Assessment of Anorectal Function in Patients With Inflammatory Bowel Disease

Inflammatory Bowel Diseases Clinical Trial

Official title:

Assessment of Anorectal Function in Healthy Volunteers and Patients With Inflammatory Bowel Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05185609
• Other study ID #: Regionorebrolan 252641
• Status: Recruiting
• Start date: September 1, 2021
• Est. completion date: December 30, 2027

Study information

• Verified date: December 2021
• Source: Region Örebro County
• Contact: Lucian Marinica Grando, phd student
• Phone: 0046196021794
• Email: lucian.marinica-grando[@]regionorebrolan.se
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

Anorectal function (ARF) disorders in patients with IBD cause disabling symptoms such as fecal incontinence, increases in the stool frequency, urgency and tenesmus.

Patients with IBD in remission frequently experience diarrhea, fecal incontinence and lower GI symptoms. However, ARF in IBD patients is underexplored.

Chronic mucosal inflammation may induce visceral hypersensitivity and rectal wall fibrosis, but the casual relationship is hypothetical.

The absence of active inflammation and the presence of symptoms resemble IBS leading to the speculation that an IBD diagnosis is a distressing event, and can induce mood disorders, and an IBS-like condition.

Anorectal manometry detects abnormalities of sphincter function and rectoanal coordination. Recently, a standardized HRAM protocol was published (The London consensus protocol) witch also evaluates rectal sensitivity (RS) and rectal compliance (RC).

Earlier studies, using water-perfused AM, indicated that patients with active ulcerative colitis (UC) may have increased RS, contractility and impaired RC whereas patients with quiescent UC may have impaired RC, suggesting that chronic fibrotic changes of the rectal wall may occur.[14, 15] IBS is characterized by abdominal pain and changes in stool pattern. Its biological hallmark is increased visceral perception with disturbed bidirectional brain-gut signaling, associated with serotonergic dysregulation, illustrated by the high prevalence of mood disorders.

IBS is diagnosed using the Rome IV symptom criteria. Phenotyping IBS patients, as described in a consensus paper by Boeckxstaens et al. in 2017, relies on GI symptom severity scales and measurements of RS and RC using a barostat procedure. There is frequently overlap with other functional GI disorders (FGIDs). Hence these should also be assessed, as well as psychological comorbidities.

The gold standard for phenotyping is the use of validated questionnaires and a standardized barostat protocol as described in a publication from the European COST action GENIEUR group.[16] The level of agreement between the barostat protocol and the HRAM testing procedure regarding sensory testing and measurement of rectal compliance is not established.

Progress in various types of -omics techniques has enhanced our possibilities to identify markers of complex diseases such as IBD. Recent studies have associated gut microbiota, genome, transcriptome and proteome-profiles with various aspects of the disease. Both individual markers and panels of markers, so called "molecular signatures" are currently tested for their predictive capacity and possible source for future biomarker identification. Accumulating data indicate that some of this novel potential markers may reflect non-inflammatory processes such as fibrosis.

The overarching aim of this study is to explore the anorectal function in symptomatic patients with quiescent IBD compared to healthy volunteers and asymptomatic patients with quiescent IBD, using both HRAM and a standardized barostat procedure. Symptom severity and psychological parameters will be evaluated by validated questionnaires. Molecular characterization will be performed by analyses of blood, faecal samples and mucosal biopsies.

Examination of single-layers of molecular data will be followed by integrated analyses of several layers of - omics data and correlated to clinical and psychological phenotypes. This "multi-omics" approach requires development of bioinformatic methods, which currently are underway.

The study goals are:

1. To determine the level of agreement and correlation of rectal sensitivity- and compliance measurements between the HRAM method and the barostat method in healthy volunteers and asymptomatic patients with IBD in remission

2. To study ARF in symptomatic patients with IBD in remission and to compare the results with data from healthy volunteers and asymptomatic patients with IBD in remission.

