Intestinal Diseases, Irritable Bowel Syndrome, Constipation
Conditions
Brief summary
Our overall objective with this study is firstly to provide a comprehensive assessment of intestinal permeability, mucosal barrier function using existing biomarkers and secondly to explore novel biomarkers for measuring intestinal permeability in patients with constipation predominant Irritable Bowel Syndrome (IBS-C).
Detailed description
In order to determine the differences in permeability in IBS-C in comparison with healthy volunteers, the following will be determined: differences in in vivo small intestinal and colonic permeability, differences in small intestinal and colonic mucosal barrier function, differences in effects of fecal supernatants on barrier function of T84 monolayers, and differences in novel biomarkers for intestinal permeability
Interventions
DIAGNOSTIC_TESTPermeability measurement
Saccharide excretion was compared between IBS-C and healthy volunteers
PROCEDUREEsophagogastroduodenoscopy
Duodenal biopsies were collected from IBS-C and healthy volunteers
PROCEDUREFlexible sigmoidoscopy
Colonic biopsies were collected from IBS-C and healthy volunteers
Sponsors
Takeda Pharmaceuticals International, Inc.
Mayo Clinic
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. 18 - 65 years old 2. IBS-C by Rome III criteria (for IBS-C participants) 3. No abdominal surgery (except appendectomy and cholecystectomy)
Exclusion criteria
1. History of Inflammatory Bowel Disease (IBD) , microscopic colitis or celiac disease 2. Use of tobacco products within the past 6 months 3. Use of NSAIDs or aspirin within the past week 4. Use of oral corticosteroids within the previous 6 weeks 5. Ingestion of artificial sweeteners such as Splenda (sucralose), Nutrasweet (aspartame), lactulose or mannitol 2 days before the study begins, e.g., foods to be avoided are sugarless gums or mints and diet soda 6. Ingestion of any prescription, over the counter, or herbal medications which can affect gastrointestinal transit 7 days before study begins 1. Any treatment specifically taken for IBS, including loperamide, cholestyramine, alosetron 2. Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors (e.g, tegaserod, ondansetron, tropisetron, granisetron, dolasetron, mirtazapine); 3. All narcotics (e.g, codeine, morphine, and propoxyphene, either alone or in combination) 4. Anti-cholinergic agents (e.g, dicyclomine, hyoscyamine, propantheline). 5. Ultram 6. GI preparations * Anti-nausea agents (e.g, trimethobenzamide, promethazine, prochlorperazine, dimenhydrinate, hydroxyzine) * Osmotic laxative agents (e.g, lactulose, sorbitol or PEG solutions as Miralax and Glycolax) * Prokinetic agents (e.g, cisapride, metoclopramide, itopride, domperidone); 7. Antimuscarinics; 8. Peppermint oil; 9. Systemic antibiotics, rifaximin, metronidazole. 7. Bleeding disorders or medications that increase risk of bleeding from mucosal biopsies. 8. Score \> 8 for anxiety or depression on Hospital anxiety and depression scale. 9. Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lactulose:C13 Mannitol Excretion Ratio 8-24hrs. | 8-24 hr post test-dose administration | In vivo measurement of intestinal permeability using 13C mannitol & lactulose was used. High performance liquid chromatography-tandem mass spectrometry was used to measure concentrations calculated using the overall urine volume excreted in each interval. Concentrations of 13C adjusted for the % of 13C in 12C mannitol (4.98% of 12C mannitol excreted was subtracted from 13C mannitol values; determined by analyzing replicate samples of control urine). All lactulose or 13C mannitol concentrations 8-24hr post-ingestion were used to determine colonic permeability. Lactulose to 13C mannitol excretion ratios, as a measure of dose of saccharide administered, were calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa | Baseline | — |
| Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa | 3 hours post FITC-Dextran (4kDa) administration | This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration. |
| Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa | Over 3 hours post FITC-Dextran (4kDa) administration | This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration. |
| Baseline Transmucosal Resistance (TMR) of Colonic Mucosa | Baseline | — |
| Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa | 3 hours post FITC-Dextran (4kDa) administration | — |
| Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa | Over 3 hours post FITC-Dextran (4kDa) administration | — |
| Lactose:C13 Mannitol Excretion Ratio 0-2hours | 0-2 hr post-test dose administration | — |
| Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa | Over 3 hours post E.coli Bio- Particle administration | — |
| Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa | 3 hours post E.coli Bio- Particle administration | — |
| Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa | Over 3 hours post E.coli Bio- Particle administration | — |
| Duodenal Impedance | Baseline | — |
| Mean Serum Endotoxin (Bacterial LPS) Levels | Fasting, one time measurement after 8 hours | — |
| Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa | 3 hours post E.coli Bio- Particle administration | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteers Healthy volunteers between ages 18 - 65, who have not history of IBS. | 18 |
| IBS-C Volunteers who have been diagnosed with IBS - Constipation (IBS-C) | 19 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Healthy Volunteers | IBS-C | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 37 Participants |
| Age, Continuous | 45.37 years STANDARD_DEVIATION 2.82 | 43.06 years STANDARD_DEVIATION 2.78 | 44.24 years STANDARD_DEVIATION 1.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 19 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 19 Participants | 37 Participants |
| Region of Enrollment United States | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 0 / 18 | 1 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Lactulose:C13 Mannitol Excretion Ratio 8-24hrs.
In vivo measurement of intestinal permeability using 13C mannitol & lactulose was used. High performance liquid chromatography-tandem mass spectrometry was used to measure concentrations calculated using the overall urine volume excreted in each interval. Concentrations of 13C adjusted for the % of 13C in 12C mannitol (4.98% of 12C mannitol excreted was subtracted from 13C mannitol values; determined by analyzing replicate samples of control urine). All lactulose or 13C mannitol concentrations 8-24hr post-ingestion were used to determine colonic permeability. Lactulose to 13C mannitol excretion ratios, as a measure of dose of saccharide administered, were calculated.
Time frame: 8-24 hr post test-dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Lactulose:C13 Mannitol Excretion Ratio 8-24hrs. | 0.01 Ratio | Standard Error 0.004 |
| IBS - C | Lactulose:C13 Mannitol Excretion Ratio 8-24hrs. | 0.02 Ratio | Standard Error 0.005 |
p-value: 0.87Wilcoxon (Mann-Whitney)
Secondary
Baseline Transmucosal Resistance (TMR) of Colonic Mucosa
Time frame: Baseline
Population: One participant in IBS-C was not analysed for the Baseline Transmucosal Resistance (TMR) of Colonic Mucosa due to various reasons such inadequate size of the biopsy specimen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Baseline Transmucosal Resistance (TMR) of Colonic Mucosa | 17.60 Ω*sq.cm | Standard Error 1.7 |
| IBS - C | Baseline Transmucosal Resistance (TMR) of Colonic Mucosa | 19.06 Ω*sq.cm | Standard Error 1.1 |
Secondary
Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa
Time frame: Baseline
Population: Two participants ( 1 in Healthy volunteers and 1 in IBS-C ) were not analysed for the Baseline transmucosal resistance (TMR) of duodenal mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa | 29.8 Ω*sq.cm | Standard Error 1.94 |
| IBS - C | Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa | 28.16 Ω*sq.cm | Standard Error 1.96 |
Secondary
Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa
Time frame: 3 hours post E.coli Bio- Particle administration
Population: 7 participants (2 in Healthy volunteers and 5 in IBS-C) were not analysed for Cumulative E.coli Bio- Particle K12 Concentration Across Colonic Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Volunteers | Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa | 1.07*10^4 CFU/ml |
| IBS - C | Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa | 2.09*10^4 CFU/ml |
Secondary
Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa
Time frame: 3 hours post E.coli Bio- Particle administration
Population: 11 participants (4 in Healthy volunteers and 7 in IBS-C) were not analysed for Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Volunteers | Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa | 1.48*10^4 CFU/ml |
| IBS - C | Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa | 1.82*10^4 CFU/ml |
Secondary
Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa
Time frame: 3 hours post FITC-Dextran (4kDa) administration
Population: 7 participants (2 in Healthy volunteers and 5 in IBS-C) were not analysed for the Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa | 132.2 ng/mL | Standard Error 24.23 |
| IBS - C | Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa | 122.5 ng/mL | Standard Error 27.44 |
Secondary
Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa
This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration.
