Clinical trial NCT03462966
Conditions: Visceral Hypersensitivity Irritable Bowel Syndrome
Keywords: Rifaximin Xifaxan
Sponsor: Cedars-Sinai Medical Center
Start date: 2018-07-01; Completion date: 2021-11-19
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, with a global prevalence of 11% according to a recent meta-analysis. The total cost of managing IBS in the United States is in excess of $30 billion per year, including indirect costs relating to loss of productivity of more than $20 billion. Abdominal pain/discomfort (i.e. visceral hypersensitivity) is present in all patients with IBS and remains the most therapy-resistant symptom. Apart from abdominal pain, which is measured subjectively using visual scales, several studies have shown a significant increase in rectal sensitivity, which is measured objectively using an inflatable balloon. Drugs which are shown to have objective effects on visceral hypersensitivity are crucial in the management of IBS.

While certain drugs have shown to decrease abdominal pain, there is very little data to substantiate objective changes in visceral hypersensitivity. Rifaximin is a poorly absorbed antibiotic and the exact underlying mechanism of action for rifaximin in reducing the pain component of IBS remains unknown. However, rifaximin has been shown in randomized controlled trials to decrease abdominal discomfort in all subtypes of IBS.

The investigators hypothesize that rifaximin is effective in decreasing rectal visceral hypersensitivity in IBS patients. In this study, the investigators propose to test this hypothesis by measuring visceral hypersensitivity using the graded balloon distention test, before and after a course of rifaximin. To test whether this effect is accompanied by treating SIBO, the investigators will also perform lactulose breath tests before and after rifaximin therapy.

Detailed description:

Arms: arm 1: 40 subjects with diarrhea-predominant IBS (IBS-D) or mixed IBS (IBS-M) will be enrolled in the study. At the first clinic visit, subjects will undergo rectal sensitivity testing, as well as lactulose breath testing. Subjects will be asked to record their symptoms and bowel habits in a diary over the next 7 days. During the second clinic visit, subjects will receive a 14-day course of rifaximin (550 mg PO TID). During these 14 days, subjects will record their symptoms and bowel habits. Subjects will return to the clinic after completion of the medication and will undergo repeat evaluation via rectal sensitivity testing to assess for change in rectal sensitivity.
Interventions: intervention 1: Rifaximin
Intervention descriptions: intervention 1: Rifaximin will be administered to patients diagnosed with IBS-D or IBS-M to evaluate whether the medication is effective in decreasing rectal hypersensitivity. The secondary objective of the study is to assess the role of SIBO in rectal sensitivity.

Protocol documents:
Prot_SAP_001.pdf: 
1 
 
 
Rifaximin on Visceral Hypersensitivity 
 
Identifiers: 
NCT03462966 
 
Document date : 2/11/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
 
 
Investigator-Initiated Study Proposal 
 
Rifaximin on Visceral Hypersensitivity 
Protocol ID: 49509 
 
To: Salix Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
CEDARS-SINAI 
700 N San Vicente, Suite G271, West Hollywood CA 90069 
Office 310.423.0617 : Fax 310.423.0962 cedars-sinai.org 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
TABLE OF CONTENTS 
1.0 
Introduction ..................................................................................................................... 5 
1.1 
Background and Scientific Rationale ........................................................................ 5 
1.2 
Current Standard Therapy ........................................................................................ 5 
1.3 
Rationale for the Study ............................................................................................. 6 
2.0 
Objective ......................................................................................................................... 7 
3.0 
STUDY DESIGN ............................................................................................................. 8 
3.1 
Program Type/Scope of Trial/Clinical Design ............................................................ 8 
3.2 
Study Population/Demographics/Disorder ................................................................ 8 
3.3 
Number of Subjects (Statistical Justification) ............................................................ 8 
4.0 
Eligibility Criteria .............................................................................................................10 
4.1 
Inclusion Criteria ......................................................................................................10 
4.2 
Exclusion Criteria .....................................................................................................10 
5.0 
Investigational Product ...................................................................................................12 
5.1 
Formulation and Supply ...........................................................................................12 
5.2 
Packaging ................................................................................................................12 
5.3 
Labeling ...................................................................................................................12 
5.4 
Storage and Handling ..............................................................................................13 
5.5 
Rationale for Xifaxan dose selection ........................................................................13 
6.0 
Study Procedures and Regimens ...................................................................................14 
6.1 
Subject identification and recruitment ......................................................................14 
6.2 
Therapy phase .........................................................................................................14 
6.3 
Study Flowchart .......................................................................................................16 
6.4 
Study Duration .........................................................................................................16 
6.5 
Medications Not Permitted .......................................................................................16 
7.0 
Outcome Measures ........................................................................................................17 
7.1 
Primary Outcome Measure ......................................................................................17 
7.2 
Secondary Outcome Measures ................................................................................17 
8.0 
Side Effects ....................................................................................................................18 
8.1 
Clinical criteria for withdrawing an individual subject from the study ........................19 
8.2 
Criteria for stopping or changing the study protocol .................................................20 
8.3 
Follow-up of AEs and SAEs .....................................................................................20 
8.4 
Prompt Reporting of SAEs to Salix Pharmaceuticals. ..............................................20 
8.5 
Pregnancy Reporting ...............................................................................................21 


