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Assessment of Anorectal Function in Patients With Inflammatory Bowel Disease

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ClinicalTrials.gov Identifier: NCT05185609
Recruitment Status : Recruiting
First Posted : January 11, 2022
Last Update Posted : February 3, 2022
Sponsor:
Information provided by (Responsible Party):
Region Örebro County

Brief Summary:

Active inflammatory bowel disease (IBD) causes disabling symptoms such as diarrhea, involuntary loss of bowel control, abdominal pain and urges to pass stool. However, even patients with inactive IBD frequently experience such symptoms. The cause is not well understood and the functionality of the bowel in IBD patients is underexplored.

Earlier studies show a wide range of results, but most find that patients with IBD in remission are up to four times as likely to report gastrointestinal symptoms when compared to healthy controls.

Chronic inflammation may cause changes of the bowel wall, like increased collagen deposits (fibrosis) and thus cause symptoms, but the absence of active inflammation in combination with presence of symptoms may also be regarded as resembling the clinical condition of irritable bowel syndrome (IBS).

IBS is characterized by abdominal pain and changes in stool frequency and consistence and is often associated with disorders like depression and anxiety. Up to a third of IBD patients without signs of disease activity meet the criteria for IBS (irritable bowel syndrome. It can be speculated that an IBD diagnosis is a distressing event that can induce mood disorders, and an IBS-like condition.

Characterization of IBS patients relies on the Rome IV symptom criteria, symptom severity scales and measurements of rectal sensibility and rectal compliance using a barostat procedure.

Motor function assessment relies on anorectal manometry which detects abnormalities of muscle function and coordination. Recently, a standardized high-resolution anorectal manometry protocol (HRAM) was published which also evaluates sensitivity and compliance. The level of agreement between the barostat method and the HRAM testing procedure regarding sensibility and rectal compliance is largely unknown.

Recent studies have associated gut microorganisms, genetic factors, and proteins with various aspects of IBD. There is evidence that these potential markers may reflect non-inflammatory processes such as fibrosis.

The aim of this study is to explore the anorectal function in symptomatic patients with inactive IBD compared to healthy volunteers and asymptomatic patients, evaluate symptom severity and psychological parameters and perform molecular characterization.

The level of agreement of rectal sensitivity and compliance measurements with the barostat method and HRAM protocol will also be evaluated.


Condition or disease Intervention/treatment
Inflammatory Bowel Diseases Irritable Bowel Syndrome Other: Exposure 1: Visceral hypersensitivity or phenotype suggestive of IBS Other: Exposure 2: Changes in anorectal motor function or compliance.

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Study Type : Observational
Estimated Enrollment : 70 participants
Observational Model: Case-Control
Time Perspective: Retrospective
Official Title: Assessment of Anorectal Function in Healthy Volunteers and Patients With Inflammatory Bowel Disease
Actual Study Start Date : September 1, 2021
Estimated Primary Completion Date : December 30, 2027
Estimated Study Completion Date : December 30, 2027

Group/Cohort Intervention/treatment
Healthy volunteers
Healthy volunteers aged 18-to 65
Other: Exposure 1: Visceral hypersensitivity or phenotype suggestive of IBS
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Other: Exposure 2: Changes in anorectal motor function or compliance.
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Asymptomatic patients with quiescent IBD
Asymptomatic patients with IBD in remission.
Other: Exposure 1: Visceral hypersensitivity or phenotype suggestive of IBS
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Other: Exposure 2: Changes in anorectal motor function or compliance.
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Symptomatic patients with quiescent UC
Symptomatic patients with UC in remission
Other: Exposure 1: Visceral hypersensitivity or phenotype suggestive of IBS
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Other: Exposure 2: Changes in anorectal motor function or compliance.
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Symptomatic patients with quiescent CD with anorectal involvement
Symptomatic patients with CD with distal involvement of the colon or perianal disease
Other: Exposure 1: Visceral hypersensitivity or phenotype suggestive of IBS
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.

Other: Exposure 2: Changes in anorectal motor function or compliance.
Assess the relation between the exposure and the outcome which is persistent symptoms in the patients with quiescent disease.




Primary Outcome Measures :
  1. Rectal compliance testing with the HRAM and Barostat methods [ Time Frame: 15 minnutes ]
    RC is defined as the relation between volume (ml) respective pressure (mmHg) at half the maximum volume observed and at thresholds for first sensation, first urge, intense urge and maximum tolerated volume.

