Non-Coeliac Wheat Sensitivity (NCWS)ATINCT05157867
In Vivo Effects of Amylase Trypsin Inhibitors
A study testing Amylase trypsin inhibitors in people with Non-Coeliac Wheat Sensitivity (NCWS) and Irritable Bowel Syndrome, run by Maastricht University.
Trial summary
Wheat is the most important staple food consumed in the Western world and provides beneficial health effects and functional properties. Nevertheless, an increasing proportion of the general population is avoiding or reducing its consumption of wheat products due to self-reported gastrointestinal (GI) symptoms, such as… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Non-Coeliac Wheat Sensitivity (NCWS), Irritable Bowel Syndrome
- What is being tested?
- Amylase trypsin inhibitors
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 8 participants
- Where
- No sites listed yet
- Study dates
- Sep 2023to Sep 2024
- 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
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Based on medical history and previous self-admitted examination, no gastrointestinal complaints and/or disease can be defined.
- Age between 18 and 65 years.
- Body Mass Index (BMI) between 20 and 30 kg/m2.
Who cannot join
- History of severe cardiovascular, respiratory, urogenital, gastrointestinal/hepatic, hematological/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurological/psychiatric diseases, allergy, major surgery and/or laboratory assessments which might limit participation in or completion of the study protocol. The severity of the disease (major interference with the execution of the experiment or potential influence on the study outcomes) will be decided by the principal investigator.
- Use of medication, including vitamin supplementation, pre- and probiotic supplementation, except oral contraceptives, within 14 days prior to testing.
- Administration of investigational drugs or participation in any scientific intervention study, which may interfere with this study (to be decided by the principal investigator), in the 180 days prior to the study.
- Major abdominal surgery interfering with gastrointestinal function (uncomplicated appendectomy, cholecystectomy and hysterectomy allowed, and other surgery upon judgement of the principal investigator).
- Pregnancy, lactation.
- Excessive alcohol consumption (> 14 alcoholic consumptions per week).
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- Smoking.
- Drug use.
- Blood donation within 3 months before or after the study period.
- Self-admitted HIV-positive state.
- Plan to lose weight or follow a specific diet (e.g. weight loss or gluten-free diet) within the study period.
Trial locations and contacts
No sites are listed yet.
About this study
Official title: In Vivo Effects of Amylase Trypsin Inhibitors From Wheat in the Human Gut: Proof of Cause of Non-coeliac Wheat Sensitivity in Irritable Bowel Syndrome?
Wheat is the most important staple food consumed in the Western world and provides beneficial health effects and functional properties. Nevertheless, an increasing proportion of the general population is avoiding or reducing its consumption of wheat products due to self-reported gastrointestinal (GI) symptoms, such as patients with non-coeliac wheat sensitivity (NCWS) and/or irritable bowel syndrome (IBS). There is increasing evidence that the amylase trypsin inhibitors (ATIs), accounting for up to 15% of wheat proteins, play a role in the symptom generation in NCWS and IBS. In vitro studies showed ATIs can induce an innate immune response via direct interaction with the toll-like receptor 4 (TLR4), activating the TLR4-MD2-CD14 complex with subsequent release of pro-inflammatory cytokines. These results were confirmed in mice. Furthermore, in mice ATIs triggered intestinal epithelial lymphocytosis and barrier dysfunction, and modified microbiota composition and metabolism. Thus far, there have been no placebo-controlled studies investigating these effects of isolated ATIs in human subjects. Understanding the role of ATIs in symptom generation in NCWS and IBS patients is important to provide these patients with appropriate dietary advice, improving their quality of life and decreasing their risk of nutritional deficiencies.
The investigators aim to perform a proof-of-concept study to assess the effect of ATIs on the intestinal barrier and immune function in healthy volunteers. The investigators hypothesise that the ATIs either directly affect the intestinal barrier function, or indirectly by activating an immune response via TLR4.
