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

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01327300
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arms: 2
• Duration (Months): 24
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Irritable Bowel Syndrome	Drug: Mesalamine; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Cross-over Study of the Efficacy of Mesalamine in Diarrhea-predominant Irritable Bowel Syndrome (dIBS)
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mesalamine 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; 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.; Other Names: Apriso ™
Placebo Comparator: Placebo 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; 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.

Outcome Measures

Primary Outcome Measures

1. Changes in GIS Scores Between Baseline and After a 12 Week Intervention With Mesalamine or Placebo [Baseline and at 12 weeks post-intervention]

   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

1. Number of Participants Who Had Evidence of Increased Levels of Pathologic Indicators of Colonic Mucosal Inflammation at 12 Weeks Compared to Baseline. [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)]

   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.

2. Functional Bowel Disorder Severity Index (FBDSI) [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.]

   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.

3. IBS - Quality of Life (IBS-QOL)Score. [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)]

   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.

4. Hospital Anxiety and Depression Scale (HADS) [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)]

   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.

5. Intestinal Permeability Testing [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)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610

Sponsors and Collaborators

• University of Florida

Investigators

• Principal Investigator: Baharak Moshiree, MD, MS, University of Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995 May;108(5):1566-81. Review.
• 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.
• Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997 Jun;112(6):2120-37. Review.
• 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. Erratum in: Am J Gastroenterol. 2006 Aug;101(8):1944.
• 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.
• 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.
• Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology. 1990 Aug;99(2):409-15.
• 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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01327300
• Other Study ID Numbers: 106-2010
• First Posted: Apr 1, 2011
• Last Update Posted: Feb 12, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by University of Florida: Irritable Bowel Syndrome; Irritable Bowel Syndrome Treatment; Mesalamine; Anti-inflammatory drugs; 5-ASA drugs; Apriso ™
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Syndrome; Diarrhea; Mesalamine

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the gastroenterology specialty clinics at the University of Florida or by referral from other primary care physicians. Recruitment was from 2011 until March, 2012
Pre-assignment Detail	A washout period of 3 weeks was given between treatment periods with 2 weeks prior to recruitment.

Arm/Group Title	Mesalamine Then Placebo	Placebo Then Mesalamine
Arm/Group 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. Mesalamine : 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.	This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm. Placebo : 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.
Period Title: First Intervention (12 Weeks)
STARTED	5	2
COMPLETED	5	2
NOT COMPLETED	0	0
Period Title: First Intervention (12 Weeks)
STARTED	5	2
COMPLETED	4	2
NOT COMPLETED	1	0
Period Title: First Intervention (12 Weeks)
STARTED	4	2
COMPLETED	4	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All participants were randomized to receive both mesalamine and placebo.
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32 (11.3)
Sex: Female, Male (Count of Participants)
Female	4 57.1%
Male	3 42.9%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The first part of the analysis compares the differences between baseline and mesalamine to baseline and placebo. The P value provided below list the comparison of baseline-placebo to baseline-mesalamine using the Mann-Whitney statistical analysis.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	This group received the drug Mesalamine for 12 weeks Mesalamine : 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	This group will receive the Placebo for 12 weeks. Placebo : 4 capsules (.375 gm sugar pill capsules) administered orally once a day. This group will receive the placebo for 12 weeks.
Measure Participants	7	6
Mean (Standard Deviation) [units on a scale]	2.72 (1.82)	2.22 (1.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine
	Comments	The GIS scoring system is from 1-7 with one being a worse outcome and 7 the better outcome. Comparisons below list the p values for comparison of difference in GIS between baseline and mesalamine.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.72
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Comparisons of mean difference in GIS scores between baseline and placebo is made below.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.22
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mesalamine	Placebo
Arm/Group 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. The data below reflect the change in the increase in inflammation with regards to increased mast cells, eosinophils counts and number of activated T lymphocytes after 12 week mesalamine from baseline level of inflammation.	This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm. The data below reflect the change in the increase in inflammation with regards to increased mast cells, eosinophils counts and number of activated T lymphocytes after 12 week mesalamine from baseline level of inflammation
Measure Participants	7	6
Increased Mast cells-CD 117 Positive staining	2 28.6%	2 NaN
Increased eosinophil counts	3 42.9%	3 NaN
Increased Activated T lymphocytes-CD3	2 28.6%	3 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine
	Comments	Correlation coefficients were used for each of three biomarkers in relation to other biomarkers and to the questionnaires and patient's symptoms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.873
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The study tested three biomarkers and symptom domains at baseline and the end of 12 weeks of placebo using the Mann-Whitney test, as well as correlations between domains with Pearson's linear correlation coefficient.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.810
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Pearson's linear coefficient

