Clinical trial NCT01412372
Conditions: Irritable Bowel Syndrome
Keywords: Irritable Bowel Syndrome Diarrhea Mesalamine Gastroenteritis abdominal pain hypersensitivity
Sponsor: University of Utah
Start date: 2010-06-01; Completion date: 2019-04-22
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effects of long acting mesalamine (Lialda) in patients with Post-Infective Irritable Bowel Syndrome (PI-IBS). The investigators will evaluate gastrointestinal symptoms, IBS specific quality of life (IBS-QOL), and plasma cytokines before and after treatment with Lialda.

Detailed description:
This study will test long acting mesalamine in the management of PI-IBS. It has the potential to improve QOL and perhaps gastrointestinal symptoms, in patients with PI-IBS. The results of this study, if positive, will provide preliminary data for a large scale clinical trial.

This study will also provide information about plasma cytokines in patients with PI-IBS and whether improvement in symptoms correlates with improvement in plasma cytokines.

Arms: arm 1: This arm will include those who are randomized to the placebo arm 2: This arm is for subjects randomized to the study drug, Mesalamine
Interventions: intervention 1: Mesalamine intervention 2: Placebo
Intervention descriptions: intervention 1: 2 1.2g tablets once daily for 8 weeks. Patients randomized 50/50 to either Mesalamine or the Placebo intervention 2: This is an inactive pill

Protocol documents:
Prot_SAP_000.pdf: 
 
The Effect of Long-Acting Mesalamine on Post-Infective Irritable Bowel Syndrome- A Double-
Blind Placebo Controlled Pilot Study 
 
 
NCT01412372 
 
 
Document Date: 9/14/2019 


 
 
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Protocol Summary 
Version December 21, 2015 
 
The Effect of Long-Acting Mesalamine on Post-Infective Irritable Bowel Syndrome: A Double-
Blind Placebo Controlled Pilot Study 
 
 
Principal Investigator 
Ashok Tuteja, M.D. 
University of Utah 
Division of Gastroenterology 
30 North 1900 East, SOM 4R118 
Salt Lake City, UT 84132 
(801) 581-7802 
ashok.tuteja@hsc.utah.edu 
 
Co-Investigator(s) 
John Fang, M.D. 
University of Utah 
Division of Gastroenterology 
30 North 1900 East, SOM 4R118 
Salt Lake City, UT 84132 
(801) 581-7802 
john.fang@hsc.utah.edu 
 
 
Daniel Leung, M.D. 
University of Utah 
Division of Infectious Disease 
30 N 1900 E RM 4B319 
Salt Lake City, UT 84132-2101 
Daniel.leung@hsc.utah.edu 


 
 
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BACKGROUND AND INTRODUCTION: Up to one-third of patients with irritable bowel syndrome 
(IBS) describe the onset of their symptoms following an episode of acute gastroenteritis. This is called 
post-infective IBS (PIIBS). 1 It is associated with an increase in inflammatory mediators such as 
prostaglandins, cytokines, and nerve growth factors. 2  Routine colon histology is usually normal; 
however, there is often an increase in the number of mast cells and T-cells on microscopic examination.3 
It is thought that the initial inflammatory response triggers a cascade of events (mediated by incorporation 
of Toll-like receptors and NF-KB) leading to proliferation of mast cells and activation of 
enterochromaffin (EC) cells. Intestinal mucosal mast cells attract inflammatory cells and initiate the 
innate and adaptive immune system manifested by invasion of T-lymphocytes, and also enhance visceral 
hypersensitivity and abdominal pain.4 Enterochromaffin cells secrete serotonin which regulates intestinal 
motility and secretion. It remains unclear whether the inflammation is the response to injury or initiates 
the disease. Nor is it known why the disease becomes self-perpetuating.  
 
NF-κB (nuclear factor kappa-light chain-enhancer of activated B cells) is a transcription factor that plays 
a central role in inflammation and immune regulation. 5 Mesalamine (5-ASA) is a PPAR γ (peroxisome 
proliferator-activated receptor γ) agonist which among other things inhibits NF- κB.  6 There is anecdotal 
evidence that it is effective in the treatment of microscopic colitis which has many pathophysiologic 
similarities to PI-IBS7-9. We hypothesize that patients with PI-IBS are also likely to respond to 
mesalamine. 
 
A recent study in IBS patients demonstrated a reduction in colonic mast cells after mesalamine but no 
improvement in symptoms.10 A double-blind placebo controlled study of mesalamine by our group also 
failed to show improvement in symptoms but did demonstrate a trend toward improvement in quality-of-
life (QOL) suggesting that other mechanisms may be involved- perhaps suppression of the immune 
response which is partly responsible for the extraintestinal symptoms of fatigue, etc. Compliance was a 
problem in this study as patients were not receptive to taking 4 tablets of mesalamine twice per day. We 
propose that compliance and therapeutic response could be improved by using long acting mesalamine. 
Salt Lake City is an ideal area to conduct this study in that there is a large population of Mormon 
missionaries and who return from abroad with altered bowel function.  We have previously demonstrated 
that most of these patients have PI-IBS.11, 12  
 
The purpose of this study is to evaluate the effects of long acting mesalamine (Lialda ®) in patients with 
PI-IBS. We will evaluate gastrointestinal symptoms, IBS specific quality of life (IBS-QOL) before and 
after treatment with Lialda ®. 
 