The study conforms a randomized, double-blind, placebo-controlled, cross-over design, using healthy human volunteers (male and female), 18-65 years old. Volunteers will each undergo two test days, separated by a wash-out period of at least 4 weeks. At the test day, volunteers receive either isolated ATIs or placebo (physiological saline), ingested using a nasogastric intraduodenal feeding catheter.
- Being tested
- Amylase trypsin inhibitors, Placebo
- Keywords
- Non-Coeliac Wheat Sensitivity, Irritable Bowel Syndrome, Amylase Trypsin Inhibitors
- Medical subject headings
- Irritable Bowel Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Amylase trypsin inhibitorsOther
Intraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (wheat), dissolved in physiological saline.
PlaceboOther
Intraduodenal administration of placebo (physiological saline).
| Study group | Role | What they receive |
|---|---|---|
| Amylase trypsin inhibitors (ATIs), then placebo | Experimental | Test day 1: intraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (bread wheat), dissolved in physiological saline. After a wash-out period of 4-6 weeks, test day 2: intraduodenal administration of placebo (physiological saline). Receives: Other: Amylase trypsin inhibitors; Other: Placebo |
| Placebo, then Amylase trypsin inhibitors | Experimental | Test day 1: intraduodenal administration of placebo (physiological saline). After a wash-out period of 4-6 weeks, test day 2: intraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (bread wheat), dissolved in physiological saline. Receives: Other: Amylase trypsin inhibitors; Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in gene expression associated with intestinal barrier function, measured in duodenal biopsies collected after intervention with ATIs or placebo
Gene expression associated with intestinal barrier function, such as gene expression of tight junction and adherens junction proteins: e.g. peri-junctional Factin, myosin, ZO-1, claudin-3, occluding, myosin light chain kinase, phosphorylated myosin light chain, E-cadherin.
Duodenal biopsies will be obtained using upper gastrointestinal endoscopy.
Measured: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Secondary outcomes (7)
Difference in protein levels associated with intestinal barrier function, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Expression of proteins associated with intestinal barrier function, such as tight junction and adherens junction proteins by Western blot and immunofluorescent staining. Duodenal biopsies will be obtained using upper gastrointestinal endoscopy.
Measured: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Differences in gene expression associated with immune function, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Gene expression associated with immune activation, such as TLR4, and pro-inflammatory cytokines and antimicrobiota peptides.
Duodenal biopsies will be obtained using upper gastrointestinal endoscopy.
Measured: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Differences in infiltration of immune cells in duodenal tissue, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Infiltration of immune cells (neutrophils, mast cells, dendritic cells) into duodenal tissue by immunofluorescent staining. Duodenal biopsies will be obtained using upper gastrointestinal endoscopy.
Measured: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Difference in change in gastrointestinal symptoms from baseline after intervention with ATIs or placebo.
Measured on the Visual Analogue Scale ranged from 0-100, in which 0 is absence of symptoms and 100 is severe symptoms; ATIs vs placebo
Measured: Various time points throughout each test day: 1 hour before and 5 minutes before intervention with ATIs or placebo, and 1 hour, 2 hours and 12 hours after intervention with ATIs or placebo
Difference in blood immune cell populations after intervention with ATIs or placebo
Quantification of immune cell populations (T helper cells, cytotoxic T cells, CD25+ effector T cells, CD69+ effector T cells, regulatory T cells, and NK-cells) in whole blood.
Measured: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Difference in blood biomarkers of immune stimulation after intervention with ATIs or placebo
Measurement of biomarkers of immune stimulation (such as the human cytokines IL-10, TGF-β, IL-12p40 subunit, IL-12p70 subunit, IL-1β, IL-2, IL-6, IL-4, IL-17, IL-22 and IFN-γ, TNFα) in whole blood.
Measured: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Blood markers for intestinal barrier function after intervention with ATIs or placebo
Markers for intestinal barrier function (plasma citrulin, metabolites) and small intestinal mucosal tissue injury (intestinal fatty acid binding protein (I-FABP)), measured in whole blood.