4 
 
9.0 
Audits .............................................................................................................................22 
10.0 
References .....................................................................................................................23 
11.0 
Support Requested (Study Budget) ................................................................................25 
 
 
LIST OF APPENDICES 
Appendix 1:  Baseline Questionnaire ................................................................................. 32 
Appendix 2:  Lactulose Breath Test ................................................................................... 36 
Appendix 3:  Stool Diary .................................................................................................... 37 
Appendix 4:  Bristol Stool Chart ......................................................................................... 39 
Appendix 5:  Rectal sensitivity testing and scale ................................................................ 40 
Appendix 6:  Weekly Questionnaire ................................................................................... 41 
 
 
 
 
 
 


5 
 
1.0 
INTRODUCTION 
1.1 
Background and Scientific Rationale 
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, 
with a global prevalence of 11% according to a recent meta-analysis 1. Patients with IBS visit 
the doctor more frequently, consume more medications, and use more diagnostic tests, such 
that the total costs of managing IBS in the United States in excess of $30 billion per year, 
including indirect costs relating to loss of productivity of more than $20 billion 2. IBS manifests 
itself in 3 major forms; diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), and 
mixed (IBS-M) 3, and is predominantly characterized by symptoms of abdominal pain, changes 
in stool frequency and consistency, and abdominal bloating 4.The diagnosis of IBS involves the 
identification of these key clinical symptoms 5, 6. Abdominal pain/discomfort (i.e. visceral 
hypersensitivity) is present in all patients and remains the most therapy-resistant symptom in 
IBS. Apart from abdominal pain, which is measured subjectively using visual scales, several 
studies have shown a significant increase in rectal sensitivity, which is measured objectively 
using an inflatable balloon. Hence, drugs which are shown to have objective effects on visceral 
hypersensitivity are crucial in the management of IBS. 
 
Over the last decade, our group has demonstrated that small intestinal bacterial 
overgrowth (SIBO) may play a significant role in IBS 7-11. SIBO is a condition in which there is an 
increase in the number of bacteria in the small bowel 12-14, and typically includes an overgrowth 
of coliform bacteria which are normally found in the colon 15. These are predominantly gram-
negative aerobes and anaerobic species that produce gas during fermentation of carbohydrates 
15, 16, and the SIBO hypothesis proposes that it is this expansion of bacteria in the small bowel 
that leads to IBS symptoms including bloating, abdominal discomfort and changes in stool form 
17. Two separate studies using cultures of small bowel aspirates have now confirmed that IBS 
subjects have higher coliform counts in the small bowel than non-IBS subjects 15, 18. 
Significantly, 60% of IBS-D subjects were found to meet the definition of SIBO 18.  
 
1.2 
Current Standard Therapy 
Currently, three drugs for IBS-D (rifaximin, alosetron and eluxadoline) and two 
(linaclotide and lubiprostone) for IBS-C are approved by FDA 19.  While these drugs have shown 
to decrease abdominal pain based on subjective scales in their respective clinical trials, there is 
very little data to substantiate objective changes in visceral hypersensitivity. While rifaximin is an 


6 
 
antibiotic, the exact underlying mechanism of action for rifaximin in reducing the pain 
component of IBS remains unknown. However, rifaximin is the only medication that has been 
shown in randomized controlled trials to decrease abdominal discomfort in all subtypes of IBS. 
This suggests that rifaximin, unlike other approved medications, addresses the underlying 
pathophysiology of IBS rather than simply targeting symptom relief. 
Given the role of altered bacterial populations in IBS, a number of randomized controlled 
trials have been conducted examining the utility of antibiotics in treating IBS 20-23.  All of these 
controlled trials have demonstrated significant success with antibiotic therapy. The two principal 
antibiotics studied to date are neomycin 8 and rifaximin (Xifaxan)  21, 24, 25.  While neomycin was 
a successful therapy for IBS, it was disappointing in its ability to normalize the lactulose breath 
test (LBT) 8. In contrast rifaximin, a non-absorbed antibiotic (99.6% retained in the GI tract), has 
been shown to normalize the LBT in 70% of subjects 26. The most recent phase III randomized 
controlled trial of rifaximin demonstrated three important findings 23:  
 
First, rifaximin was effective in improving the primary endpoint (adequate relief of global 
IBS symptoms and newer FDA endpoints for IBS) compared to placebo. Second, rifaximin 
treatment resulted in significantly greater improvement in all major IBS symptoms (abdominal 
pain, bloating, and stool consistency). Third, the drug had a durable effect for over 3 months 
after the cessation of therapy23.  
 
 
1.3 
Rationale for the Study 
Currently in clinical practice and research, visceral sensitivity can be objectively, safely, 
easily and reliably measured using an inflatable rectal balloon attached to a barometer. We 
hypothesize that rifaximin is effective in decreasing rectal visceral hypersensitivity in IBS 
patients. In this study, we propose to test this hypothesis. Moreover, we will explore whether this 
effect is mediated by SIBO and accompanied by improvement in breath test results.