Significance of this study: 
This study will test long acting mesalamine in the management of PI-IBS. It has the potential to improve 
QOL and perhaps gastrointestinal symptoms, in patients with PI-IBS. The results of this study, if positive, 
will provide preliminary data for a large scale clinical trial.  
 
Aim: 
To determine if mesalamine will relieve symptoms, improve QOL and reduce inflammation in patients 
with PI-IBS. 
 
IBS 
IBS is characterized by abdominal pain or discomfort associated with altered bowel function (diarrhea 
and/or constipation) in the absence of any structural abnormality.13 It is a poorly understood disorder that 
is probably a heterogeneous group of conditions producing similar symptoms. IBS is associated with 
reduced QOL and significant economic burden.14 It is the most frequent GI disorder seen by physicians, 
comprising 50% of referrals to gastroenterologists and as many as 3.5 million visits to physicians each 


 
 
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year in the United States. 15 The direct cost of IBS in the US is estimated at $1.5 to 10 billion and the 
indirect cost, $20 billion. The cause of IBS is not known. The speculated mechanisms of IBS include 
altered GI motility, visceral hypersensitivity, aberrant brain-gut interaction, and psychological factors, 
perhaps with a genetic predisposition. 16 A proposed triggering mechanism in patients with PI-IBS is 
mucosal injury with subsequent inflammatory/ immune response which becomes self-perpetuating.2  
 
PI-IBS 
IBS occurs in 7% to 30% of subjects after an episode of gastroenteritis.1 Several factors have been shown 
to predispose to PI-IBS: severity of the initial illness, bacterial toxigenicity, hypochondriasis, depression 
and adverse life events in the previous 3 months. 17 PI-IBS is characterized by predominance of diarrheal 
symptoms, less psychiatric illness, and increased serotonin-containing enterochromaffin cells compared to 
those with non-PI-IBS.17 
 
There are several factors which suggest that inflammation plays a part in the pathogenesis of PI-IBS.  For 
example, an infection activates mast cells in the GI tract. When activated, mast cells release humoral 
mediators which induce the adaptive and subsequently the innate immune response leading to attraction 
of both cytotoxic and helper T- lymphocytes.  Mast cell derived cytokines TNF-α and IL-Iβ also play an 
important role in generation of visceral hypersensitivity and abdominal pain. Activated enterochromaffin 
cells secrete serotonin which regulates intestinal motility and secretion. 18 Anxiety and depression which 
are more common in IBS are also related to serotonin and can cause bowel symptoms compatible with 
IBS. 
 
Recent studies have demonstrated that acute gastroenteritis triggers a self-perpetuating immune and 
chemical response which is responsible for maintaining symptoms after the acute injury has resolved. 19-22 
In PI-IBS, the colon is grossly normal but biopsy reveals an increased number of EC and mast cells as 
well as sub-epithelial inflammatory cells, specifically T-lymphocytes.23 Chadwick et al demonstrated an 
increased number of activated T lymphocytes in all 77 symptomatic patients with IBS. Patients with PI-
IBS show an increased level of expression of the pro-inflammatory cytokine IL-1β in the rectal mucosa. 
Other studies have shown high levels of the proinflammatory cytokines IL-1β, IL-6 and TNF-α in 
peripheral blood mononuclear cells. It has also been speculated that IBS patients may be more susceptible 
to infection and are thus genetically predisposed to produce lower amounts of the anti-inflammatory 
cytokine, IL-10.  A recent study has shown abnormalities in the IL-10/1L-12 ratio in patients with IBS 
favoring inflammation. Mast cell degranulation and increased pro-inflammatory cytokines may contribute 
to symptom perception as they have been shown to generate visceral hypersensitivity via direct activation 
of sensory nerves. 4, 24  
 
Enterochromaffin cells contain 85 percent of the total body serotonin which is involved in visceral 
hypersensitivity, the peristaltic reflex and intestinal secretions. 25 However, inflammation alone is not 
sufficient to cause IBS as most of the patients with gastroenteritis recover completely. Psychologic stress 
is also known to affect gut function. It has been shown to release mast cell and enterochromaffin cell 
mediators in the colon and thus may play a role in the perpetuation of IBS. 26, 27 
 
Mesalamine 
5-aminosalicylic acid (5-ASA) is a topically acting anti-inflammatory agent that is used in the treatment 
of inflammatory bowel disease. 5-ASA activates the peroxisome proliferator-activated receptor γ (PPAR-
γ). 6 PPAR-γ is a transcription factor which is highly expressed in the colonic epithelium. It modulates 
cytokine production and, specifically, decreases activity of NF-κβ, which is a central factor in 
inflammation.5 It also reduces synthesis of prostaglandins and leukotrines which are also mediators of the 
inflammatory response.  
  
