Tryptophan for Impaired AhR Signaling in Celiac Disease (TIARSCeD)

Restoration of Impaired Microbiota-mediated Aryl Hydrocarbon Receptor Signaling in Celiac Disease by Oral Tryptophan Supplementation: an Exploratory, Pilot Trial

This is a prospective, randomized, double-blind, placebo-controlled exploratory trial to evaluate the effect of L-tryptophan supplementation on celiac-related symptoms in individuals who have biopsy-confirmed celiac disease (CeD) and symptoms non-responsive to a gluten-free diet (GFD). Fifty participants, aged 18 to 75 years, who self-report persistent CeD-related symptoms despite taking a GFD for more than 1 year and who score > 40 on the Celiac Symptom Index (CSI) will be randomized to receive L-tryptophan or placebo for 3 weeks.

Study Overview

• Status: Recruiting
• Conditions: Celiac Disease; Tryptophan Metabolism Alterations
• Intervention / Treatment: Drug: L-Tryptophan; Drug: Freedom SimpleCap Powder

Detailed Description

At Visit 1, consented participants will receive study instructions and be randomized 1:1 to L-tryptophan or placebo (SimpleCap). A dietitian will counsel all 50 participants on how to maintain a low tryptophan, gluten-free diet. This diet provides an adequate intake of protein (50 g/day) and energy (1800 kcal/day) while limiting the consumption of high tryptophan-containing foods. Study participants will receive all their intervention capsules at Visit 1 to be taken for 3 weeks, starting the day after Visit 2. At Visits 2 and 3, just before and after the intervention, participants will complete dietary and symptom questionnaires, provide blood, stool, and urine samples, and undergo upper endoscopy to obtain aspirates from the second part of the duodenum, using a sterile catheter followed by six duodenal biopsies, 2 from the first part (bulb) and 4 from the second part of the duodenum. Dietary compliance will be assessed 3-day recalls which will further be analysed by using ESHA Food Processor, a Nutritional Analysis Software.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Gaston H Rueda, MD; Phone Number: 21875 905 521-2100; Email: ruedag@mcmaster.ca
• Study Contact Backup: Name: Utkarshini N Kirtikar, MSc; Phone Number: 21875 905 521-2100; Email: kirtikau@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N3Z5
      • Recruiting
      • McMaster University
      • Contact: David Armstrong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• 18 and 75 years of age
• Celiac disease (CeD) diagnosis: Individuals with histological and serological evidence of CeD serology (positive biopsy and anti-tTG IgA)
• Persistent CeD related symptoms (>40 on the Celiac Symptom Index) despite >1 year of a gluten free diet (GFD)

Exclusion criteria:

• Acid anti-secretory and antacid medications
• Antibiotics, antibacterial agents or probiotics, currently, or within the last 8 weeks
• Current organic gastrointestinal or other autoimmune diseases, such as inflammatory bowel disease or diabetes mellitus (type 1)
• Lactose and/or fructose intolerance
• History of bariatric surgery, fundoplication or gastrectomy (partial or complete)
• Connective tissue disease
• Concurrent organic GI pathology other than benign polyps, haemorrhoids, lipomas, Helicobacter pylori infection, diverticulosis and melanosis coli
• Chronic treatment with high dose opioids
• Alcohol or drug abuse
• Concurrent systemic disease and/or laboratory abnormalities considered by investigators to be a risk or that could interfere with data collection
• Allergy or sensitivity to any component of the study medication or placebo
• Use of lithium and monoamine oxidase inhibitors (MAOIs)
• Participation in another dietary treatment study within the last 4 weeks