7 
 
2.0 
OBJECTIVE  
 
The primary objective of this study is to assess the effect of rifaximin in decreasing rectal 
hypersensitivity in patients with IBS-M and IBS-D. The secondary objective of this study is to 
assess the role of SIBO in rectal sensitivity.  
 
 
 
 


8 
 
3.0 
STUDY DESIGN 
3.1 
Program Type/Scope of Trial/Clinical Design 
The proposed study is a prospective clinical trial to determine whether Xifaxan can 
decrease rectal visceral hypersensitivity in diarrhea-predominant and mixed type IBS patients. 
IBS-D and IBS-M patients will undergo baseline rectal sensitivity testing. Patients will 
then receive rifaximin 550 mg by mouth three times daily for 14 days. On day 15, patients will 
undergo repeat rectal sensitivity testing.  
 
3.2 
Study Population/Demographics/Disorder  
Adult patients (age 18-75) with IBS-D or IBS-M (diagnosed based on Rome IV criteria 27) 
will be assessed for eligibility to participate in this study. Potential subjects will be identified and 
recruited through the GI Motility Clinic at Cedars-Sinai Medical Center. 
 
3.3 
Number of Subjects (Statistical Justification) 
We are planning a study of a continuous response variable before and after therapy. In 
our previous study of 122 patients, we showed that the rectal balloon volume to cause the 
sensation of urge to defecate had a mean of 87 cc and standard deviation of 42 cc 28. We 
consider a 20 cc increase in threshold of urge to defecate to be clinically significant. The effect 
size associated with this assumption is 0.50. We need to study 34 subjects be able to reject the 
null hypothesis that the rectal sensitivity after rifaximin is equal with probability (power) of 0.8. 
The Type I error probability associated with this test of this null hypothesis is 0.05. As this is a 4 
month follow up study, we expect a 15% dropout rate based on our previous clinical experience. 
Therefore, we will need to consent 40 subjects to achieve our statistical goals. Statistical 
analysis will be performed using STATA ver 14.0. Paired t test will be used to assess the 
primary outcome of interest and selected secondary outcomes. Logistic regression will be used 
to assess the determinants of responders (improvement of 20 cc in rectal volume to cause 
urge).  


9 
 
 
 
 
 


10 
 
4.0 
ELIGIBILITY CRITERIA 
4.1 
Inclusion Criteria 
- 
Male or female subjects aged 18-75 years old inclusive 
- 
Meet Rome IV criteria for IBS-D or IBS-M 
- 
Subjects should report urgency with bowel movement at least once a week 
- 
If subjects are ≥50 years old, a colonoscopy must have been completed within the 
past 5 years 
- 
Subjects are capable of understanding the requirements of the study, are willing to 
comply with all the study procedures, and are willing to attend all study visits. 
- 
Agree to use an acceptable method of contraception throughout their participation in 
the study. Acceptable methods of contraception include: 
- 
double barrier methods (condom with spermicidal jelly or a diaphragm with 
spermicide), 
- 
hormonal methods (e. g. oral contraceptives, patches or medroxyprogesterone 
acetate), or 
- 
an intrauterine device (IUD) with a documented failure rate of less than 1% per 
year. 
- 
Abstinence or partner(s) with a vasectomy may be considered an acceptable 
method of contraception at the discretion of the investigator. 
- 
All subjects will provide Institutional Review Board (IRB)-approved informed 
written consent prior to beginning any study-related activities 
 
NOTE: Female subjects who have been surgically sterilized (e.g. hysterectomy or bilateral 
tubal ligation) or who are postmenopausal (total cessation of menses for >1 year) will not 
be considered “females of childbearing potential”. 
 
4.2 
Exclusion Criteria 
-  Treatment with antibiotics or Xifaxan in the last two months 
-     Subjects with history of intestinal surgery (except appendectomy or 
cholecystectomy) 
-  Subjects with known pelvic floor dysfunction 
-  Pregnancy 


11 
 
- 
Nursing mothers 
-  Poorly controlled/uncontrolled significant medical condition that would interfere with 
study procedures 
-  History of bowel obstruction 
-  History of celiac disease 
-  History of inflammatory bowel disease 
-  Cirrhosis 
-     IBS-C/chronic idiopathic constipation 
-  Poorly controlled diabetes (hemoglobin A1c >8.0% for ≥1 year) 29 
- 
History of anorectal radiation/surgery 
-     History of prostatitis 
- 
Known allergy or hypersensitivity to rifaximin or rifamycin 
-     Current treatment with eluxadoline or opiates 
 
 
NOTE: Development of any of the exclusion criteria during the study will be considered a 
basis for subject discontinuation. 
 
 
 


12 
 
5.0 
INVESTIGATIONAL PRODUCT 
5.1 
Formulation and Supply 
 
Xifaxan will be supplied by Salix pharmaceuticals. Xifaxan is approved by FDA to be 
used in patients with IBS-D, hepatic encephalopathy and E. coli-associated traveler’s diarrhea. 
5.2 
Packaging 
On day 0 (see section 6.0 – Study Procedures and Regimens), subjects will be provided 
medication packs sufficient for 14 days.  
For all study investigational product, a system of investigational product numbering in 
accordance with all requirements of current Good Manufacturing Practice (GMP) will be used. 
This will ensure that for each subject, any measured quantity of study investigational product 
can be identified and traced back to the original pack of medication. 
Lists linking all numbering levels will be maintained by the institutions in charge of 
investigational product packaging including the Sponsor. 
 
