Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS) (IBS)
Primary Purpose
Irritable Bowel Syndrome
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Mesalamine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Irritable Bowel Syndrome focused on measuring Irritable Bowel Syndrome, Irritable Bowel Syndrome Treatment, Mesalamine, Anti-inflammatory drugs, 5-ASA drugs, Apriso ™
Eligibility Criteria
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
Sites / Locations
- University of Florida
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Mesalamine
Placebo
Arm Description
This group received the drug Mesalamine for 12 weeks then a wash out for 3 weeks prior to crossing over to the placebo arm.
This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01327300
Brief Title
Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)
Acronym
IBS
Official Title
Randomized, Double-blind, Cross-over Study of the Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)
Study Type
Interventional
2. Study Status
Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Florida
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Irritable Bowel Syndrome
Keywords
Irritable Bowel Syndrome, Irritable Bowel Syndrome Treatment, Mesalamine, Anti-inflammatory drugs, 5-ASA drugs, Apriso ™
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Mesalamine
Arm Type
Active Comparator
Arm Description
This group received the drug Mesalamine for 12 weeks then a wash out for 3 weeks prior to crossing over to the placebo arm.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm.
Intervention Type
Drug
Intervention Name(s)
Mesalamine
Other Intervention Name(s)
Apriso ™
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Changes in GIS Scores Between Baseline and After a 12 Week Intervention With Mesalamine or Placebo
Description
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.
Time Frame
Baseline and at 12 weeks post-intervention
Secondary Outcome Measure Information:
Title
Number of Participants Who Had Evidence of Increased Levels of Pathologic Indicators of Colonic Mucosal Inflammation at 12 Weeks Compared to Baseline.
Description
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.
Time Frame
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)
Title
Functional Bowel Disorder Severity Index (FBDSI)
Description
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.
Time Frame
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.
Title
IBS - Quality of Life (IBS-QOL)Score.
Description
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.
Time Frame
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)
Title
Hospital Anxiety and Depression Scale (HADS)
Description
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.
Time Frame
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)
Title
Intestinal Permeability Testing
Description
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.
Time Frame
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Baharak Moshiree, MD, MS
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
9178709
Citation
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Results Reference
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PubMed Identifier
2365191
Citation
Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology. 1990 Aug;99(2):409-15. doi: 10.1016/0016-5085(90)91023-y.
Results Reference
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PubMed Identifier
7729650
Citation
Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995 May;108(5):1566-81. doi: 10.1016/0016-5085(95)90708-4.
Results Reference
background
PubMed Identifier
16771951
Citation
Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, Spiller RC. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol. 2006 Jun;101(6):1288-94. doi: 10.1111/j.1572-0241.2006.00672.x. Erratum In: Am J Gastroenterol. 2006 Aug;101(8):1944.
Results Reference
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PubMed Identifier
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Citation
Corinaldesi R, Stanghellini V, Cremon C, Gargano L, Cogliandro RF, De Giorgio R, Bartesaghi G, Canovi B, Barbara G. Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study. Aliment Pharmacol Ther. 2009 Aug;30(3):245-52. doi: 10.1111/j.1365-2036.2009.04041.x. Epub 2009 May 12.
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Gordon S, Ameen V, Bagby B, Shahan B, Jhingran P, Carter E. Validation of irritable bowel syndrome Global Improvement Scale: an integrated symptom end point for assessing treatment efficacy. Dig Dis Sci. 2003 Jul;48(7):1317-23. doi: 10.1023/a:1024159226274.
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PubMed Identifier
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Citation
Zhou Q, Fillingim RB, Riley JL 3rd, Malarkey WB, Verne NG. Central and peripheral hypersensitivity in the irritable bowel syndrome. Pain. 2010 Mar;148(3):454-461. doi: 10.1016/j.pain.2009.12.005. Epub 2010 Jan 13.
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Myers CD, Robinson ME, Riley JL 3rd, Sheffield D. Sex, gender, and blood pressure: contributions to experimental pain report. Psychosom Med. 2001 Jul-Aug;63(4):545-50. doi: 10.1097/00006842-200107000-00004.
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Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)
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