 


 
 
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Mesalamine and PI-IBS 
There is strong evidence that PI-IBS is triggered by inflammation and persists because of self 
perpetuating immune response: 1) it starts after gastroenteritis, 2) presence of mast cells which induce the 
innate and adaptive immune systems 3) the increase in pro-inflammatory and decrease in anti-
inflammatory cytokines in blood, 4) PI-IBS shares many of the features of lymphocytic colitis (chronic 
diarrhea, grossly normal endoscopic findings, mucosal inflammation and a benign course). 7-9 
 
It is logical that an anti-inflammatory agent will be effective in PI-IBS. Experimental data show that 
inflammation, even if mild, can lead to persistent changes in gastrointestinal nerve and smooth muscle 
function, resulting in dysmotility, rectal hypersensitivity and gastrointestinal dysfunction.28, 29 Research 
has also shown that functional changes in mice intestine after infection may be reversed using non-
selective or selective anti-inflammatory agents administered after recovery from infection 30, 31 Dunlop et 
al studied the role of oral steroids in reducing inflammation and enterochromaffin cells numbers.  Their 
study demonstrated a significant decrease in the T-lymphocyte number in the lamina propria but was not 
associated with an improvement in symptoms.  A recent study evaluated mesalamine in non-selective 
patients with IBS. There was improvement in colon histology but no improvement in symptoms.10 We 
have shown that there is trend to improvement in QOL with mesalamine.  
 
The purpose of this study is to evaluate the effects of long acting mesalamine (Lialda®) in patients with 
PI-IBS. We will evaluate gastrointestinal symptoms and IBS specific quality of life (IBS-QOL) before 
and after treatment with Lialda® 
 
OBJECTIVES: 
 
Objective #1: Determine the efficacy of mesalamine in patients with PI-IBS.  
Hypothesis: Treatment with mesalamine compared to placebo will improve QOL, and global as well as 
individual symptoms of IBS 
 
 
PARTICIPANT SELECTION CRITERIA:  
Patient Population 
Ambulatory patients, 18 years of age or older with PI-IBS symptoms for at least 6 months, will be 
enrolled in the study.  The study population will consist of previously healthy patients who developed IBS 
after an episode of gastroenteritis. Patients will be identified by the Bowel Disease Questionnaire which is 
sensitive to Rome Criteria.32 Rome III criteria will be used to define IBS. PI-IBS patients are usually 
diarrhea-predominant and patients whose predominant symptom is constipation will not be enrolled in 
this study. Patients will be recruited from the Internal Medicine and Gastroenterology clinics at the 
University Hospital and the VA Medical Center.  
 
Inclusion Criteria 
1. Men and women age 18-75 years 
2. Rome III criteria for IBS 
3. Symptom onset after apparent acute gastroenteritis  
4. Symptoms of 6 months or greater duration 
5. Normal gross appearance of the colonic mucosa other than erythema and polyps  
6. Negative markers for celiac disease (tissue transglutaminase antibody or endomysial antibody).  
7. No clinically significant abnormality in thyroid function (Thyroid Stimulating Hormone) and 
serum calcium 
8. Stable medication regimens for more than 1month. 


 
 
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9. Sexuallly active female patient of child bearing potential have negative urine pregnancy test or  
practices accepted method of birth control during the study. 
10.  
 
Exclusion Criteria 
1. Age <18 or > 75 years 
2. Constipation-predominant IBS.  
3. Clinically significant chronic cardiac, pulmonary, hepatic, renal dysfunction or HIV 
4. Presence of active malignancy Current evidence of any gastrointestinal disorder such as celiac 
disease, inflammatory bowel disease, chronic pancreatitis, scleroderma, HIV, small bowel or 
colonic resection, paraplegia or quadriplegia 
5. Current evidence of drug or alcohol abuse as judged by the investigator 
6. Allergy to mesalamine or aspirin 
7. Investigator perception of patient’s inability to comply with the study protocol 
8. Unstable psychiatric disease 
9. Recent change in gastrointestinal medications 
 
 
DESIGN: Randomized double-blind placebo-controlled. 
Study End-points 
Primary: Improvement in self reported overall Bowel Symptom Scores (BSS) after 8 weeks of treatment 
will be used as the primary endpoint.  
Secondary:  
1) Change in specific bowel symptoms: bowel frequency, bowel consistency, abdominal pain, urgency, 
and bloating after 8 weeks treatment.  
2) IBS-QOL at end of treatment  
 
Definition of a Responder: Patient who report at least 50% of the weeks of treatment with satisfactory 
relief (30% or more reduction in symptom) will be designated as responders.  
 
Methods 
Rome III criteria for IBS13 
Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with two or 
more of the following: 
1. Improvement with defecation 
2. Onset associated with change in frequency of stool 
3. Onset associated with change in form (appearance) of stool. 
Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.  
Diarrhea-predominant IBS is defined by the presence of loose (mushy) or watery stools at least 25% of 
times and hard or lumpy stool <25% of times (in the absence of anti-diarrheal or laxative use).  
Constipation-predominant IBS: hard or lumpy stools ≥25% and loose (mushy) or watery stools <25% of 
bowel movements. 
Mixed IBS: hard or lumpy stools ≥25% and loose (mushy) or watery stools ≥25% of bowel movements. 
Unsubtyped IBS: insufficient abnormality of stool consistency to meet criteria for IBS-C, D, or M.  
 