3. To measure parameters of brain-gut interaction in IBD patients using validated GI symptom scales and psychometric questionnaires on anxiety, somatization, personality and depression and to compare the results with data from healthy volunteers.

4. To analyse plasma, stool and rectal mucosa samples from symptomatic patients with IBD in remission for proteomics, micro-RNA and microbial composition and to compare the results with findings in healthy participants and asymptomatic patients with IBD in remission.

Part 1 and 2. Anorectal manometry, barostat assessment and validated questionnaires in healthy volunteers and asymptomatic IBD patients.

Awareness of rectal filling is critical to normal bowel function. Abnormal visceral sensitivity and/or biomechanical function (most commonly described by evaluation of rectal compliance) is often found in fecal incontinence and evacuation disorders, providing the rationale for measurement of anorectal sensory and motor function.

Aims:

To determine the correlation between sensitivity testing and the level-of-agreement of rectal compliance testing between the HRAM and the barostat protocol.

To obtain normal values regarding anorectal function from healthy volunteers and asymptomatic IBD patients which will be used for comparison with the values obtained from symptomatic patients with IBD.

To obtain normal values regarding gastrointestinal symptoms and psychometric scales using standardized questionnaires, which will be used for comparison with the values obtained from symptomatic patients with IBD.

To obtain biological samples. Results of the analyses of these samples will be compared with the results from the symptomatic IBD patients as outlined in the part 6 of the research plan.

Design: reliability and method comparison study but at the same time the participants will constitute the control cases in the planed case control studies.

No data is available regarding normal values for rectal compliance using the HRAM method. In a study comparing a rapid non-elastic barostat bag measurement with a standardized barostat procedure, a total of 25 subjects was sufficient to detect a difference in sensitivity threshold volumes.

The following validated questionnaires will be used:

ROME IV diagnostic criteria, IBS symptom severity index, Gastrointestinal symptom severity scale, Bristol stool form scale, Nepean dyspepsia index, Depression Module (PHQ-9), Anxiety module (GAD-7), Symptomatic severity module (PHQ-15), Visceral sensitivity index, Assessment of disease-specific quality of life, Assessment of socioeconomic status of IBS patients, Assessment of personality (NEO-FFI-3), Vaizey score for incontinence.

HRAM The investigation consists of a series of pressure measurements that assess resting pressure of the anal canal, voluntary function during short and long squeeze, assessment of the cough reflex, rectoanal inhibitory reflex during rectal distension and rectoanal coordination and propulsive force during simulated defecation.

Rectal sensitivity testing and rectal compliance studies will be performed through inflation of an elastic balloon connected to the HRAM catheter, placed within the rectum. During inflation, perceived sensations are reported: first sensation, desire to defecate, urgency and maximum toleration or pain.

The distending volume and pressure will be recorded and the rectal compliance after correction for the internal compliance of the elastic balloon will be calculated (ΔV⁄ΔP).

Barostat protocol tests:

Ascending method of limits protocol: ramp inflation starting at 0 mmHg and increasing in steps of 4 mmHg for 1 min per step to a maximum of 60 mmHg. Thresholds for first sensation, first desire to defecate, urgency, discomfort and pain will be recorded and the rectal compliance calculated.

Random order phasic distensions protocol: phasic distensions (60 sec) of 12, 24, 36 and 48 mmHg above basic operating pressure (BOP) will be each applied once in a random order. The maximum pressure is limited by the pain threshold from the AML. The subjects will rate the intensity of four different sensations during the last 30 sec of each distension (gas, urgency, discomfort and pain).

Biological samples will be obtained during a separate visit to the gastroenterology department.

Part 3 and 4. Assessment of symptoms and anorectal function in patients with quiescent ulcerative colitis respective quiescent Crohns disease with anorectal involvement.

Aim To obtain values regarding anorectal function from patients with IBD in remission using the HRAM protocol and the standardized barostat protocol.

To phenotype the patients by obtaining data regarding gastrointestinal symptoms and psychometric values using standardized questionnaires, and to analyse these data together with the anorectal function data.