Measured: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2021
- Study startSep 2023 (estimated)
- Primary completionSep 2024 (estimated)
- Study completionSep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-Coeliac Wheat Sensitivity (NCWS)Studies 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized, double-blind, placebo-controlled, cross-over study
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 8 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Maastricht University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Daisy MAE Jonkers, Prof, PhD, Principal investigator, Maastricht University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05157867
- Sponsor's protocol ID
- NL77666.608.21
- Acronym
- ATI
- Status last verified
- Mar 2023
- First submitted
- 6 Oct 2021
- Last updated
- 27 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- In Vivo Effects of Amylase Trypsin Inhibitors From Wheat in the Human Gut: Proof of Cause of Non-coeliac Wheat Sensitivity in Irritable Bowel Syndrome?
- ClinicalTrials.gov ID
- NCT05157867
- Acronym / sponsor ID
- ATI / NL77666.608.21
- Keywords
- Non-Coeliac Wheat Sensitivity, Irritable Bowel Syndrome, Amylase Trypsin Inhibitors
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 8 participants (estimated)
- Lead sponsor
- Maastricht UniversityUniversity, hospital or other
- Study start
- Sep 2023 (estimated)
- Primary completion
- Sep 2024 (estimated)
- Study completion
- Sep 2024 (estimated)
- First posted
- 15 Dec 2021 (actual)
- 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.
Wheat is the most important staple food consumed in the Western world and provides beneficial health effects and functional properties. Nevertheless, an increasing proportion of the general population is avoiding or reducing its consumption of wheat products due to self-reported gastrointestinal (GI) symptoms, such as patients with non-coeliac wheat sensitivity (NCWS) and/or irritable bowel syndrome (IBS). There is increasing evidence that the amylase trypsin inhibitors (ATIs), accounting for up to 15% of wheat proteins, play a role in the symptom generation in NCWS and IBS. In vitro studies showed ATIs can induce an innate immune response via direct interaction with the toll-like receptor 4 (TLR4), activating the TLR4-MD2-CD14 complex with subsequent release of pro-inflammatory cytokines. These results were confirmed in mice. Furthermore, in mice ATIs triggered intestinal epithelial lymphocytosis and barrier dysfunction, and modified microbiota composition and metabolism. Thus far, there have been no placebo-controlled studies investigating these effects of isolated ATIs in human subjects. Understanding the role of ATIs in symptom generation in NCWS and IBS patients is important to provide these patients with appropriate dietary advice, improving their quality of life and decreasing their risk of nutritional deficiencies.
The investigators aim to perform a proof-of-concept study to assess the effect of ATIs on the intestinal barrier and immune function in healthy volunteers. The investigators hypothesise that the ATIs either directly affect the intestinal barrier function, or indirectly by activating an immune response via TLR4.
The study conforms a randomized, double-blind, placebo-controlled, cross-over design, using healthy human volunteers (male and female), 18-65 years old. Volunteers will each undergo two test days, separated by a wash-out period of at least 4 weeks. At the test day, volunteers receive either isolated ATIs or placebo (physiological saline), ingested using a nasogastric intraduodenal feeding catheter.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Randomized, double-blind, placebo-controlled, cross-over study
| Arm | Type | Receives |
|---|---|---|
| Amylase trypsin inhibitors (ATIs), then placebo | Experimental | Other: Amylase trypsin inhibitors, Other: PlaceboTest day 1: intraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (bread wheat), dissolved in physiological saline. After a wash-out period of 4-6 weeks, test day 2: intraduodenal administration of placebo (physiological saline). |
| Placebo, then Amylase trypsin inhibitors | Experimental | Other: Amylase trypsin inhibitors, Other: PlaceboTest day 1: intraduodenal administration of placebo (physiological saline). After a wash-out period of 4-6 weeks, test day 2: intraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (bread wheat), dissolved in physiological saline. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Based on medical history and previous self-admitted examination, no gastrointestinal complaints and/or disease can be defined.