5.3 
Labeling 
Each pack will bear a label which includes, but is not limited to, the following information: 
- 
Product: Xifaxan  
- 
Kit Number 
- 
Quantity 
- 
Instructions for taking product 
- 
Storage conditions:  Store packets/kit at 20-25oC (68-77oF): excursions permitted 
between 15-30oC (59-86oF) 
- 
Manufacturer 
In addition, each kit label will contain an area for the site to write the following 
information: 
- 
Subject initials 
- 
Subject ID Number 
- 
Date Dispensed 


13 
 
- 
Date Returned 
 
5.4 
Storage and Handling 
All investigational product will be kept in a locked area with limited access to study staff 
only.  The locked area will be maintained under controlled temperature conditions at 20-25°C 
(68-77°F); excursions are permitted to 15-30°C (59-86°F). 
 
5.5 
Rationale for Xifaxan dose selection 
Currently, Xifaxan is approved for treatment of IBS-D. The dosing is 550 mg PO TID for 
14 days. In addition, two 14-day retreatment courses of Xifaxan is allowed by FDA if the patient 
does not respond to initial therapy. We have designed our study so that subjects will receive 
one standard 14-day course of Xifaxan during the study. This is less than the three courses of 
Xifaxan allowable for IBS-D patients per the FDA. 
 
 
 
 


14 
 
6.0 
STUDY PROCEDURES AND REGIMENS  
6.1 
Subject identification and recruitment  
Potential subjects with IBS-D and IBS-M will be identified through the GI Motility Clinic at 
Cedars-Sinai Medical Center and assessed for eligibility to participate in this study.  
 
6.2 
Therapy phase 
If patients meet the inclusion criteria and provide informed written consent, they will:   
 
Visit 1: Day -7 
-   Undergo a urine pregnancy test (if a woman of childbearing 
potential) 
-   Complete a baseline symptom questionnaire (see Appendix 1). 
This can either be filled online using REDCap, a secure, web-
based application for building and managing online surveys and 
databases with which Cedars-Sinai is partnered, or completed in 
paper format  
- 
Present fasting for a full lactulose breath test (see Appendix 2) 
-     Up to 60 cc of exhaled breath gas at baseline and 120 minutes of 
testing will be stored for additional testing by mass spectroscopy 
(Exetainer® 12ml flat-bottom vacuumed vials, LabCo, UK).  
- 
Subjects will be given a stool diary (see Appendix 3) and asked to 
complete this at home over the next 7 days, using the Bristol Stool 
Chart (see Appendix 4) as a visual aid 
-     Patient will undergo a rectal sensitivity assessment (Appendix 5) 
 
Day -7 to Day 0 
-  Complete a 7-day baseline stool and symptom diary (see 
Appendix 3) using the Bristol Stool Chart (see Appendix 4) 
 
Visit 2: Day 0 
-  A 14-day supply of Xifaxan will be provided to the patient 
Each subject will be instructed by the investigator or his 
representative on the proper self-administration, handling and storage 
of the product. Each subject will be instructed to take Xifaxan 550 mg 
PO TID for 14 days. For the purpose of accountability, all unused 


15 
 
packets from each kit dispensed to the subject should be returned to 
the site at each visit.  In order to maintain compliance with federal 
regulations, records of the disposition of drug will include:  dates 
dispensed, quantity, use by the subject and dates of returns. 
 
Day 0 to Day 14 
- 
Subjects will complete weekly symptom questionnaires (see 
Appendix 6) at home, beginning on Days 0 and 7. Again, these 
can either be filled online using REDCap, or completed in paper 
format 
-  Subjects will complete a Daily Stool Diary (see Appendix 3)   
    Visit 2: Day 15            -  
Subject will undergo a rectal sensitivity assessment (Appendix 5) 
                                         -     Subject will undergo an LBT 
-     Up to 60 cc of exhaled breath gas at baseline and 120 minutes of 
testing will be stored for additional testing by mass spectroscopy 
(Exetainer® 12ml flat bottom vials, LabCo, UK). 
 
 


16 
 
 
6.3 
Study Flowchart 
 
 
 
 
 
 
6.4 
Study Duration  
 The study duration will be approximately 1 year. Each subject will be involved in the 
study for 3 weeks (see Study Flowchart). 
 
6.5 
Medications Not Permitted 
The following medications may not be taken while on this study: 
- 
Opiates or new pain modulating medications 
- 
Eluxadoline 
40 subjects with IBS-D and IBS-
M will undergo rectal sensitivity 
testing along with LBT
Symptom diary recording over 7 
days
14-day therapy with Xifaxan 
along with symptom diary 
collection
Rectal sensitivity testing on day 
15 along with LBT


17 
 
7.0 
OUTCOME MEASURES 
7.1 
Primary Outcome Measure 
The primary outcome of the study is the mean change in the balloon volume that leads 
to first urge to defecate. A 100-mm visual analogue scale with verbal descriptors (0=no 
sensation, 20=first sensation, 40=first sense of urge, 60=normal urge to defecate, 
80=severe urge to defecate, and 100=discomfort/pain) will be used to score evoked 
sensations 30.  
 