  2. Rectal sensitivity testing with whit the HRAM and Barostat methods [ Time Frame: 15 minutes ]
    RS is defined as the volume (ml) respective pressure (mmHg) observed at 4 (HRAM) respective 5 (Barostat) predefined sensation thresholds.

  3. Anal squeeze pressure [ Time Frame: 3 minutes ]
    Anal pressure in mmHg assessed from the best of three short squeezes (5seconds) and a prolonged squeeze of 30 seconds during the HRAM investigation.

  4. Anal rest pressure [ Time Frame: 3 minutes ]
    Anal rest pressure in mmHg assessed during the HRAM investigation.

  5. Anorectal coordination during simulated defecation [ Time Frame: 2 minutes ]
    Binary outcome. Anorectal coordination is assessed from the changes in rectal and anal pressure during simulated defecation. The outcomes are: Effective simulated defecation: yes/no

  6. Dyssynergic defecation [ Time Frame: 2 minutes ]
    Categorical binary outcome. Anorectal coordination is assessed from the changes in rectal and anal pressure during simulated defecation. The outcome is: dyssynergic defecation: yes/no

  7. GI symptoms based on the GSRS-IBS questionaire [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  8. GI symptoms based on the IBS symptom severity index [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  9. GI specific anxiety based on the Visceral sensitivity index [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  10. Symptom severity based on the Symptomatic severity module (PHQ 12) [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  11. Assessment of personality using the NEO-FFI-3questionnaire (Big five inventory) [ Time Frame: 20 minutes ]
    The NEO-FFI is a 44-item personality inventory that examines a person's Big Five personality traits (openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism). Each item is assigned a value between 1 to 5 by the participant. Scores for each of the 5 personality traits are calculated and interpreted with the help of the adequate tables.

  12. Pathogenic variants [ Time Frame: 30 minutes ]
    Arrays such as Illumina Global Screening Array and available exonic content databases like ClinVar, will be used to define "Pathogenic" and "Likely Pathogenic" variants in the likelihood of developing a phenotype and the frequency of such alleles within a given population.

  13. Genetical risk score. [ Time Frame: 30 minutes ]
    The liability for the symptomatic phenotype will be calculated by the sum of an individual's risk alleles, weighted by risk allele effect sizes derived from genome-wide associated study data.

  14. Methylation status [ Time Frame: 30 minutes ]
    Commercially available arrays such as the Illumina infinium 450K methylation array will also be used for the analyses of methylation status.

  15. Aspects of proteomics [ Time Frame: 30 minutes ]
    Olink precision inflammatory panel allows simultaneous analysis of 92 inflammation-related protein biomarkers, both in serum and in the rectal mucosa. Thereafter, we will use the Ingenuity Pathway Analysis (IPA) which allows for matching the results of our data against earlier IPA analyses.

  16. Aspects of microbiome. [ Time Frame: 30 minutes ]
    Fecal microbiota as well as mucosa-associated microbiota will be analysed both for qualitative and quantitative composition with both 16S-RNA sequencing and next-generation metagenomic sequencing, to identify the bacterial profile in the patients.

  17. Aspects of transcriptome [ Time Frame: 30 minutes ]
    Blood samples (Pax-gene tubes) and Rectal biopsies will be used for extraction of miRNA and subsequent analysis. In order to analyze the total RNA expression, Next Generation Sequencing (NGS) will be used.

  18. The correlation between proteomics in the mucosa and in blood [ Time Frame: 30 minutes ]
    Olink® precision proteomics inflammatory panel which allows simultaneous analysis of 92 inflammation-related protein biomarkers, both in serum and in the rectal mucosa.


Secondary Outcome Measures :
  1. Cough reflex during HRAM [ Time Frame: 2 minutes ]
    Recto anal inhibitory reflex is defined as the drop in anal rest pressure observed after inflating a balloon in the rectum to 60 ml. The studies are interpreted as positive or negative and the amplitude of the pressure change is recorded.

  2. RAIR reflex during HRAM [ Time Frame: 2 minutes ]
    Cough reflex is the increase in anal pressure during cough. The studies are interpreted as positive or negative and the amplitude of the pressure change is recorded.

