Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)

Study Overview
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Brief Summary
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The purpose of this study is to find whether treating patients with diarrhea predominant Irritable Bowel Syndrome (IBS) with an anti-inflammatory drug called Mesalamine will help improve their symptoms of diarrhea, bloating and abdominal pain.

Detailed Description
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Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting about 20% of the United States population and comprising almost 50% of referrals to gastroenterology practices. Although the pathophysiology of IBS is poorly understood, more recently, both inflammation and an increased intestinal permeability have been identified as potential factors in the etiology of diarrhea-predominant IBS patients(dIBS). Despite the potential of an inflammatory etiology for IBS, few studies have examined the efficacy of anti-inflammatory agents such as mesalamine in patients with IBS. The primary objective of our study is to determine the efficacy of Apriso™ (Salix Pharmaceuticals Inc), a long-acting mesalamine, in the treatment of patients with dIBS. Apriso™, is a mesalamine approved by the Food and Drug Administration (FDA) on October 31, 2008 for the maintenance of remission in patients with active, mild to moderate ulcerative colitis. The investigators will perform a randomized, double-blind, cross-over trial of mesalamine compared to placebo in patients with dIBS. This study will analyze both the objective and subjective measures of improvement in IBS symptoms. The subjective measures will include improvements in the overall symptom severity scores and the Global Improvement Scale (GIS) and the objective measures will include histological measures of inflammation as well as improvements in the intestinal membrane permeability of treated subjects. The investigators will demonstrate that during the 12 weeks treatment period with mesalamine, subjects will have improvements in their overall symptom scores, GIS scores, and will have a reduction in intestinal inflammation and also prohibit a likely improvement in Intestinal membrane permeability.

Official Title
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Randomized, Double-blind, Cross-over Study of the Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Mesalamine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female aged 18-65 years old Functional Bowel Disorder Severity Index Score above 37 Normal complete blood count, liver function studies and renal function studies Serologies done to rule out Celiac Spure or patient has prior negative EGD with small bowel biopsies which have been negative Infectious diarrhea ruled out by stool studies Negative colonoscopy Exclusion Criteria: Any history of chronic liver disease, heart disease, pulmonary or renal disease Abnormal EKG Women with positive pregnancy tests Patient on steroids, antacids, or warfarin or chronic pain conditions other than fibromyalgia Patients who drink over 2oz alcohol/day on a regular basis Any other causes for diarrhea such as IBD, microscopic colitis, celiac disease, history of abdominal obstruction, pancreatitis, ileus, or any gastrointestinal bleeding. Patients with active malignancy in the past five years Patient with any history of hypersensitivity reactions to salicylate containing medications due to cross-sensitivity with mesalamine or allergy to mesalamine medications in the past Any subjects with fibromyalgia will be excluded from the pain testing portion only History of Phenylketonuria due to the aspartame contained in Apriso