7.2 
Secondary Outcome Measures 
 Secondary outcome measures will include:  
- 
mean change in the balloon pressure and volume that leads to first urge to defecate 
- 
mean change in the balloon pressure and volume that leads to severe urge to 
defecate 
- 
mean change in the balloon pressure and volume that leads to severe urge to 
defecate 
- 
mean change in the balloon pressure and volume that leads to severe urge to 
defecate 
- 
mean change in the balloon pressure and volume that leads to first sensation 
- 
mean change in the balloon pressure and volume that leads to first sensation  
- 
mean change in the balloon pressure and volume that leads to first sensation 
- 
Association of urgency symptom and rectal sensitivity testing 
- 
Normalization of LBT as a predictor of improvement of rectal hypersensitivity 
 
 
 
 


18 
 
8.0 
SIDE EFFECTS 
 
All side effects will be captured, evaluated and categorized as follows: 
-    An Adverse Event (AE) will be a side effect that is an event reported by the subject 
that is deemed related to Xifaxan but may or may not prevent continuation of the trial 
(examples include body aches, loose stool) 
-  A Serious Adverse Event (SAE) will be an event report by a subject during the trial 
may or may not be deemed related to Xifaxan that forces discontinuation of the trial 
(examples include anaphylaxis, etc.).  
 
All side effects will be reported to a data safety monitor who is independent of the study.  
The assessment of the relationship of an AE to the administration of the study medical 
food supplement is a clinical decision based on all available information at the time of the 
completion of the source documentation of the AE or of the SAE form, if applicable. 
An assessment of “Not” or “Unlikely” would include (Note: “Unlikely” is considered not 
related to the study medical food supplement): 
- 
The existence of a clear alternative explanation, e.g., mechanical bleeding at 
surgical site; or 
- 
Non-plausibility, e.g., the subject is struck by an automobile when there is no 
indication that the study medical food supplement caused disorientation that may 
have caused the event; cancer developing a few days after the first therapy 
administration.  
An assessment of “Possible” or “Related” indicates that there is a reasonable suspicion 
that the AE is associated with the use of the study medical food supplement. 
Factors to be considered in assessing the relationship of the AE to the study medical food 
supplement include: 
- 
The temporal sequence from administration of the study medical food supplement: 
The event should occur after the therapy is given. The length of time from therapy 
exposure to event should be evaluated in the clinical context of the event. 
- 
Recovery of discontinuation (de-challenge), recurrence on re-introduction (re-
challenge): Subject’s response after discontinuation of the study medical food 
supplement (de-challenge), or response after re-introduction of the study medical 


19 
 
food supplement (re-challenge) should be considered in the view of the usual 
clinical course of the event in question. 
- 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have. 
- 
Concomitant medication or treatment: The other therapies the subject is taking or 
the treatment the subject receives should be examined to determine whether any 
of them may be suspected to cause the event in question. 
- 
Concurrent study procedures: Study procedures should also be considered as 
possible causes of an AE. Invasive procedures such as biopsies have their own 
profile of expected AEs and the Investigator should consider these. 
The Investigator will make a separate and independent assessment of every AE’s 
relationship not just to the study the study medical food supplement, but also to the subject’s 
pre-existing medical condition(s). 
The severity of AEs should be graded as follows: 
- 
Mild – usually transient in nature and generally not interfering with normal activities 
- 
Moderate – sufficiently discomforting to interfere with normal activities 
- 
Severe – prevents normal activities 
 
8.1 
Clinical criteria for withdrawing an individual subject from the study  
 
Clinical criteria for withdrawing an individual subject from the study are as follows: 
- 
Subject chooses to withdraw 
- 
The occurrence of an adverse event, which, in the judgment of the Investigator 
or independent monitor, suggests an unacceptable risk to the subject 
- 
Pregnancy 
- 
Investigator discretion 
- 
Subject noncompliance 
 


20 
 
8.2 
Criteria for stopping or changing the study protocol 
Criteria for stopping or changing the study protocol due to safety concerns are as 
follows: 
- 
Should the investigator, independent monitor, the FDA, or local regulatory 
authorities become aware of conditions arising during the conduct of this study 
that may warrant the cessation of the study, such action may be taken. Prior to 
such action, consultation between the investigator, and, as appropriate, the 
FDA and/or local regulatory authorities will take place  
- 
If there are >2 subjects with serious adverse events, the independent study 
monitor will examine and audit the cases and determine the relevance to the 
assigned study medical food supplement and whether the trial should continue 
or if there are grounds for discontinuing the study 
 
8.3 
Follow-up of AEs and SAEs  
 
All AEs and SAEs must be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or the subject is lost to follow-up.  The investigator is responsible 
to ensure that follow-up includes any supplemental investigations as may be indicated to 
elucidate as completely as practical the nature and/or causality of the AE or SAE.  This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
8.4 
Prompt Reporting of SAEs to Salix Pharmaceuticals.  
 