The validated Bristol Stool Form scale will be used to determine the participants usual stool 
consistency.33 
 
Criteria for PI-IBS 


 
 
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Acute onset of symptoms of IBS subsequent to two or more of the following: 1) fever, 2) vomiting, 3) 
diarrhea.  
 
STUDY PROCEDURES:  
This study will be conducted at the University of Utah and the VA Medical Center.  Information collected 
at the VA will be stored at the VA.  For purposes of statistical analysis the information from the VA will 
be de-identified and sent to the University of Utah.   
 
All patients will have a complete blood count, comprehensive biochemical profile (including serum 
calcium), thyroid-stimulating hormone (TSH), tissue transglutaminase antibody (TTG), C- reactive 
protein, and stool examination for electrolytes (optional), ova and parasite, C.difficile toxin (not required 
if stool is formed), Calprotectin or lactoferrin, and Giardia antigen.  These tests will not be repeated if 
they were collected in the last 6 months.    Blood and stool samples will be collected for storage if the 
patient consents.  Flexible sigmoidoscopy and biopsy of the colonic mucosa will be performed in all 
patients at the beginning of treatment. Patients with red flag symptoms (onset in older than >50 years, 
progressive or non-fluctuating symptoms, unexplained weight loss, rectal bleeding or anemia, family 
history of colon cancer, fever, abnormal examination or laboratory tests) will have colonoscopy and 
biopsy.  Patients with structural, biochemical, or infective disorders will be excluded from the study. A 
flexible sigmoidoscopy or colonoscopy will not be done if an acceptable biopsy was completed within 5 
years.  If the procedures are done a biopsy will be collected for storage. 
 
Questionnaires 
Bowel Disease Questionnaire  
The Bowel Disease Questionnaire (BDQ) will be used to identify patients with IBS.32 The BDQ has been 
modified to include Rome III criteria for functional bowel disorders. We have used the BDQ and the 
modified version in our previous studies.11, 34   
 
Bowel Symptom Scale (BSS) 
BSS is a validated IBS outcome measure which consists of 100-mm visual analog scales related to each 
symptom of IBS (pain/ discomfort, bloating, constipation, diarrhea) and an overall severity scale.35 All 
questions contribute equally to the total score, which ranges from 0-400. Similarly reflux disease 
questionnaire (RDQ) measures change in upper gastrointestinal symptoms before and after treatment.  
 
Psychological Symptom Questionnaire  
The BSI-18 questionnaire (Brief Symptom Inventory, a short form of symptom check list-90-revised, 
SCL-90-R) will be used.36 The BSI-18 has 18 items, six each on the somatization, depression, and anxiety 
dimensions. The global severity index represents the global or total score, which summarizes the 
respondent’s overall level of distress. Each item response is scored 0-4.  This questionnaire can be 
completed in 4 minutes. The psychological symptoms and composite scores from BSI-18 test correlate 
highly (i.e.>0.90) with SCL-90-R.  
 
IBS-QOL Questionnaire  
The disease-specific IBS-QOL will be used for evaluation of subjects QOL.37 The IBS-QOL is a validated 
disease specific quality of life questionnaire for use in patients with IBS. It has 34 items and measures 8 
domains found to be relevant to patients with IBS: dysphoria, interference with activity, body image, 
health worry, food avoidance, social reaction, sexual, and relationships. The IBS-QOL has high internal 
consistency and high reproducibility. IBS-QOL has been shown to be sensitive to treatment response in 
patients with IBS. 38 
 
Nepean Dyspepsia Index 


 
 
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The Nepean Dyspepsia Index (NDI) will be used to evaluate how a patient’s life and daily activities are 
affected by their stomach problems. 
 
 
Treatment Schedule 
This study will compare mesalamine two (Lialda®) 1.2 gm tablets orally daily to placebo in 68 patients 
with diarrhea predominant PI-IBS. The patients will be consented and enter into the screening which can 
last up to 8 weeks.  This will be followed by an 8 week treatment period.  
 
Patients will be re-consented to the newest version of the consent form if changes have been made while 
they are enrolled on the study. The patient may not be rescreened if there is no change in patient’s 
symptoms if they are outside the screening window.  
All patients will fill out the following questionnaires:  
 
1) The Bowel Symptom Scale (BSS) at the beginning, at 4 weeks and at the end of the study period 
to assess any change based simply on admission to the trial.  
2) The BSI-18 at the beginning of the screening period. 
3) The IBS-QOL at the beginning, at 4 weeks and end of treatment.  
4) The Nepean Dyspepsia Index at the beginning, 4 weeks and end of treatment as well as during the 
mail-in/phone call visits.BDQ (Bowel Disease Questionnaire) at screening.  
 
 
Drug, Dose and Duration Rationale  
Mesalamine with MMX (Multi Matrix System) technology (Lialda®) will be used for this study. This is a 
novel oral, high strength (1.2 gm/tablet) formulation of 5-ASA designed for once or twice daily 
administration. Lialda has been shown to be well tolerated for the treatment of mild to moderate 
ulcerative colitis.40 Previous studies have shown that clinical and endoscopic remission with 2.4 and 4.8 
gm/ day was similar.40 Therefore the 2.4gm once daily dose will be used for this study. A placebo capsule 
will be provided by the makers of Lialda, Shire Pharmaceuticals, Inc. All study medication will be stored 
and dispensed at the University of Utah and VA pharmacies.  
 
