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Biomarkers for Intestinal Permeability in Patients With Constipation

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ClinicalTrials.gov Identifier: NCT02246647
Recruitment Status : Completed
First Posted : September 23, 2014
Results First Posted : August 21, 2019
Last Update Posted : August 21, 2019
Sponsor:
Collaborator:
Takeda Pharmaceuticals International, Inc.
Information provided by (Responsible Party):
Madhusudan (Madhu) Grover, MBBS, Mayo Clinic

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).

Condition or disease Intervention/treatment
Intestinal Diseases Irritable Bowel Syndrome Constipation Diagnostic Test: Permeability measurement Procedure: Esophagogastroduodenoscopy Procedure: Flexible sigmoidoscopy

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

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Study Type : Observational
Actual Enrollment : 39 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Biomarkers for Intestinal Permeability in Patients With Functional Lower Gastrointestinal Disorders Associated With Constipation.
Study Start Date : September 2014
Actual Primary Completion Date : December 8, 2016
Actual Study Completion Date : December 8, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Constipation
Drug Information available for: Mannitol

Group/Cohort Intervention/treatment
Healthy volunteers
Permeability measurement: Ingestion of saccharides {mannitol (regular, 12C) 100 mg, lactulose 1 g and labelled (13C mannitol) 100 mg} in 250ml of water Esophagogastroduodenoscopy Flexible sigmoidoscopy
Diagnostic Test: Permeability measurement
Saccharide excretion was compared between IBS-C and healthy volunteers
Other Names:
  • 12C Mannitol
  • 13C Mannitol
  • Lactulose

Procedure: Esophagogastroduodenoscopy
Duodenal biopsies were collected from IBS-C and healthy volunteers

Procedure: Flexible sigmoidoscopy
Colonic biopsies were collected from IBS-C and healthy volunteers

IBS-C
Permeability measurement: Ingestion of saccharides (mannitol (regular, 12C) 100 mg, lactulose 1 g and labelled (13C mannitol) 100 mg} in 250ml of water Esophagogastroduodenoscopy Flexible sigmoidoscopy
Diagnostic Test: Permeability measurement
Saccharide excretion was compared between IBS-C and healthy volunteers
Other Names:
  • 12C Mannitol
  • 13C Mannitol
  • Lactulose

Procedure: Esophagogastroduodenoscopy
Duodenal biopsies were collected from IBS-C and healthy volunteers

Procedure: Flexible sigmoidoscopy
Colonic biopsies were collected from IBS-C and healthy volunteers




Primary Outcome Measures :
  1. Lactulose:C13 Mannitol Excretion Ratio 8-24hrs. [ Time Frame: 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 Outcome Measures :
  1. Lactose:C13 Mannitol Excretion Ratio 0-2hours [ Time Frame: 0-2 hr post-test dose administration ]
  2. Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa [ Time Frame: Baseline ]
  3. Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa [ Time Frame: 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.

  4. Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa [ Time Frame: 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.

  5. Baseline Transmucosal Resistance (TMR) of Colonic Mucosa [ Time Frame: Baseline ]
  6. Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa [ Time Frame: 3 hours post FITC-Dextran (4kDa) administration ]
  7. Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa [ Time Frame: Over 3 hours post FITC-Dextran (4kDa) administration ]
  8. Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa [ Time Frame: 3 hours post E.coli Bio- Particle administration ]
  9. Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa [ Time Frame: Over 3 hours post E.coli Bio- Particle administration ]
  10. Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa [ Time Frame: 3 hours post E.coli Bio- Particle administration ]
  11. Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa [ Time Frame: Over 3 hours post E.coli Bio- Particle administration ]
  12. Duodenal Impedance [ Time Frame: Baseline ]
  13. Mean Serum Endotoxin (Bacterial LPS) Levels [ Time Frame: Fasting, one time measurement after 8 hours ]

Biospecimen Retention:   Samples With DNA
Colonic Biopsies Duodenal Biopsies Blood Urine Fecal


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
IBS-Constipation patients and healthy volunteers
Criteria

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

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): NCT02246647


Locations
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United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Takeda Pharmaceuticals International, Inc.
Investigators
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Principal Investigator: Madhusudan Grover, MBBS Mayo Clinic

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Responsible Party: Madhusudan (Madhu) Grover, MBBS, Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT02246647     History of Changes
Other Study ID Numbers: 14-002382
First Posted: September 23, 2014    Key Record Dates
Results First Posted: August 21, 2019
Last Update Posted: August 21, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Irritable Bowel Syndrome
Intestinal Diseases
Constipation
Signs and Symptoms, Digestive
Signs and Symptoms
Colonic Diseases, Functional
Colonic Diseases
Gastrointestinal Diseases
Digestive System Diseases
Mannitol
Lactulose
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Gastrointestinal Agents