Clinical trial NCT05185609: Assessment of Anorectal Function in Patients With Inflammatory Bowel Disease
Official title: Assessment of Anorectal Function in Healthy Volunteers and Patients With Inflammatory Bowel Disease
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Inflammatory Bowel Diseases
Irritable Bowel Syndrome
Keywords: Anorectal function
Anorectal manometry
Rectal barostat
Lead sponsor: Region Örebro County
Sponsor class: OTHER
First posted: 2022-01-11
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
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.

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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Rectal compliance testing with the HRAM and Barostat methods
timeFrame: 15 minnutes
measure: Rectal sensitivity testing with whit the HRAM and Barostat methods
timeFrame: 15 minutes
measure: Anal squeeze pressure
timeFrame: 3 minutes
measure: Anal rest pressure
timeFrame: 3 minutes
measure: Anorectal coordination during simulated defecation
timeFrame: 2 minutes
measure: Dyssynergic defecation
timeFrame: 2 minutes
measure: GI symptoms based on the GSRS-IBS questionaire
timeFrame: 10 minutes
measure: GI symptoms based on the IBS symptom severity index
timeFrame: 10 minutes
measure: GI specific anxiety based on the Visceral sensitivity index
timeFrame: 10 minutes
measure: Symptom severity based on the Symptomatic severity module (PHQ 12)
timeFrame: 10 minutes
measure: Assessment of personality using the NEO-FFI-3questionnaire (Big five inventory)
timeFrame: 20 minutes
measure: Pathogenic variants
timeFrame: 30 minutes
measure: Genetical risk score.
timeFrame: 30 minutes
measure: Methylation status
timeFrame: 30 minutes
measure: Aspects of proteomics
timeFrame: 30 minutes
measure: Aspects of microbiome.
timeFrame: 30 minutes
measure: Aspects of transcriptome
timeFrame: 30 minutes
measure: The correlation between proteomics in the mucosa and in blood
timeFrame: 30 minutes
Secondary outcomes:
measure: Cough reflex during HRAM
timeFrame: 2 minutes
measure: RAIR reflex during HRAM
timeFrame: 2 minutes
measure: The adaptive function of the rectum during barostat investigation
timeFrame: 12 minutes
measure: The aggregate sensation intensity scores for gas
timeFrame: 12 minutes
measure: The aggregate sensation intensity scores for urgency
timeFrame: 12 minutes
measure: The aggregate sensation intensity scores for discomfort
timeFrame: 12 minutes
measure: The aggregate sensation intensity scores for pain
timeFrame: 12 minutes
measure: Stool consistence using the Bristol stool form scale
timeFrame: 10 minutes
measure: Dyspeptic symptoms using the Nepean dyspepsia index
timeFrame: 10 minutes
measure: Depression using the Depression Module (PHQ-9)
timeFrame: 15 minutes
measure: Aanxiety using the Anxiety module (GAD-7)
timeFrame: 15 minutes
measure: Assessment of disease-specific quality of life using the IBS-qol questionnaire
timeFrame: 15 minutes
measure: Incontinence using the Vaizey score for incontinence
timeFrame: 10 minutes
Other outcomes:
Locations:
city: Örebro
country: Sweden
facility: University hospital Örebro
Study officials:
affiliation: University Hospital Örebro
name: Michiel van Nieuwenhoven, assoc prof
role: PRINCIPAL_INVESTIGATOR
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