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: L-Tryptophan; L-tryptophan* supplements (Tryptan, Valeant Canada LP): each treatment capsule contains 500 mg of L-Tryptophan; talc and magnesium stearate. Study participants will be instructed to take 2 x 500 mg capsules (1000 mg) every 8 hrs, three times a day. (total daily dose: 3000 mg) for a total of 3 weeks. Instructions will be printed on the label of the pill container.	Drug: L-Tryptophan; L-tryptophan is an essential amino acid responsible for activating the aryl hydrocarbon receptor (AhR). Dietary tryptophan is metabolized by the gut microbiota producing several 'indoles' such as (indole-3-aldehyde (IAld), indole-3-acetic acid (IAA), indole-3 propionic acid (IPA), indole-3-acetaldehyde (IAAld), indole-3-lactic acid (ILA) and indole-acrylic acid) and tryptamine, which are ligands for the AhR, a nuclear transcription factor involved in activating target genes responsible for maintaining gut integrity. Prior literature suggests that patients with active celiac disease have a lower functional capacity to produce these AhR ligands, which further impairs the AhR pathway. Hence, the aim of this study is to assess the effects of tryptophan supplementation in patients with celiac disease, non-responsive to a GFD for more than 1 year compared with the effects of an inactive, placebo comparator, L-leucine.
Placebo Comparator: Freedom SimpleCap Powder; 500 mg of SimpleCap Powder. Study participants will be instructed to take 2 x 500 mg capsules (1000 mg) every 8 hrs, three times a day. (total daily dose: 3000 mg) for a total of 3 weeks. Instructions will be printed on the label of the pill container.	Drug: Freedom SimpleCap Powder; Freedom SimpleCap Powder is a high functionality capsule and tablet excipient composite comprised of filler, glidant, disintegrant and lubricant (ingredients include: Microcrystalline Cellulose, Silicon Dioxide Colloidal, Sodium Starch Glycolate, Sodium Stearyl Fumarate). This capsule is dye, lactose and gluten free and will not interfere with the AhR pathway. Freedom SimpleCap Powder makes oral capsule formulation convenient, quick and simple Thus, this SimpleCap Powder will be an appropriate placebo comparator for this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Celiac Symptom Index (CSI)	Change in CSI score; a 7-point decrease in CSI score indicates meaningful improvement.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life questionnaire (PAGI-QoL).	Change in PAGI-QoL score from baseline to week 3; an increase in score indicates an improvement in quality of life. PAGI-QoL score ranges from 0 to 5, 0 being the lowest and 5 being the highest.	3 weeks
Hospital Anxiety and Depression Scale (HADS)	Change in the anxiety and depression scores for the HADS from baseline to week 3; a decrease in the scores indicate decreases in anxiety and depression respectively. The anxiety and depression scales score separately, each ranging from 0 to 21, 0 being the lowest and 21 being the highest.	3 weeks
Gastrointestinal Symptoms Rating Scale (GSRS)	Change in GSRS score from baseline to week 3. Score ranges from 1-7; decrease in score indicates improvement.	3 weeks
Intestinal indole production in the duodenum	Change in duodenal indole production from baseline to week 3	3 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duodenal mucosal villus-crypt ratio (VCR)	Change in the duodenal mucosal VCR from baseline to week 3; an increase in the mucosal VCR ratio indicates decreased mucosal injury	3 weeks
Aryl hydrocarbon Receptor (AhR) activation in the duodenum	Change in duodenal mucosal AhR activation from baseline to week 3	3 weeks
Tissue transglutaminase IgA (tTG) titres	Change in tTG titers from baseline to week 3; a decrease in tTG titres is associated with decreased gluten exposure and, hence, with decreased celiac disease activity	3 weeks

Collaborators and Investigators

• Sponsor: McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2022
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 12, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Aryl Hydrocarbon Receptor; Celiac disease; Tryptophan
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Gastrointestinal Diseases; Intestinal Diseases; Malabsorption Syndromes; Celiac Disease; Psychotropic Drugs; Antidepressive Agents; Antidepressive Agents, Second-Generation; Tryptophan
• Other Study ID Numbers: 14582

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will not be shared among other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No