Serious adverse events must be reported promptly to Salix pharmaceuticals. once the 
investigator determines that the event meets the protocol definition of an SAE. 
 
 
Prompt reporting of a SAE requires: 
- 
Completion and transmission of SAE information to Salix pharmaceuticals. within 24 
hours of the investigator’s knowledge of the event. The SAE It is very important that 
the investigator provide his/her assessment of causality to investigational product at 
the time of initial reporting of the SAE. SAE information should include at a minimum:  
- 
AE description (diagnosis) 
- 
Onset Date 


21 
 
- 
Resolution date 
- 
Duration 
- 
Seriousness (Fatal, Life Threatening, Hospitalization require or 
prolonged, Congenital anomaly, Disabling/Incapacitating, Other – 
describe) 
- 
Contributing factors (underlying disease being studied, concurrent illness 
– specify if yes, concurrent therapy – specify if yes, other - describe) 
- 
List relevant medical conditions (past or current), include onset and 
resolution dates if known 
- 
List any medications taken to treat this SAE 
- 
Provide any relevant diagnostic procedures and laboratory results 
- 
Add a narrative/comments providing a textual description of the SAE 
including chronological presentation and evaluation of the SAE, 
associated signs and symptoms, treatment of the SAE and outcome of 
the SAE. 
 
Prompt reporting of additional information for previously reported SAEs should follow the same 
reporting timeframe as initial reports. 
 
8.5 
Pregnancy Reporting 
 
Pregnancies detected during study conduct should be promptly reported to Salix 
pharmaceuticals as soon as the investigator is notified. should be notified via fax of any updates 
on the status of the pregnancy as soon as the information becomes available by update and/or 
amendment of the initial pregnancy reporting form. Pregnancies will be followed to term and 
information will be collected on the pregnancy outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, abnormalities, 
or complications.   
 
 


22 
 
9.0 
AUDITS 
 
At its discretion, Salix pharmaceuticals may conduct a quality assurance audit of this 
study.  If such an audit occurs, the investigator agrees to allow the auditor direct access to all 
relevant documents and to schedule his/her time and the time of his/her staff to permit meetings 
with the auditor to discuss findings and any relevant issues. 
 
In addition, regulatory agencies may conduct a regulatory inspection of this study.  If 
such an inspection occurs, the investigator agrees to allow the inspector direct access to all 
relevant documents and to schedule his/her time and the time of his/her staff to permit meetings 
with the auditor to discuss findings and any relevant issues. 
 
 


23 
 
10.0 
REFERENCES 
1. 
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Cash B, Sullivan S, Barghout V. Total costs of IBS: employer and managed care 
perspective. Am J Manag Care 2005;11:S7-16. 
3. 
Low K, Hwang L, Hua J, et al. A combination of rifaximin and neomycin is most effective 
in treating irritable bowel syndrome patients with methane on lactulose breath test. J Clin 
Gastroenterol 2010;44:547-50. 
4. 
Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. 
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5. 
Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement 
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6. 
Dalrymple J, Bullock I. Diagnosis and management of irritable bowel syndrome in adults 
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7. 
Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth 
reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-6. 
8. 
Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with 
symptom improvement in irritable bowel syndrome. a double-blind, randomized, 
placebo-controlled study. Am J Gastroenterol 2003;98:412-9. 
9. 
Lupascu A, Gabrielli M, Lauritano EC, et al. Hydrogen glucose breath test to detect small 
intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel 
syndrome. Aliment Pharmacol Ther 2005;22:1157-60. 
10. 
Cuoco L, Salvagnini M. Small intestine bacterial overgrowth in irritable bowel syndrome: 
a retrospective study with rifaximin. Minerva Gastroenterol Dietol 2006;52:89-95. 
11. 
Majewski M, McCallum RW. Results of small intestinal bacterial overgrowth testing in 
irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med 
Sci 2007;52:139-42. 
12. 
Toskes PP. Bacterial overgrowth of the gastrointestinal tract. Adv Intern Med 
1993;38:387-407. 
13. 
Bouhnik Y, Alain S, Attar A, et al. Bacterial populations contaminating the upper gut in 
patients with small intestinal bacterial overgrowth syndrome. Am J Gastroenterol 
1999;94:1327-31. 
14. 
Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. 
World J Gastroenterol 2010;16:2978-90. 
15. 
Posserud I, Stotzer PO, Bjornsson ES, et al. Small intestinal bacterial overgrowth in 
patients with irritable bowel syndrome. Gut 2007;56:802-8. 
16. 
Sachdev AH, Pimentel M. Antibiotics for irritable bowel syndrome: rationale and current 
evidence. Curr Gastroenterol Rep 2012;14:439-45. 
17. 
Pimentel M, Lezcano S. Irritable Bowel Syndrome: Bacterial Overgrowth--What's Known 
and What to Do. Curr Treat Options Gastroenterol 2007;10:328-37. 
18. 
Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, et al. The Prevalence of Overgrowth by 
Aerobic Bacteria in the Small Intestine by Small Bowel Culture: Relationship with Irritable 
Bowel Syndrome. Dig Dis Sci 2012. 
19. 
Nee J, Zakari M, Lembo AJ. Current and emerging drug options in the treatment of 
diarrhea predominant irritable bowel syndrome. Expert Opin Pharmacother 
2015;16:2781-92. 
20. 
Pimentel M, Chatterjee S, Chow EJ, et al. Neomycin improves constipation-predominant 
irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: 
subanalysis of a double-blind randomized controlled study. Dig Dis Sci 2006;51:1297-
301. 


