms after a strict standard elimination diet (oligoantigenic diet, free of wheat, cow's milk, eggs, tomatoes, chocolate, and other foods self-reported by patient as cause of symptoms) continued for at least 4 weeks, followed by the recurrence of symptoms after double-blind placebo-controlled wheat challenge or open challenges for the others self-reported foods;

Show all 10Show fewer

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;
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.

Who cannot join

For NCWS diagnosis it will be evaluated the following exclusion criteria:
self-elimination of wheat from the diet and refusal to reintroduce it for a diagnostic purpose, before entering in to the study;
treatment with corticosteroids and non steroidal anti-inflammatory (FANS) drugs during the 2 weeks before the duodenal biopsies;
EMA positivity in the culture medium of duodenal biopsies (EMA biopsy), even with a normal villo/crypt ratio in the mucosa;
pregnancy or breastfeeding;
alcohol and/or drug abuse;

Show all 10Show fewer

chronic inflammatory bowel disease or other intestinal organic disease; nervous system disease or major psychiatric disorders; infectious diseases; immunological deficits and physical impairments; 7) diagnosis of uro-gynecological organic diseases (uro-genital infections, endometriosis, neoplasms, etc.), confirmed by an uro-gynecologist both before the diagnosis of NCWS and during the follow-up period.
Additional specific inclusion/exclusion criteria for NCWS patients were used in this study: 1) female patient complaining of uro-gynecological disorders; 2) at least one uro-gynecological visit, including an uro-gynecological ultrasound and microbiological tests, that excluded uro-gynecological organic diseases within 6 months before the recruitment in the study; 3) follow-up period of at least 12 months after the initial diagnosis of NCWS and at least 2 outpatient, every 6 months, visits during the follow-up; 4) strict adherence to WFD 12 months after NCWS diagnosis.
Healthy controls had to respect the following inclusion criteria: 1) female gender; 2) age ≥18 years and ≤65 years; 3) negative serology for anti- Deamidated Gliadin Peptide (DGP) IgA and IgG antibodies, anti-tissue TransGlutaminase (tTG) IgA and IgG antibodies; 4) absence of self-reported symptoms related to wheat intake; 5) at least one uro-gynecological visit, including an uro-gynecological ultrasound and microbiological tests, that excluded uro-gynecological organic diseases within 6 months before the recruitment in the study.
Additional exclusion criteria for both NCWS patients and healthy controls were: 1) use of drugs potentially causes of the uro-gynecological disorders; 2) diagnosis of uro-gynecological organic diseases (uro-genital infections, endometriosis, neoplasms, etc.), confirmed by an uro-gynecologist; 3) previous surgical interventions on the uro-genital system; 4) absence of signed informed consent form.

Trial locations and contacts

3 sites in 1 country.

Italy3 sites

Department of Internal Medicine, University Hospital
Palermo, Palermo, 90129
Internal Medicine Unit, 'V. Cervello' Hospital
Palermo, Palermo, 90146
Department of Internal Medicine, Giovanni Paolo II Hospital
Sciacca, Agrigento, 92019

Other trials in Italy

About this study

Official title: Gynaecological Disorders in Patients With Not-celiac Wheat Sensitivity

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and very different extra-intestinal and systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays, there no data about a possible relationship between gynaecological disorders and food ingestion and food allergy/intolerance. Therefore, the aims of the present study are to investigate 1) the prevalence and characteristics of gynaecological disorders in NCWS patients compared to healthy, CD and irritable bowel syndrome (IBS) controls, 2) the modification of such disorders in NCWS patients after a gluten (wheat)-free diet, and 3) whether cytological alterations could be identified on samples taken during Papanicolaou (PAP) tests performed in NCWS patients with uro-gynecological disorders on strict WFD and after a 7-day open challenge with wheat.