Assessment of Compliance 
Every subject will be evaluated so that they are at least 80% compliant for continuous dosing of 
medication by pill count. Adverse reactions will be assessed. Patients will be called by the study 
coordinator every two weeks during the 8 week treatment period to check for medication compliance.  
 
Concomitant Medications 
All concomitant medications will be recorded. Drugs which affect the gastrointestinal motility will not be 
allowed during the study unless the patient has been on a stable dose for >1 month and symptoms are still 
persisting. - The following medications will be prohibited: oral anti-cholinergics (dicyclomine, 
hyocyamine, and propatheline), narcotics, tramadol, colchicine, misoprostol, antacids, antidiarrheal 
agents, bismuth compounds and laxatives.  
 
Time Line 
Location of Study 
This study will be performed at the University of Utah Hospital and Clinics and the VA Medical Center.  
 
Time Table of study:  Approximately 1 Years from the start of patient recruitment 
 


 
 
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Subject recruitment will start immediately upon IRB approval and continue throughout the duration of the 
study. We estimate that 50% of recruited patients will qualify for enrollment. Sixty-eight patients with 
diarrhea-predominant or mixed IBS (with diarrhea as predominant symptom) will be enrolled at the rate 
of 1-2 per week. The estimated dropout rate is 10%, leaving 64 patients to study. This population will 
include but not be limited to returned missionaries. We have previously worked with missionaries who 
have high prevalence of PI-IBS.   
 
Study visits (Table 1. Figure 1.) 
First visit:   
Orientation to the study and informed Consent 
Inclusion/Exclusion check 
History and physical examination,  
Questionnaires: BDQ, IBS-QOL, BSI-18, BSS, Nepean Dyspepsia Index (NDI) 
Blood and stool tests (not repeated if done in past 6 months unless there has been an alteration in the 
symptoms) 
Collection of stool sample for storage (if consent is given) 
Urine pregnancy Test for women of child bearing potential 
Instructions to complete 2 week stool diary during 8-week run in period  
 
 
Second visit:  
Flexible sigmoidoscopy/ colonoscopy with biopsy, if indicated (not repeated if performed during last 5 
years, results within normal limits and no change in symptoms)  
 
Third visit 
Subjects will be randomly assigned to either two Lialda 1.2gm tablets daily or two placebo tablets daily 
according to a block randomization schedule generated by the statistician. Medicines will be provided by 
and dispensed at the Pharmacy.  Medication may be mailed at patients’ convenience and they will be 
informed on dosing and storage of medication by telephone. 
 
 
Mail-in/ telephone visit 
Patients will be asked to fill BSS IBS-QOL and NDI at week 4 of  the 8 week treatment  either by mail or 
on telephone.  
 
 
Fourth visit 
End of treatment- Questionnaires-BSS, IBS-QOL, andNDI and physical examination 
Study drug count 
Return all unused study drug and the study drug bottle(s) 
 
Standard of Care vs. Research-Related Procedures:  all procedures for this study are research-related.   
Data Safety and Monitoring:  
Patient Safety: Adverse Events (AE) and Serious Adverse Events (SAE):   
Any untoward medical occurrence in a patient temporarily associated with the use of Lialda whether or 
not considered related will be recorded. SAE is defined as life threatening event or death. Safety data will 
be assessed by the age and race. The study side effects will be reviewed by the PI, and unexpected side 
effects will be reported to the IRB. All adverse events will be recorded and reported to Shire 
Developmental Inc.  
 


 
 
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The Data Safety Monitoring Plan consists of setting up a Data Safety Monitoring Board (DSMB). The 
DSMB will consist of a physician (Dr. Harry Rosado-Santos, M.D., Division of Infectious Disease), a 
pharmacist (Anthony Dalpiaz, Pharm.D) and a biostatistician (Tom Greene, PhD).  The board will meet 
every 4 months to review the study’s progress and endpoints, monitoring of safety data (adverse events or 
serious adverse events), and recommendations whether to continue, modify or stop the study. 
 
STATISTICAL METHODS, DATA ANALYSIS AND INTERPRETATION:  
Sample Size 
The sample size for this trial is based on primary end-point of overall improvement in BSS. A previous 
IBS treatment trial reported baseline BSS of 183±65. 35 To detect 25% change in BSS, 32 patients in each 
group will provide 80% power using two-sided alpha 0.05 comparisons. Assuming 5% drop out rate, we 
would require a total of 68 patients (n=34 in each group). Assuming proportional estimates for the 
individual symptoms of IBS, a similar power will be achieved with this sample size. 
 
The Lialda treated group will be compared to the placebo group on improvement in the BBS global 
symptoms of IBS (continuous scale, range 0 to 400) and BBS individual symptoms of IBS (continuous 
scales, range 0 to 100). Given the repeated measurements on continuous outcomes, the data will be 
analyzed with mixed effects linear regression.  
 