  3. The adaptive function of the rectum during barostat investigation [ Time Frame: 12 minutes ]
    The adaptive function of the rectum is defined as the change (increase) in volume necessary to maintain the same rectal pressure during the random phasic distensions of the barostat investigation.

  4. The aggregate sensation intensity scores for gas [ Time Frame: 12 minutes ]
    The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.

  5. The aggregate sensation intensity scores for urgency [ Time Frame: 12 minutes ]
    The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.

  6. The aggregate sensation intensity scores for discomfort [ Time Frame: 12 minutes ]
    The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.

  7. The aggregate sensation intensity scores for pain [ Time Frame: 12 minutes ]
    The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.

  8. Stool consistence using the Bristol stool form scale [ Time Frame: 10 minutes ]
    Categorical ordered variable assigning a numeric value to stool consistency. Higher values correspond to softer stools.

  9. Dyspeptic symptoms using the Nepean dyspepsia index [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  10. Depression using the Depression Module (PHQ-9) [ Time Frame: 15 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  11. Aanxiety using the Anxiety module (GAD-7) [ Time Frame: 15 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.

  12. Assessment of disease-specific quality of life using the IBS-qol questionnaire [ Time Frame: 15 minutes ]
    The answers are converted to a numerical value were the higher score corresponds to worse symptoms.

  13. Incontinence using the Vaizey score for incontinence [ Time Frame: 10 minutes ]
    The answers are converted to a numerical value where the higher score corresponds to worse symptoms.


Biospecimen Retention:   Samples With DNA
Serum. Stool samples. Rectal mucosal biopsies.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Remission is defined as endoscopic absence of active inflammation and f-calprotectin < 100 mg/kg.

Moderate to severe disease is defined as patients treated with the immune modulating drugs thiopurine or methotrexate, and/or biological drugs infliximab, adalimumab, golimumab, vedolizumab or ustekinumab.

Presence of symptoms is evaluated by the short health scale and symptom index questionnaires that all IBD patients fill before their visit to the outpatient ward.

Criteria

Inclusion Criteria:

  • Healthy volunteers
  • Symptomatic IBD patients: Moderate to severe IBD in remission with persistent symptoms as reported by symptom index and short health scale.
  • Asymptomatic IBD patients: moderate to severe IBD in remission without symptoms

Exclusion Criteria:

Healthy volunteers:

  • gastrointestinal disease, functional gastrointestinal symptoms,
  • psychiatric disease
  • anal or pelvic surgery, inclusive interventions during delivery
  • diabetes, cardiovascular, renal, or hepatic disease,
  • concurrent or recent treatment with drugs affecting intestinal function or mood (antidepressants), nutritional supplements or herb products affecting intestinal function (probiotics), abuse of alcohol or drugs, and a recent (< 2 weeks) history of systemic steroid therapy.

IBD patients

  • active disease
  • anal or pelvic surgery, inclusive interventions during delivery
  • diabetes, cardiovascular, renal, or hepatic disease,
  • concurrent or recent treatment with drugs affecting intestinal function or mood (antidepressants), nutritional supplements or herb products affecting intestinal function (probiotics), abuse of alcohol or drugs, and a recent (< 2 weeks) history of systemic steroid therapy. Patients taking antidiarrhoeal or laxatives can be included after a 48 h washout period.

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): NCT05185609


Contacts
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Contact: Lucian Marinica Grando, phd student 0046196021794 lucian.marinica-grando@regionorebrolan.se

Locations
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Sweden
University hospital Örebro Recruiting
Örebro, Sweden, 70185
Contact: Lucian Marinica Grando, phd student    0046196021794    lucian.marinica-grando@reionorebrolan.se   
Sponsors and Collaborators
Region Örebro County
Investigators
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Principal Investigator: Michiel van Nieuwenhoven, assoc prof University Hospital Örebro
Publications:

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Responsible Party: Region Örebro County
ClinicalTrials.gov Identifier: NCT05185609    
Other Study ID Numbers: Regionorebrolan 252641
First Posted: January 11, 2022    Key Record Dates
Last Update Posted: February 3, 2022
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Region Örebro County:
Anorectal function
Anorectal manometry
Rectal barostat
Additional relevant MeSH terms:
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Intestinal Diseases
Inflammatory Bowel Diseases
Irritable Bowel Syndrome
Gastrointestinal Diseases
Digestive System Diseases
Gastroenteritis
Colonic Diseases, Functional
Colonic Diseases