Time frame: 3 hours post FITC-Dextran (4kDa) administration
Population: Four participants (2 in Healthy volunteers and 2 in IBS-C) were not analysed for the Cumulative FITC-Dextran (4kDa) concentration across duodenal mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa | 123.3 ng/mL | Standard Error 24.29 |
| IBS - C | Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa | 156.8 ng/mL | Standard Error 33.73 |
Secondary
Duodenal Impedance
Time frame: Baseline
Population: 12 participants (2 in Healthy volunteers and 10 in IBS-C) were not analysed for Duodenal impedance due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Duodenal Impedance | 705.9 Ω | Standard Error 42.73 |
| IBS - C | Duodenal Impedance | 729.5 Ω | Standard Error 64.85 |
Secondary
Lactose:C13 Mannitol Excretion Ratio 0-2hours
Time frame: 0-2 hr post-test dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Lactose:C13 Mannitol Excretion Ratio 0-2hours | 0.007 Ratio | Standard Error 0.0004 |
| IBS - C | Lactose:C13 Mannitol Excretion Ratio 0-2hours | 0.01 Ratio | Standard Error 0.001 |
Secondary
Mean Serum Endotoxin (Bacterial LPS) Levels
Time frame: Fasting, one time measurement after 8 hours
Population: 2 participants (1 in healthy volunteers and 1 in IBS-C) were not analysed for Mean Serum Endotoxin (Bacterial LPS) Levels due to various reasons such as non-availability of the blood sample, technical errors, etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Mean Serum Endotoxin (Bacterial LPS) Levels | 0.35 EU/mL | Standard Error 0.02 |
| IBS - C | Mean Serum Endotoxin (Bacterial LPS) Levels | 0.36 EU/mL | Standard Error 0.03 |
Secondary
Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa
Time frame: Over 3 hours post E.coli Bio- Particle administration
Population: 7 participants (2 in Healthy volunteers and 5 in IBS-C) were not analysed for Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Volunteers | Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa | 4.26*10^5 CFU/h/sq.cm |
| IBS - C | Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa | 7.67*10^5 CFU/h/sq.cm |
Secondary
Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa
Time frame: Over 3 hours post E.coli Bio- Particle administration
Population: 11 participants (4 in Healthy volunteers and 7 in IBS-C) were not analysed for Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Volunteers | Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa | 5.42*10^5 CFU/h/sq.cm |
| IBS - C | Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa | 5.70*10^5 CFU/h/sq.cm |
Secondary
Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa
Time frame: Over 3 hours post FITC-Dextran (4kDa) administration
Population: 7 participants (2 in Healthy volunteers and 5 in IBS-C) were not analysed for the Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure, etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa | 4931 ng/hr/sq.cm | Standard Error 1156 |
| IBS - C | Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa | 6069 ng/hr/sq.cm | Standard Error 1030 |
Secondary
Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa
This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration.
Time frame: Over 3 hours post FITC-Dextran (4kDa) administration
Population: Four participants ( 2 in Healthy volunteers and 2 in IBS-C ) were not analysed for the Rate of FITC-Dextran (4kDa) flux across duodenal mucosa due to various reasons such inadequate size of the biopsy specimen, participant did not show up for the procedure etc.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Volunteers | Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa | 4980 ng/hr/sq.cm | Standard Error 1044 |
| IBS - C | Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa | 6528 ng/hr/sq.cm | Standard Error 1584 |