Read the detailed description

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have CD or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. Other areas of doubt in NCWS regard its pathogenesis, while some papers reported intestinal immunologic activation, others linked NCWS to the dietary short chain carbohydrate (fermentable oligo-di-monosaccharides and polyols, FODMAPs) load. The investigators recently demonstrated that higher proportions of patients with NCWS develop autoimmune disorders, are antinuclear antibodies (ANA) positive, and show DQ2/DQ8 haplotypes compared with patients with IBS, supporting an immunologic involvement in NCWS. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and very different extra-intestinal and systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays, there no data about a possible relationship between gynaecological disorders (i.e. menstrual cycle alterations, vaginitis, recurrent vulvovaginitis, recurrent cystitis, chronic pelvic pain, recurrent pregnancy loss, infertility) and food ingestion and food allergy/intolerance. Therefore, the aims of the present study are to investigate 1) the prevalence and characteristics of gynaecological disorders in NCWS patients compared to healthy, CD and IBS controls, 2) the modification of such disorders in NCWS patients after a gluten (wheat)-free diet, and 3) whether cytological alterations could be identified on samples taken during Papanicolaou (PAP) tests performed in NCWS patients with uro-gynecological disorders on strict WFD and after a 7-day open challenge with wheat.

Conditions: Non-celiac Wheat Sensitivity
Being tested: Gluten free diet, NCWS open challenge with wheat
Keywords: Non-celiac Wheat Sensitivity, gynaecological disorders, gluten-free diet, celiac disease, irritable bowel syndrome
Medical subject headings: Celiac Disease, Irritable Bowel Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Gluten free dietOther
The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
NCWS open challenge with wheatOther
In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).

Study groups in NCT03027492
Study group	Role	What they receive
1. NCWS retrospective patients	Active comparator	The clinical charts of NCWS female patients attending the outpatient centers of the Department of Internal Medicine at the University Hospital of Palermo, Italy, the Department of Internal Medicine of the Hospital of Sciacca, Agrigento, Italy, and the Internal Medicine Unit, 'V. Cervello' Hospital of Palermo, Italy, will be reviewed with a retrospective method. They had all been diagnosed with NCWS between January 2001 and June 2024 and included in a previously published study. These charts included specific sections for associated gynaecological disorders. Incomplete clinical charts will be excluded. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
2. CD retrospective control patients	Active comparator	To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients had been randomly chosen by a computer-generated method from female patients diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
3. IBS retrospective control patients	Active comparator	To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients had been randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
4. NCWS prospective patients	Active comparator	The investigators prospectively will survey adult female patients with functional gastroenterological symptoms according to the Rome III criteria, and a suspected diagnosis of NCWS. The patients will be recruited between January 2017 and December 2024 at the same 3 centers. Most of the patients will be referred owing to gastrointestinal and extraintestinal symptoms, the onset of which, they reported, could be related to wheat ingestion. In addition, patients will be asked about the presence and characteristics of gynaecological disorders using an ad hoc questionnaire. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
5. CD prospective control patients	Active comparator	To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
6. IBS prospective control patients	Active comparator	To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet. Receives: Other: Gluten free diet
7. Healthy female controls	No intervention	During the same period (2011-2024), age-matched healthy female controls have been consecutively recruited in several General Practitioners (GPs) outpatients' clinics of Palermo, Italy.
8. NCWS femal patients open challenge with wheat	Active comparator	In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina). Receives: Other: NCWS open challenge with wheat

What is being measured

The primary outcome is the main question the study is designed to answer.

Gynaecological disorders in NCWS female patients at baseline
Prevalence of gynaecological disorders in retrospective and prospective NCWS female patients, compared to retrospective and prospective CD and IBS female patients.
Measured: Up to 200 months

Secondary outcomes (3)

Gynaecological disorders in NCWS female patients after gluten-free diet.
Gynaecological disorders evaluation after at least 6 months of gluten-free diet after the NCWS diagnosis, by visual analogic scales, specific questionnaire, and clinical examination, both in retrospective and prospective NCWS female patients.
Measured: Change from baseline to at leats 6 months of gluten-free diet
PAP test in NCWS female patients after gluten-free diet.
PAP smear after at least 6 months of gluten-free diet after the NCWS diagnosis, both in retrospective and prospective NCWS female patients.
Measured: Change from baseline at 6 months of gluten-free diet
PAP test in NCWS female patients after 7-day open challenge with wheat.
In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).
Measured: After at least 6 months of gluten-free diet