Primary analysis will be based on intention to treat. Exploratory analyses assessing “compliers” will also 
be reported. We will compare the results of placebo and Lialda treated group. The key comparisons 
between treatment arms will assess changes from baseline to end of treatment using parametric 
approaches such as the t- test and, when data is highly skewed, nonparametric approaches such as the 
Wilcoxon test. We note that it is feasible to construct confidence intervals as well as significance tests in 
the setting of nonparametric comparisons. For some of the secondary efficacy approaches, such as those 
with binary/ categorical outcomes, follow-up status will be compared between treatment arms using the 
chi-squared test of the Mantel-Haenszel chi-square for ordered categorical outcomes. Exact versions of 
these tests will be performed when cell sizes are excessively small.  
 
In addition to the unadjusted primary analyses we will perform exploratory analyses which will use the 
logistic regression model for binary outcomes, and the linear regression model for continuous outcomes 
(transformations or categorization may be necessary for the cell count variables). We expect that 
psychological factors may affect the response to treatment and therefore will do pre-study psychological 
analysis and will control for them while evaluating response to treatment. 
 
We note that IBS-QOL will be collected at 4-week intervals. Therefore, approaches incorporating 
repeated measures, notably the linear mixed model, will be implemented to assess and quantify trends 
(e.g., a linear divergence between treatment arms) over time. These approaches also allow the inclusion of 
available data from patients who drop out in the middle of the study in the analysis.  We are aware, 
however, that the dropout pattern in this study may not be the "Missing at Random" pattern required for 
such available-data models to yield valid inference. We will examine and report characteristics of study 
completers versus dropouts, to obtain some empirical evidence for or against this missingness 
assumption. 
 
 
We are familiar with imputation approaches, and will implement these when appropriate. Simplistic 
approaches such as substituting each subject’s “worst” value, or the “worst” value observed for any 
subject, for missing values may shed light on the robustness of any significant findings to missing data. 
However, such substitution approaches are not useful for formal statistical inference.  
 
 


 
 
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ADMINISTRATIVE RESPONSIBILITIES:  
Study Resources:  
Study procedures will be conducted at the University of Utah Hospital and the VA Medical Center. The 
data gathered for the study at the University of Utah will be stored in the Division of Gastroenterology at 
The University of Utah Hospital. Data collected at the VA Medical Center will be stored in the 
Gastroenterology Division of the VA Medical Center.  The data analysis for all patients will be conducted 
at the University of Utah.  All information will be de-identified and securely transferred to the University 
of Utah for analysis. Confidentiality and privacy of patient’s research data (patient’s demographics) will 
be maintained by saving the documents in locked cabinets and keeping them in secure files in the GI 
research offices. The computerized data will be saved on password-protected computers, also in secured 
research offices.  The principal investigator, co-investigator, study coordinator, and research staff, will 
have access to this data. The patients’ names will not be recorded in this database.  Patients will be 
identified by an assigned number and patient’s initials only.  The database will be password-protected to 
ensure security. 
 
The data and results of the study may be published or presented.  In this case, patients' will be identified 
by number only in order to maintain confidentiality.  The data will be stored indefinitely. 
 
For data verification purposes, authorized representatives, a regulatory authority, or IRB may require 
direct access to parts of the hospital or practice records relevant to the study, including patients’ medical 
history.  The principal investigator, co-investigators study coordinator and research staff as well as the 
Federal Drug Administration, a regulatory agency, will also have access to patient’s information and 
collected data. 
 
Subjects will be given the opportunity to read the consent form and ask questions to the study staff until 
subjects express that they fully understand the consent form and their responsibilities for participation in 
the study.  Subjects will sign and date the consent form and will be given a copy of the consent form to 
keep.  No study procedures will be performed until the consent form is signed.  The data and results of the 
study may be published or presented.  In this case, patients will be identified by number only in order to 
maintain confidentiality.  
 
The Gastroenterology Division at the University of Utah Hospital and Clinics has 12 examination rooms 
and the GI Laboratory has four endoscopy rooms. More than 25 procedures are performed in the 
laboratory each day. More than 150 patients are seen in the Gastroenterology clinics each week. The 
University of Utah draws patients from throughout intermountain region. There is deep freezer available 
to the PI for specimen storage at the University of Utah and VA Medical Center.  
The PI has two full time study coordinators and facilities for questionnaire optical scanning, printing, and 
copying. Ashok Tuteja, M.D., M.P.H., is the principal investigator of this project. John Fang, M.D. 
(Division of Gastroenterology, University of Utah) and Rahul Anand, M.D. (Division of Infectious 
Diseases, University of Utah) are co-investigators. They will help the PI in patient recruitment and 
conducting study related procedures. The study coordinators will help the study team in arranging 
patients’ study visits, recruitment, and other study related procedures. Nicholas J. Talley, M.D. PhD. 
(Pro-Vice-Chancellor, University of Newcastle, Australia) and Keith G. Tolman, M.D. (University of 
Utah) are consultant to this grant. Dr. Talley is an internationally known expert in IBS and Dr. Tolman, 
Professor of Medicine and Pharmacology has expertise in conducting pharmaceutical trials.  
Future studies 
We will store blood, stool, and colon biopsy specimens obtained before and after treatment (as indicated 
above) for future studies looking at genetic and histo-chemical biomarkers which may predict response to 
mesalamine.  