To obtain biological samples from symptomatic patients with IBD in remission

There are no data available regarding normal values for rectal compliance and sensitivity using the HRAM method in IBD patients. However, earlier studies, comparing healthy volunteers with IBS patients using a similar standardized barostat protocol, demonstrated that a total of 13 IBS patients and 13 healthy controls was sufficient to detect a difference in sensitivity threshold volumes and rectal compliance. For this reason, 15 patients will be included.

The same protocol as for part 1 will be applied.

Part 5. Assessment of IBS-like symptoms and psychological comorbidities in patients with UC and Crohn's disease in remission.

Increased visceral perception (hypersensitivity) with disturbed bidirectional brain-gut signaling is considered the biological hallmark of IBS.

Aim: to investigate whether patients with quiescent IBD meet the Rome IV criteria for IBS with concomitant psychological comorbidity, or that these patients suffer from gastrointestinal symptoms due to the effects of a long-lasting inflammatory process leading to rectal fibrosis. This knowledge has consequences for the treatment of these patients.

The HRAM measurements will be used to establish the presence of an eventual rectal motor dysfunction as the cause for symptoms. The barostat data will be used to establish whether there is a decreased rectal compliance, suggestive for fibrosis, as well as to establish whether the IBD patients show a visceral hypersensitivity, in comparison with healthy controls.

The symptom and psychometric questionnaires will be used to establish whether the quiescent IBD patients demonstrate a typical IBS phenotype with high comorbidities of anxiety, depression, somatization and a personality treat with a high level of neuroticism.

Part 6. Molecular profile of symptomatic patients with quiescent IBD compared to healthy volunteers and asymptomatic patients with quiescent IBD Aspects of gut microbiota, genome, transcriptome and proteome-profiles will be compared between the study groups.

The microbiological data will be combined with proteomic data from plasma and rectal biopsies, data from the mi-RNA analysis and correlated with data on the clinical and psychological phenotype of the patients. This "multi-omics" approach requires development of bioinformatics methods, which currently are underway in IBD studies.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: December 30, 2027
• Est. primary completion date: December 30, 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Inflammatory Bowel Diseases
• Intestinal Diseases
• Irritable Bowel Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
Sweden	University hospital Örebro	Örebro

Sponsors (1)

Lead Sponsor	Collaborator
Region Örebro County

Country where clinical trial is conducted

Sweden, 

References & Publications (23)

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Mavroudis G, Strid H, Jonefjäll B, Simrén M. Visceral hypersensitivity is together with psychological distress and female gender associated with severity of IBS-like symptoms in quiescent ulcerative colitis. Neurogastroenterol Motil. 2021 Mar;33(3):e13998. doi: 10.1111/nmo.13998. Epub 2020 Oct 9. — View Citation

Menees SB, Almario CV, Spiegel BMR, Chey WD. Prevalence of and Factors Associated With Fecal Incontinence: Results From a Population-Based Survey. Gastroenterology. 2018 May;154(6):1672-1681.e3. doi: 10.1053/j.gastro.2018.01.062. Epub 2018 Feb 3. — View Citation

Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Henegouwen GP, Smout AJ. IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior. Dig Dis Sci. 2004 Mar;49(3):469-74. — View Citation

Simrén M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J, Björnsson ES. Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol. 2002 Feb;97(2):389-96. — View Citation

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Spiller RC, Humes DJ, Campbell E, Hastings M, Neal KR, Dukes GE, Whorwell PJ. The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease. Aliment Pharmacol Ther. 2010 Sep;32(6):811-20. doi: 10.1111/j.1365-2036.2010.04402.x. — View Citation

Stewart DB Sr. Fecal Incontinence Among Patients With Crohn's Disease: Does Awareness Change Anything? Dis Colon Rectum. 2017 Aug;60(8):759-760. doi: 10.1097/DCR.0000000000000811. — View Citation