- Age between 18 and 65 years.
- Body Mass Index (BMI) between 20 and 30 kg/m2.
Key exclusion criteria (11 listed)
- History of severe cardiovascular, respiratory, urogenital, gastrointestinal/hepatic, hematological/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurological/psychiatric diseases, allergy, major surgery and/or laboratory assessments which might limit participation in or completion of the study protocol. The severity of the disease (major interference with the execution of the experiment or potential influence on the study outcomes) will be decided by the principal investigator.
- Use of medication, including vitamin supplementation, pre- and probiotic supplementation, except oral contraceptives, within 14 days prior to testing.
- Administration of investigational drugs or participation in any scientific intervention study, which may interfere with this study (to be decided by the principal investigator), in the 180 days prior to the study.
- Major abdominal surgery interfering with gastrointestinal function (uncomplicated appendectomy, cholecystectomy and hysterectomy allowed, and other surgery upon judgement of the principal investigator).
- Pregnancy, lactation.
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 |
|---|---|---|
| Amylase trypsin inhibitorsIntraduodenal administration of amylase trypsin inhibitors (ATIs) isolated from Triticum aestivum (wheat), dissolved in physiological saline. | Other | Amylase trypsin inhibitors (ATIs), then placebo, Placebo, then Amylase trypsin inhibitors |
| PlaceboIntraduodenal administration of placebo (physiological saline). | Other | Amylase trypsin inhibitors (ATIs), then placebo, Placebo, then Amylase trypsin inhibitors |
Primary outcome
Difference in gene expression associated with intestinal barrier function, measured in duodenal biopsies collected after intervention with ATIs or placebo
Time frame: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Gene expression associated with intestinal barrier function, such as gene expression of tight junction and adherens junction proteins: e.g. peri-junctional Factin, myosin, ZO-1, claudin-3, occluding, myosin light chain kinase, phosphorylated myosin light chain, E-cadherin. Duodenal biopsies will be obtained using upper gastrointestinal endoscopy.
7 secondary outcomes
Difference in protein levels associated with intestinal barrier function, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Time frame: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Differences in gene expression associated with immune function, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Time frame: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Differences in infiltration of immune cells in duodenal tissue, measured in duodenal biopsies collected after intervention with ATIs or placebo.
Time frame: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Difference in change in gastrointestinal symptoms from baseline after intervention with ATIs or placebo.
Time frame: Various time points throughout each test day: 1 hour before and 5 minutes before intervention with ATIs or placebo, and 1 hour, 2 hours and 12 hours after intervention with ATIs or placebo
Difference in blood immune cell populations after intervention with ATIs or placebo
Time frame: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Difference in blood biomarkers of immune stimulation after intervention with ATIs or placebo
Time frame: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Blood markers for intestinal barrier function after intervention with ATIs or placebo
Time frame: Blood samples will be collected directly after upper gastrointestinal endoscopy, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2023.
- Individual participant dataSharing planned: No
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.
Daisy MAE Jonkers, Prof, PhD principal investigator
Maastricht University
Questions about this trial
What is this clinical trial studying?
A study testing Amylase trypsin inhibitors in people with Non-Coeliac Wheat Sensitivity (NCWS) and Irritable Bowel Syndrome, run by Maastricht University.
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 3 inclusion and 11 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: status not confirmed, as of the sponsor's last update on 27 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Marlijne CG de Graaf, MSc (+31(0)433884237, m.degraaf@maastrichtuniversity.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in gene expression associated with intestinal barrier function, measured in duodenal biopsies collected after intervention with ATIs or placebo (time frame: Biopsies will be collected 2 hours after administration of ATIs or placebo, on two separate test days. The test days are separated by a wash-out period of 4-6 weeks.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 27 Mar 2023.