24 
 
21. 
Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled 
trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol 
2006;101:326-33. 
22. 
Pimentel M PS, Kane, SV, Kong Y. Rifaximin, a non-absorbable antibiotic improves the 
symptoms of irritable bowel syndrome: A randomized, double-blind, placebo-controlled 
study. Ann Intern Med 2006;145:557-563. 
23. 
Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel 
syndrome without constipation. N Engl J Med 2011;364:22-32. 
24. 
Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed oral antibiotic 
(rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann 
Intern Med 2006;145:557-63. 
25. 
Cremonini F, Lembo A. Rifaximin for the treatment of irritable bowel syndrome. Expert 
Opin Pharmacother 2012;13:433-40. 
26. 
Di Stefano M, Malservisi S, Veneto G, et al. Rifaximin versus chlortetracycline in the 
short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 
2000;14:551-6. 
27. 
Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393–
1407. 
28. 
Rezaie A, Chua KS, Chang C, et al. Mo2026 Methane on Breath Test Predicts Altered 
Rectal Sensation During High Resolution Anorectal Manometry. Gastroenterology 
2017;146:S-721. 
29. 
Crowley MJ, Holleman R, Klamerus ML, et al. Factors associated with persistent poorly-
controlled diabetes mellitus (PPDM): clues to improving management in patients with 
resistant poor control. Chronic illness 2014;10:291-302. 
30. 
van Wanrooij SJ, Wouters MM, Van Oudenhove L, et al. Sensitivity testing in irritable 
bowel syndrome with rectal capsaicin stimulations: role of TRPV1 upregulation and 
sensitization in visceral hypersensitivity? Am J Gastroenterol 2014;109:99-109. 
 
 
 


25 
 
11.0 
SUPPORT REQUESTED (STUDY BUDGET) 
Labor 
Cost 
SubTotals 
1. Principal Investigator with fringe (1% effort) 
 $           3,248  
  
2. Co-Investigator with fringe (3% effort) 
 $           9,901 
  
3. Study Coordinator with fringe (19.5% effort) 
 $         14,120 
 $       27,269 
Other Direct Costs 
  
  
1. Lactulose breath tests  
 $        11,855 
   
2. Rectal sensitivity tests 
 $        22,902 
 
3. Pharmacy dispensing fees 
 $          1,200   
  
4. IRB fees (overhead not applicable) 
 $          3,000   
 
5. Pharmacy startup fee 
 $          1,500 
 
6. Pharmacy closeout fee 
 $             500 
 
7. Patient compensation ($80 per visit x 80 visits) 
 $          6,400 
 
8. Pregnancy tests (for exclusion criteria)* 
 $             173  
 $      47,530 
  
  
  
Direct Cost Total 
  
 $      74,799  
Overhead (30%, no overhead on IRB fees) 
  
 $      21,540 
Total Initial Budget 
  
 $      96,339   
Additional Annual Invoiceable Costs** 
 
 
1. IRB Continuing Expedited Review Fee (overhead not 
applicable) † or 
 $             750 
 $         750 
2. IRB Continuing Full Committee Review Fee (overhead 
not applicable) † 
$            1,500 
$       1,500 
3. Pharmacy Annual Renewal Fee (inclusive of 30% 
overhead) 
$               975 
$           975 
 
 
 
Total Study Costs (including one (1) Pharmacy 
Renewal at $975 including overhead and One IRB 
Continuing renewal at the maximum $1,500 fee). 
 
 $     98,814   
 
*   Assuming 50% of subjects are females of childbearing age 
** Paid only if study extends into second year 
† Either the $750 Continuing Review fee or the $1500 Continuing Review fee may be charged 
at annual renewal depending on the type of review the IRB does, but both fees won’t be 
charged for the same review. 
 
Labor 
Cost 
Sub-Totals 


26 
 
1. Principal Investigator with fringe (1% effort) 
 $           3,248  
  
2. Co-Investigator with fringe (3% effort) 
 $           9,901 
  
3. Study Coordinator with fringe (19.5% effort) 
 $         14,120 
 $       27,269 
Other Direct Costs 
  
  
1. Lactulose breath tests  
 $        11,855 
   
2. Rectal sensitivity tests 
 $        22,902 
 
3. Pharmacy dispensing fees 
 $          1,200   
  
4. IRB fees (overhead not applicable) 
 $          3,000   
 
5. Pharmacy startup fee 
 $          1,500 
 
6. Pharmacy closeout fee 
 $             500 
 
7. Patient compensation ($80 per visit x 80 visits) 
 $          6,400 
 
8. Pregnancy tests (for exclusion criteria)* 
 $             173  
 $      47,530 
  
  
  
Direct Cost Total 
  
 $      74,799  
Overhead (30%, no overhead on IRB fees) 
  
 $      21,540 
Total Initial Budget 
  
 $      96,339   
Additional Annual Invoiceable Costs** 
 
 
4. IRB Continuing Expedited Review Fee (overhead not 
applicable) † or 
 $             750 
 $         750 
5. IRB Continuing Full Committee Review Fee (overhead 
not applicable) † 
$            1,500 
$       1,500 
6. Pharmacy Annual Renewal Fee (inclusive of 30% 
overhead) 
$               975 
$           975 
 
 
 
Total Study Costs (including one (1) Pharmacy 
Renewal at $975 including overhead and One IRB 
Continuing renewal at the maximum $1,500 fee). 
 