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mesalamine<br>This group received the drug Mesalamine for 12 weeks then a wash out for 3 weeks prior to crossing over to the placebo arm. | Drug: Mesalamine<br>* Apriso is a 5-ASA drug with Intellicor ™ extended-release delivery technology. A 1.5 gram dosage of Apriso (equaling four 375 mg capsules) once a day will be administered orally for a period of 12 weeks followed by a 3 week wash out prior to crossing over to the placebo arm.<br>* Other names: Apriso ™;|
| Placebo Comparator: Placebo<br>This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm. | Other: Placebo<br>* 4 capsules (.375 gm sugar pill capsules) administered orally once a day. This group will receive the placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in GIS Scores Between Baseline and After a 12 Week Intervention With Mesalamine or Placebo | Patients rated the severity of their GI symptoms. The GIS scale goes from 1 to 7 with 1 being the worse and 7 as the best score showing improvement in symptoms. The GIS was performed at week one and at week 12 during each of the interventions. The comparisons below list the mean difference for each intervention from baseline (BL) with standard deviations then we list the p-value for the differences of baseline to intervention are reported using the Mann-Whitney test with a two-tailed p value provided. | Baseline and at 12 weeks post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had Evidence of Increased Levels of Pathologic Indicators of Colonic Mucosal Inflammation at 12 Weeks Compared to Baseline. | Colonoscopy/flexible sigmoidoscopy will be performed and mucosal biopsies will be obtained. Each biopsy was stained for activated t lymphocytes, mast cells and eosinophils . CD117 staining was done for Mast cells. H and E staining was used to identify lymphocytes and eosinophils. Each path specimen was then noted to have increased versus normal number of these inflammatory cells. | For 2 times: First time: at the time of patient recruitment in the study Second time: after the completion of first 12-week treatment period, all of which are during the time period from 02/25/2010 to 02/01/2012 (up to 2 years) | 
| Functional Bowel Disorder Severity Index (FBDSI) | Subjects rate pain on a standardized scale. This is a standardized test used to evaluate patients with IBS. Baseline values are compared to 12 weeks after mesalamine and 12 weeks after placebo treatments. The FBDSI is score is interpreted as such: Severity of IBS is rated as none (0 points), mild (1-36 points), moderate as 37-110 points and severe as >110 points. Therefore patients can have a score higher than 110. | An FBDSI score is administered at the beginning of each 12-week treatment period (baseline) and at the end of each 12-week treatment period. | 
| IBS - Quality of Life (IBS-QOL)Score. | A questionnaire is given to each patient and was completed at baseline then after 12 weeks of intervention with mesalamine and then placebo in the cross-over study. The IBS-QOL comprises 34 items with 5-point response scales (0 to 4) that cover eight dimensions of HRQL: dysphoria (8 items), interference with activity (7 items), body image (4 items), health worry (3 items),food avoidance (3 items), social reaction (4 items), sexual concerns (2 items) and relationships (3 items). Higher values indicate better HRQL after converting the raw score on the IBS-QOL into 0 to 100 points. | at the time of recruitment and after completion of each 12-week treatment period, all of which are during the time period from 03/25/2010 to 02/01/2012 (up to 2 years) | 
| Hospital Anxiety and Depression Scale (HADS) | A questionnaire is given to each patient with scoring done on a Likert scale ranking from 0-42 which combines anxiety and depression scales. Each of these are scored from 0-21 depending on anxiety versus the depression parameters. Comparison of change in HADs after 12 weeks of intervention with either mesalamine or placebo is provided here with only the total value provided-range is from 0-42. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 3 with zero being none at all or occasional and 3 as most of the time. The scale used is a Likert scale and therefore the data returned from the HADS is ordinal. The best score for the HADS therefore is a 0 with the worst score a 42 for combined anxiety and depression scores. For the subscales of depression and anxiety, the best score is a 0 and the worst is a 21. This data is not provided here. Data below includes the change from baseline in the HADS scores. | at the time of recruitment and after completion of each 12-week treatment period, all of which are during the time period from 03/25/2010 to 02/01/2012 (up to 2 years) | 
| Intestinal Permeability Testing | Ability of test substances to permeate the intestinal mucosa. The Lactulose/Mannitol test (Genova Diagnostics®, Ashville, NC) directly measures the ability of mannitol and lactulose to permeate the intestinal mucosa. Patient ingests 5 grams of lactulose and 2 grams of mannitol dissolved in a 100 ml of water. Urine is then collected for 24 hours and the ratio of the urinary excretion of lactulose to mannitol is measured. This testing is performed only after completion of each treatment period , after 12 weeks of mesalamine and after 12 weeks of placebo. Normal ratio of lactulose/mannitol is any value <0.7. An abnormal ratio is defined as >0.7 ratio. The lactulose is measured in the urine as g/kg and the urinary excretion of mannitol is also measures as g/kg. | At the completion of each 12-week treatment period, all of which are during the time period from 03/25/2010 to 02/01/2012 (up to 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritable Bowel Syndrome, Irritable Bowel Syndrome Treatment, Mesalamine, Anti-inflammatory drugs, 5-ASA drugs, Apriso ™