 
 
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The informed consent form will ask every study patient if their blood, colon biopsy specimen, and stool 
sample(s) can be stored at the end of this research project for use in future research. A separate question 
will ask if their name and identifying information be stored along with the samples for future research. 
 
Recruitment:  
Patients will be recruited from the gastroenterology, infectious diseases and internal medicine clinic at the 
University of Utah Hospitals and clinics and VA Medical Center. Patients will also be recruited from 
community Physicians referral letters, flyers, and newspaper advertisements. A report will also be created 
of all previous patients seen in GI clinic with the diagnosis of IBS within the past year. The report will 
assist in recruiting potential patients within the department of Gastroenterology.  After reviewing the 
records from the report if it appears patients qualify we would contact the provider. The provider then 
contacts the patient to see if they are interested in the study and if it would be ok for the study staff to 
contact them. If they are, then the provider lets the study staff know and we contact the patient.  Patients 
will be contacted via phone, in person while in clinic or via mail using the recruitment letter. We will also 
post our study site contact information on the University of Utah, School of Medicine, Department of 
Internal Medicine, Division of Gastroenterology website, 
http://medicine.utah.edu/internalmedicine/gastroenterology/. Many patients and practitioners use this site 
to gather information on PI-IBS and other functional GI disorders, so a web posting may serve as 
additional advertising for our site. We also have a database of patients with IBS who have agreed to be 
participating/ to be contacted in case of any research study.   
 
Mass emails may also be used as recruitment methods. The mass emails will be sent to all the university 
staff and students as well as other organizations like Westminster College, Salt Lake Community College 
etc. The groups will be identified by cognizant Vice President or other authorized personnel. However we 
may decide on sending the mass email to one organization at a time. The university procedure for sending 
mass emails will be followed and approval for the text of the email will be obtained from the IRB prior to 
sending of the emails. Permission from the cognizant VP of the college or organization will be obtained 
before sending the mass e-mails and the form for sending the mass email will be filled with the 
Information Technology Services at the university. Similar procedure may be followed at other 
organizations. 
 
We will also use the Division of Infectious /International Travel Clinic at the University of Utah. The 
travel clinic evaluates a large number of returned missionaries and other travelers who have PI-IBS.   
 
 
 
 
 
 
 
Table: Study Procedures (Total number of patients N=66-68) 
 
Visit 1 
Visit 2 
Visit 3 
Mail/Telephone 
Visit 
Visit 4 
Trial Duration 
Screen 
8 week 
Procedure. 
Completed 
during 
screening 
period 
Treatment 
started 
4 wk. 
8wk 
(end of 
treatment 
Visit Type 
In-
In-person 
In-
Mail/ telephone 
In-person 


 
 
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person 
person/mail 
Informed consent 
X 
 
 
 
 
History & Physical 
examination 
X 
 
 
 
 
Inclusion/Exclusion check 
X 
 
 
 
 
Blood tests 
(CBC, CRP, CMP, TSH, 
TTG) 
X 
 
 
 
 
Blood sample (serum and 
buffy coat) for storage 
X 
 
 
 
X 
Stool Test (O&P, Giardia 
antigen/ C. difficile toxin, 
calprotectin) 
X 
 
 
 
 
Stool sample for storage 
X 
 
 
 
X 
Stool Diary 
X 
 
 
 
 
*Sigmoidoscopy/Colonoscopy 
Biopsy 
 
X 
 
 
 
BDQ and BSI-18 
Psychological Questionnaire 
X 
 
 
 
 
BSS questionnaire 
X 
 
 
X 
X 
IBS QOL Questionnaire 
X 
 
 
X 
X 
The Nepean Dyspepsia Index 
(NDI) 
X 
 
 
X 
X 
Study Medication Compliance 
 
 
X 
X 
X 
*Colonoscopy if needed 
Figure 1. Flow Chart. 
 
 
 
 
8 wk screening 
period 
Conducted in 
screening 
period 
window 
8 wk treatment  
1) Lialda 2.4gm qd.  
2) Placebo qd. 
Post 
treatment 
Inclusion/ exclusion 
check 
Blood/ stool tests 
Questionnaires:   
Screening IBS Questionnaire 
Bowel Symptom Scale (BSS) 
BSI-18, BDQ, NDI, 
IBS-QOL  
Sigmoid/colonoscopy 
Biopsy 
Questionnaire monthly 
BSS,  
IBS-QOL, NDI  
1. BSS 
2. IBS-QOL 
3. NDI 
 
 


 
 