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Jan 200131 Jul 2025

First posted23 Jan 2017 (estimated)
Study start1 Jan 2001
Primary completion1 Jul 2021
Study completion31 Jul 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (7)Papers the sponsor has linked to this study.
Other trials for Non-celiac Wheat SensitivityStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Other
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 500 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03027492
Sponsor's protocol ID: ACPM15
Status last verified: Apr 2026
First submitted: 30 Dec 2016
Last updated: 14 Apr 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 27388423
Mansueto P, D'Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. World J Gastroenterol. 2015 Jun 21;21(23):7089-109. doi: 10.3748/wjg.v21.i23.7089.
PubMed 26109796
Carroccio A, Soresi M, D'Alcamo A, Sciume C, Iacono G, Geraci G, Brusca I, Seidita A, Adragna F, Carta M, Mansueto P. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. BMC Med. 2014 Nov 28;12:230. doi: 10.1186/s12916-014-0230-2.
PubMed 25430806
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.
PubMed 24533607
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.
PubMed 24275240
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.
PubMed 24169272
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.
PubMed 22825366

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
Liver Steatosis and Fibrosis in Non-Celiac Wheat Sensitivity Patients: a Prospective Study
Metabolic Dysfunction-Associated Steatotic Liver Disease, Non Celiac Wheat Sensitivity
Recruiting
NCWS or IBS/FD in Relatives of CD Patients
Non Celiac Wheat Sensitivity, IBS (Irritable Bowel Syndrome)
Recruiting
Urinary Gluten Immunogenic Peptides Detection in Non-celiac Gluten/Wheat Sensitivity
Non-celiac Gluten/Wheat Sensitivity
Recruiting
Tolerability of an Ancient Grain in Patients With Non-Celiac Wheat Sensitivity
Non-celiac Gluten Sensitivity
Not yet recruiting
Inflammatory Back Pain and Gluten Free Diet
Inflammatory Back Pain

All Non-celiac Wheat Sensitivity trials

Study at a glance

From the registry record, last updated by the sponsor on 14 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Gynaecological Disorders in Patients With Not-celiac Wheat Sensitivity
ClinicalTrials.gov ID: NCT03027492
Acronym / sponsor ID: ACPM15
Conditions: Non-celiac Wheat Sensitivity
Keywords: Non-celiac Wheat Sensitivity, gynaecological disorders, gluten-free diet, celiac disease, irritable bowel syndrome
Study type: Interventional
Recruitment status: Completed
Enrolment: 500 participants (actual)
Lead sponsor: University of PalermoUniversity, hospital or other
Study start: 1 Jan 2001 (actual)
Primary completion: 1 Jul 2021 (actual)
Study completion: 31 Jul 2025 (actual)
First posted: 23 Jan 2017 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have CD or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. Other areas of doubt in NCWS regard its pathogenesis, while some papers reported intestinal immunologic activation, others linked NCWS to the dietary short chain carbohydrate (fermentable oligo-di-monosaccharides and polyols, FODMAPs) load. The investigators recently demonstrated that higher proportions of patients with NCWS develop autoimmune disorders, are antinuclear antibodies (ANA) positive, and show DQ2/DQ8 haplotypes compared with patients with IBS, supporting an immunologic involvement in NCWS. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and very different extra-intestinal and systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays, there no data about a possible relationship between gynaecological disorders (i.e. menstrual cycle alterations, vaginitis, recurrent vulvovaginitis, recurrent cystitis, chronic pelvic pain, recurrent pregnancy loss, infertility) and food ingestion and food allergy/intolerance. Therefore, the aims of the present study are to investigate 1) the prevalence and characteristics of gynaecological disorders in NCWS patients compared to healthy, CD and IBS controls, 2) the modification of such disorders in NCWS patients after a gluten (wheat)-free diet, and 3) whether cytological alterations could be identified on samples taken during Papanicolaou (PAP) tests performed in NCWS patients with uro-gynecological disorders on strict WFD and after a 7-day open challenge with wheat.

