Mesalazine for the Treatment of Diarrhoea-predominant Irritable Bowel Syndrome (IBS-D)

Study Overview
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Brief Summary
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The purpose of the trial is to define the clinical benefit and possible mediators of the benefit of mesalazine in Irritable Bowel Syndrome (IBS) with diarrhoea. The investigators will therefore evaluate symptoms (primarily bowel frequency) and markers reflecting mast cell activation and small bowel tone.

Official Title
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Efficacy and Mode of Action of Mesalazine in the Treatment of Diarrhoea-predominant Irritable Bowel Syndrome (IBS-D).

Conditions
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Irritable Bowel Syndrome With Diarrhoea

Intervention / Treatment
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* Drug: Mesalazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female patients aged 18-75 years old able to give informed consent. Patients should all have had a colonoscopy or a sigmoidoscopy within the last 12 months to exclude microscopic colitis. (If not, but they have had a negative colonoscopy within 5 years and symptoms are unchanged, then a sigmoidoscopy and mucosal biopsy of the left colon would be sufficient to exclude microscopic colitis). IBS-D Patients meeting Rome III criteria prior to screening phase. Patients with ≥ 25% soft (score > 4) and < 25% hard (score 1 or 2) stools during the screening phase, as scored by the daily symptom and stool diary*. Patients with a stool frequency of 3 or more per day for 2 or more days per week during the screening phase*. Satisfactory completion of the daily stool and symptom diary during the screening phase at the discretion of the investigator. Women of child bearing potential willing or able to use at least one highly effective contraceptive method throughout the study. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: implants, injectables, combined oral contraceptives, sexual abstinence or vasectomised partner. If inclusion criterion 4 and/or 5 is/are not met but the results are considered atypical (as observed from medical history and patient recall) then the patient can be re-screen on 1 occasion only. Exclusion Criteria: Women who are pregnant or breast feeding Prior abdominal surgery which may cause bowel symptoms similar to IBS (note appendectomy and cholecystectomy will not be an exclusion) Patients unable to stop anti-muscarinics, anti-spasmodics, high dose tricyclic antidepressants (i.e. above 50 mg/day), opiates/anti-diarrhoeal drugs*, NSAIDs (occasional over the counter use and topical formulations are allowed), long-term antibiotics, other anti-inflammatory drugs or 5-ASA containing drugs. Patients on selective serotonin re-uptake inhibitors and low dose tricyclic antidepressants (i.e. up to 50 mg/day) for at least 3 months previous unwilling to remain on a stable dose for the duration of the trial. Patients with other gastro-intestinal diseases including colitis and Crohn's disease. Patients with the following conditions: Renal impairment, severe hepatic impairment or salicylate hypersensitivity. Patients currently participating in another trial or have been in a trial within the previous 3 months Patients who in the opinion of the investigator are considered unsuitable due to inability to comply with instructions Patients with serious concomitant diseases e.g. cardiovascular, respiratory, neurological etc. Loperamide is allowed as rescue medication through-out the trial, however if > 2 doses / week are taken during the screening phase then they are not eligible, though they can be re-screened on 1 occasion only.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesalazine Granules<br>2g oral granules, once a day for 1 week, then 2g oral granules, twice a day for 11 weeks | Drug: Mesalazine<br>* 2g oral granules, once a day for 1 week, then 2g oral granules, twice a day for 11 weeks<br>|
| Placebo Comparator: Placebo Granules<br>2g oral granules, once a day for 1 week, then 2g oral granules, twice a day for 11 weeks | Drug: Placebo<br>* 2g oral granules, once a day for 1 week, then 2g oral granules, twice a day for 11 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in average stool frequency during weeks 11 and 12. | Clinical Endpoint | Week 0 and week 12 | 
| Change from baseline of number of mast cell per mm2 at week 12 | Mechanistic endpoint | Week 0 and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average daily severity of abdominal pain on a 0-10 scale | Clinical Endpoint | Week 0 to week 12 | 
| Days with urgency | Clinical Endpoint | weeks 11-12 | 
| Mean stool consistency using Bristol Stool Form Score | Clinical Endpoint | Week 0 to week 12 | 
| Global satisfaction with control of IBS symptoms | as assessed from the answer to the question Have you had satisfactory relief of your IBS symptoms this week? Yes / No.  | Week 0 to week 12 | 
| Mast cell tryptase release during 6 hour biopsy incubation | Mechanistic endpoint | Week 0 and week 12 | 
| IL-1β, TNF-a, histamine and serotonin secretion during same incubation | Mechanistic endpoint | Week 0 and week 12 | 
| Small bowel tone assessed by volume of fasting small bowel water | Mechanistic endpoint | Week 0 and week 12 | 
| Euro-Qol Score | Ancillary endpoint | Week 0 and week 12 | 
| Centres for disease control and prevention health related quality of life healthy days core module score | Ancillary endpoint | Week 0 and week 12 | 
| Hospital Anxiety Depression Scale Score | Ancillary endpoint | Week 0 and week 12 | 
| Patient Health Questionnaire -15 | Ancillary endpoint | Week 0 and week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBS, diarrhoea