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REFERENCES AND APPENDICES: 
1. Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003;124:1662-71. 
2. Barbara G, Cremon C, Pallotti F, De Giorgio R, Stanghellini V, Corinaldesi R.Postinfectious irritable 
bowel syndrome. J Pediatr Gastroenterol Nutr 2009; 48 Suppl 2:S95-7. 
3. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, 
anxiety, and depression in postinfectious IBS. Gastroenterology 2003; 125:1651-9. 
4. Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C, Di Nardo G, Trevisani M, Campi B, 
Geppetti P, Tonini M, Bunnett NW, Grundy D, Corinaldesi R. Mast cell dependent excitation of visceral-
nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007;132:26-37. 
5. Bantel H, Berg C, Vieth M, Stolte M, Kruis W, Schulze-Osthoff K. Mesalazine inhibits activation of 
transcription factor NF-kappaB in inflamed mucosa of patients with ulcerative colitis. Am J Gastroenterol 
2000;95:3452-7. 
6. Desreumaux P, Ghosh S. Review article: mode of action and delivery of 5-aminosalicylic acid - new 
evidence. Aliment Pharmacol Ther 2006;24 Suppl 1:2-9. 
7. Giardiello FM, Lazenby AJ, Bayless TM, Levine EJ, Bias WB, Ladenson PW, Hutcheon DF, 
Derevjanik NL, Yardley JH. Lymphocytic (microscopic) colitis. Clinicopathologic study of 18 patients 
and comparison to collagenous colitis. Dig Dis Sci 1989; 34:1730-8. 
8. Mullhaupt B, Guller U, Anabitarte M, Guller R, Fried M. Lymphocytic colitis: clinical presentation and 
long term course. Gut 1998; 43:629-33. 
9. Zins BJ, Sandborn WJ, Tremaine WJ. Collagenous and lymphocytic colitis: subject review and 
therapeutic alternatives. Am J Gastroenterol 1995; 90:1394-400. 
10. 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;30:245-52. 
11. Tuteja AK, Talley NJ, Gelman SS, Alder SC, Thompson C, Tolman K, Hale DC. Development of 
functional diarrhea, constipation, irritable bowel syndrome, and dyspepsia during and after traveling 
outside the USA. Dig Dis Sci 2008;53:271-6. 
12. Tuteja AK, Tolman KG, Talley NJ, Samore M, Stoddard GJ, Batt S, Verne GN.Prevalence of Bowel 
Disorders in Persian Gulf Veterans. Gastroenterology 2008; 124:A391. 
13. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel 
disorders. Gastroenterology 2006; 130:1480-91. 
14. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and hope for the 
future. J Manag Care Pharm 2004; 10:299-309. 
15. Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology 1990; 
99:409-15.  
16. Longstreth G, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller R. Functional Bowel 
Disorders In: Drossman DA, Corazziari E, Delvaux M, Talley NJ, Thompson WG, Whitehead WE, eds. 
Rome III: The Functional Gastrointestinal Disoders. First Edition ed. McLean, VA: Degnon Associates, 
2006:487-555. 
17. Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of 
postinfective irritable bowel syndrome. Am J Gastroenterol 2003; 98:1578-83. 
18. Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001; 358:2061-8. 
19. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal 
immune system in irritable bowel syndrome. Gastroenterology 2002; 122:1778-83. 
20. Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV. Interleukin 10 genotypes in 
irritable bowel syndrome: evidence for an inflammatory component? Gut 2003; 52:91-3. 
21. Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala 
SM. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable 
bowel syndrome. Gut 2003; 52:523-6. 


 
 
Page 14 of 14 
 
University of Utah IRB 
Document Version A2809 
 
22. Liebregts T, Adam B, Bredack C, Roth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, 
Talley NJ, Holtmann G. Immune activation in patients with irritable bowel syndrome. Gastroenterology 
2007; 132:913-20. 
23. Spiller RC. Role of infection in irritable bowel syndrome. J Gastroenterol 2007; 42 Suppl 17:41-7. 
24. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-
Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R. Activated mast cells in proximity to 
colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 
126:693-702. 
25. Gershon MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev 
Gastroenterol Disord 2003; 3 Suppl 2:S25-34.  
26. Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR. Release of 
mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology 1998; 114:640-8. 
27. Gue M, Del Rio-Lacheze C, Eutamene H, Theodorou V, Fioramonti J, Bueno L. Stressinduced 
visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells. Neurogastroenterol Motil 
1997; 9:271-9. 
28. Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology 2002; 
122:2078-80. 
29. Jacobson K, McHugh K, Collins SM. Experimental colitis alters myenteric nerve function at inflamed 
and noninflamed sites in the rat. Gastroenterology 1995; 109:718-22.  
30. Barbara G, De Giorgio R, Deng Y, Vallance B, Blennerhassett P, Collins SM. Role of immunologic 
factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice. 
Gastroenterology 2001; 120:1729-36. 
31. Barbara G, Vallance BA, Collins SM. Persistent intestinal neuromuscular dysfunction after acute 
nematode infection in mice. Gastroenterology 1997; 113:1224-32. 
32. Talley NJ, Phillips SF, Melton J, 3rd, Wiltgen C, Zinsmeister AR. A patient questionnaire to identify 
bowel disease. Ann Intern Med 1989; 111:671-4. 
33. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
gastroenterol 1997; 32:920-4. 
34. Tuteja AK, Tolman KG, Talley NJ, Samore M, Stoddard GJ, Batt S, Verne GN. Irritable Bowel 
Syndrome in Gulf War Veterans. Gastroenterology 2008; 124:A391. 
35. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M. Treatment of irritable bowel 
syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA 1998; 280:1585-9. 
36. Derogatis L. BSI: Administration, Scoring, and Procedure Manual for the Brief Symptom 
Inventory. Ed 3 ed. Minneapolis, MN: Lawrence Eribaum Association, Inc.', 1993.