Vanhoutvin SA, Troost FJ, Kilkens TO, Lindsey PJ, Jonkers DM, Venema K, Masclee A, Brummer RJ. Alternative procedure to shorten rectal barostat procedure for the assessment of rectal compliance and visceral perception: a feasibility study. J Gastroenterol. 2012 Aug;47(8):896-903. doi: 10.1007/s00535-012-0543-x. Epub 2012 Feb 24. — View Citation

Vollebregt PF, Visscher AP, van Bodegraven AA, Felt-Bersma RJF. Validation of Risk Factors for Fecal Incontinence in Patients With Crohn's Disease. Dis Colon Rectum. 2017 Aug;60(8):845-851. doi: 10.1097/DCR.0000000000000812. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rectal compliance testing with the HRAM and Barostat methods	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.	15 minnutes
Primary	Rectal sensitivity testing with whit the HRAM and Barostat methods	RS is defined as the volume (ml) respective pressure (mmHg) observed at 4 (HRAM) respective 5 (Barostat) predefined sensation thresholds.	15 minutes
Primary	Anal squeeze pressure	Anal pressure in mmHg assessed from the best of three short squeezes (5seconds) and a prolonged squeeze of 30 seconds during the HRAM investigation.	3 minutes
Primary	Anal rest pressure	Anal rest pressure in mmHg assessed during the HRAM investigation.	3 minutes
Primary	Anorectal coordination during simulated defecation	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	2 minutes
Primary	Dyssynergic defecation	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	2 minutes
Primary	GI symptoms based on the GSRS-IBS questionaire	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes
Primary	GI symptoms based on the IBS symptom severity index	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes
Primary	GI specific anxiety based on the Visceral sensitivity index	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes
Primary	Symptom severity based on the Symptomatic severity module (PHQ 12)	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes
Primary	Assessment of personality using the NEO-FFI-3questionnaire (Big five inventory)	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.	20 minutes
Primary	Pathogenic variants	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.	30 minutes
Primary	Genetical risk score.	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.	30 minutes
Primary	Methylation status	Commercially available arrays such as the Illumina infinium 450K methylation array will also be used for the analyses of methylation status.	30 minutes
Primary	Aspects of proteomics	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.	30 minutes
Primary	Aspects of microbiome.	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.	30 minutes
Primary	Aspects of transcriptome	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.	30 minutes
Primary	The correlation between proteomics in the mucosa and in blood	Olink® precision proteomics inflammatory panel which allows simultaneous analysis of 92 inflammation-related protein biomarkers, both in serum and in the rectal mucosa.	30 minutes
Secondary	Cough reflex during HRAM	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 minutes
Secondary	RAIR reflex during HRAM	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.	2 minutes
Secondary	The adaptive function of the rectum during barostat investigation	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.	12 minutes
Secondary	The aggregate sensation intensity scores for gas	The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.	12 minutes
Secondary	The aggregate sensation intensity scores for urgency	The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.	12 minutes
Secondary	The aggregate sensation intensity scores for discomfort	The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.	12 minutes
Secondary	The aggregate sensation intensity scores for pain	The visual analogue scale scores, in mm, marked by the patients at each distension during the random phasic distension part of the barostat study.	12 minutes
Secondary	Stool consistence using the Bristol stool form scale	Categorical ordered variable assigning a numeric value to stool consistency. Higher values correspond to softer stools.	10 minutes
Secondary	Dyspeptic symptoms using the Nepean dyspepsia index	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes
Secondary	Depression using the Depression Module (PHQ-9)	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	15 minutes
Secondary	Aanxiety using the Anxiety module (GAD-7)	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	15 minutes
Secondary	Assessment of disease-specific quality of life using the IBS-qol questionnaire	The answers are converted to a numerical value were the higher score corresponds to worse symptoms.	15 minutes
Secondary	Incontinence using the Vaizey score for incontinence	The answers are converted to a numerical value where the higher score corresponds to worse symptoms.	10 minutes