Study design

Primary purpose: Other
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 8

Arm	Type	Receives
1. NCWS retrospective patients	Active comparator	Other: Gluten free dietThe clinical charts of NCWS female patients attending the outpatient centers of the Department of Internal Medicine at the University Hospital of Palermo, Italy, the Department of Internal Medicine of the Hospital of Sciacca, Agrigento, Italy, and the Internal Medicine Unit, 'V. Cervello' Hospital of Palermo, Italy, will be reviewed with a retrospective method. They had all been diagnosed with NCWS between January 2001 and June 2024 and included in a previously published study. These charts included specific sections for associated gynaecological disorders. Incomplete clinical charts will be excluded. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
2. CD retrospective control patients	Active comparator	Other: Gluten free dietTo compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients had been randomly chosen by a computer-generated method from female patients diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
3. IBS retrospective control patients	Active comparator	Other: Gluten free dietTo compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients had been randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
4. NCWS prospective patients	Active comparator	Other: Gluten free dietThe investigators prospectively will survey adult female patients with functional gastroenterological symptoms according to the Rome III criteria, and a suspected diagnosis of NCWS. The patients will be recruited between January 2017 and December 2024 at the same 3 centers. Most of the patients will be referred owing to gastrointestinal and extraintestinal symptoms, the onset of which, they reported, could be related to wheat ingestion. In addition, patients will be asked about the presence and characteristics of gynaecological disorders using an ad hoc questionnaire. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
5. CD prospective control patients	Active comparator	Other: Gluten free dietTo compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
6. IBS prospective control patients	Active comparator	Other: Gluten free dietTo compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.
7. Healthy female controls	No intervention	–During the same period (2011-2024), age-matched healthy female controls have been consecutively recruited in several General Practitioners (GPs) outpatients' clinics of Palermo, Italy.
8. NCWS femal patients open challenge with wheat	Active comparator	Other: NCWS open challenge with wheatIn a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).

Who may qualify

Ages: 18 to 65 years
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (10 listed)

To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:
age ≥18 years and ≤65 years;
negative serum assays for celiac disease: anti-deamidated gliadin peptide (anti-DGP) Ig (Immunoglobulin)A and IgG antibodies, anti-tissue transglutaminase (anti-tTG) IgA and IgG antibodies, and anti-endomysium (anti-EMA) IgA antibodies;
absence of duodenal villous atrophy, documented in all the patients carrying the DQ2 and/or DQ8 Human Leukocyte Antigens (HLA) haplotypes, evaluated during the ingestion of at least 100g of bread and/or pasta every day for at least 45 days;
exclusion of IgE-mediated wheat allergy, documented by a negative skin prick-test and/or serum dosage of IgE specific for wheat, gluten and gliadin;

Key exclusion criteria (10 listed)

self-elimination of wheat from the diet and refusal to reintroduce it for a diagnostic purpose, before entering in to the study;
treatment with corticosteroids and non steroidal anti-inflammatory (FANS) drugs during the 2 weeks before the duodenal biopsies;
EMA positivity in the culture medium of duodenal biopsies (EMA biopsy), even with a normal villo/crypt ratio in the mucosa;
pregnancy or breastfeeding;
alcohol and/or drug abuse;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Gluten free dietThe investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.	Other	1. NCWS retrospective patients, 2. CD retrospective control patients, 3. IBS retrospective control patients, 4. NCWS prospective patients, 5. CD prospective control patients, 6. IBS prospective control patients
NCWS open challenge with wheatIn a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).	Other	8. NCWS femal patients open challenge with wheat

Primary outcome

Gynaecological disorders in NCWS female patients at baseline
Time frame: Up to 200 months
Prevalence of gynaecological disorders in retrospective and prospective NCWS female patients, compared to retrospective and prospective CD and IBS female patients.

3 secondary outcomes

Gynaecological disorders in NCWS female patients after gluten-free diet.
Time frame: Change from baseline to at leats 6 months of gluten-free diet
PAP test in NCWS female patients after gluten-free diet.
Time frame: Change from baseline at 6 months of gluten-free diet
PAP test in NCWS female patients after 7-day open challenge with wheat.
Time frame: After at least 6 months of gluten-free diet

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2026.
Results publication: PubMed 27388423Di 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.
Results publication: PubMed 26109796Mansueto P, D'Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. World J Gastroenterol. 2015 Jun 21;21(23):7089-109. doi: 10.3748/wjg.v21.i23.7089.
Results publication: PubMed 25430806Carroccio A, Soresi M, D'Alcamo A, Sciume C, Iacono G, Geraci G, Brusca I, Seidita A, Adragna F, Carta M, Mansueto P. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. BMC Med. 2014 Nov 28;12:230. doi: 10.1186/s12916-014-0230-2.
Results publication: PubMed 24533607Mansueto 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.
Results publication: PubMed 24275240Carroccio 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.
Results publication: PubMed 24169272Carroccio 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.
Results publication: PubMed 22825366Carroccio 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.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Antonio Carroccio, MD study director

University of Palermo

3 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing Gluten free diet and NCWS open challenge with wheat in people with Non-celiac Wheat Sensitivity, run by University of Palermo at 3 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Gynaecological disorders in NCWS female patients at baseline (time frame: Up to 200 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03027492, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2026.