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Change in Functional Bowel Disorder Severity Index (FBDSI)after 12 weeks of intervention.

Arm/Group Title	Mesalamine	Placebo
Arm/Group 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. Data is reported as baseline value minus 12 week mean FBDSI value with mesalamine.	This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm. Values reported at the baseline FBDSI score minus the 12 week FBDSI score with placebo.
Measure Participants	7	6
Mean (Standard Deviation) [units on a scale]	-14.5 (61.5)	17 (71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine
	Comments	The FBDSI score is based on the severity of abdominal pian. Severity is rated as the following: None= 0 points Mild= (1-36) Moderate =(37-110) Severe= (>110 points)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	t-test, 2 sided
	Comments	Two-tailed P values are listed for baseline versus 12 weeks of mesalamine
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.5
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	See prior description of the FBDSI score. Change in the FBDSI after 12 weeks of intervention is made using a two sided t-test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	17
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Data are the mean change in IBS-QOL between baseline and intervention

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	This group received the drug Mesalamine for 12 weeks. The data below show the change in IBS-QOL scores from baseline after 12 weeks of intervention.	This group will receive the Placebo for 12 weeks. The data below show the change in IBS-QOL scores from baseline after 12 weeks of intervention.
Measure Participants	7	6
Mean (Standard Deviation) [units on a scale]	11 (36.1)	-12.2 (28.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine
	Comments	For the IBS QOL we compared the change in IBS-Quality of Life (IBS-QOL) after 12 weeks of mesalamine.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Comparison of change in IBS-Quality of Life (IBS-QOL)from baseline after 12 weeks of intervention was made.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	This group received the drug Mesalamine for 12 weeks . Comparison of the change in HADS score after 12 weeks of mesalamine is made to baseline score.	This group will receive the Placebo for 12 weeks. Comparison of the change in HADS score after 12 weeks of placebo is made to baseline score.
Measure Participants	7	6
HADS score- change from baseline c/w 12 weeks	1.2 (6.1)	-2.4 (8.7)
HADS Score-end of 12 weeks	14 (6.3)	13 (10.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine
	Comments	Comparison of the change in HADS score of baseline to 12 weeks of mesalamine is made.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.3
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Comparison of change in HADS score between baseline and after 12 weeks of placebo is made.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	This group received the drug Mesalamine for 12 weeks and after a 12 week treatment period, the ratio of lactulose to mannitol was measured.	This group received the placebo for 12 weeks and after a 12 week treatment period, the ratio of lactulose to mannitol was measured. Two patients in this cross-over study did not provide a 24 hour urine sample needed to obtain the lactulose /mannitol ratio.
Measure Participants	7	5
Mean (Full Range) [ratio]	0.07	0.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Comparison of the lactulose/mannitol ratio is made after a 12 week intervention with mesalamine to 12 weeks of placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Mesalamine Then Placebo		Placebo Then Mesalamine
Arm/Group 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. Mesalamine : 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.		This group will receive the Placebo for 12 weeks then a wash out for 3 weeks prior to crossing over to the drug arm. Placebo : 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.
All Cause Mortality
	Mesalamine Then Placebo		Placebo Then Mesalamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mesalamine Then Placebo		Placebo Then Mesalamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Mesalamine Then Placebo		Placebo Then Mesalamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)

Limitations/Caveats

The recruitment for this study ended on 3/2012 when Dr. Moshiree became adjunct faculty only at the University Florida. This study was limited with over 6 months of follow-up and the need for three endoscopies.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.