 $     98,814   
 
*   Assuming 50% of subjects are females of childbearing age 
** Paid only if study extends into second year 
† Either the $750 Continuing Review fee or the $1500 Continuing Review fee may be charged 
at annual renewal depending on the type of review the IRB does, but both fees won’t be 
charged for the same review. 
 
 


27 
 
Appendix 1:  Baseline Questionnaire  
 
Patient Code:   
 
 
 
SECTION 1: DEMOGRAPHICS 
 
1. Date: 
 
 
 
2. Age: _____ 
 
3. Sex: _____ 
 
4. Height: _____  
5. Weight (lbs): _____ 
 
 
 
SECTION 2: PAST MEDICAL AND SURGICAL HISTORY 
 
 
 
1. In the following chart answer yes or no to the surgeries listed and list any other 
previous surgical procedures you have had: 
 
PLEASE PRINT CLEARLY 
 
Type of Surgery 
Circle  
YES or NO
Problem 
(symptoms)
Date of 
Surgery
1. Appendix removal 
    YES      NO 
 
 
2. Tonsils removal 
    YES      NO 
 
 
3. Gastric Bypass 
    YES      NO 
 
 
4. 
 
 
 
5. 
 
 
 
6. 
 
 
 
7. 
 
 
 
8. 
 
 
 
9. 
 
 
 
10. 
 
 
 
(If more than 10 surgical procedures…continue on reverse of this page) 
 
 
 
 


28 
 
2.  Please indicate if you have ever been told you have any of the following diagnoses: 
 
Diagnosis 
Indicate “X” if you have 
been told you had the 
diagnosis
If yes, when was it 
diagnosed? 
1. Irritable bowel
2. Crohn’s Disease
 
 
3. Ulcerative Colitis
 
 
4. Fibromyalgia
5. Gastroesophageal 
    reflux disease
 
 
6. Diabetes (Type I) 
 
 
7. Diabetes (Type II) 
 
 
 
FOR WOMEN ONLY: 
 
Do you have a history of difficultly getting pregnant? 
YES 
NO 
Do you have irregular periods? 
YES 
NO 
Have you ever been diagnosed with polycystic ovary syndrome (PCOS)? 
YES 
NO 
 
SECTION 3: MEDICATIONS 
1. List the medications that you are on currently: 
PLEASE PRINT CLEARLY 
 
Medication 
Dose 
For what problem 
Approximate start 
date
1.
2.
3.
 
 
 
4.
5.
 
 
 
6.
 
 
 
7.
8. 
 
 
 
9.
10.
 
 
 
(If more than 10…continue on reverse of this page) 
 
 
 
 
 
 
 


29 
 
2. List any antibiotics other than rifaximin you have taken in the last 6 months: 
 
Antibiotic
Dates taken
Why taken?
1.
2.
3.
 
 
4.
5.
 
 
SECTION 4: SOCIAL HISTORY 
 
1. Do you or did you ever smoke? 
 
YES 
 
 
NO 
 
If “YES”, when did you start….. __________ 
 
 
and when did you quit…__________ 
 
2. Do you drink alcohol? 
 
 
YES 
 
 
NO 
 
If “YES”, you drink ______ glasses of _______ (type of  alcohol)  
every _______ (day/week/month) 
 
3. Were you breastfed as a child? 
 
YES 
 
NO 
 
Unknown 
 
If “YES”, for how long _________? 
 
SECTION 5: TRAVEL HISTORY 
 
 
 
1. In the following chart, list the places outside of the US you have traveled: 
 
Location Traveled
Date
Did you experience excessive Diarrhea on 
this trip?
1. 
                       YES      NO
2. 
                       YES      NO
3.
                       YES      NO
4.
                        YES      NO
5.
                        YES      NO
6.
                        YES      NO
7.
                        YES      NO
8.
                        YES      NO
9.
                        YES      NO
10.
                        YES      NO
(If more than 10…continue on reverse of this page) 
 


30 
 
SECTION 6: DIETARY CHANGES 
 
1. Please list any recent changes you have made to your diet: 
 
Date started
Type of Change
Date discontinued
(if applicable)
1. 
2. 
3.
4.
5.
6.
7.
8.
9.
10.
 


31 
 
Appendix 2:  Lactulose Breath Test  
 
Preparation for the Test: 
Subjects will not be allowed to consume any heavy protein or legumes on the night before the 
test. 
Subjects will fast beginning at 7 pm on the previous evening to guarantee a 12 hour fast. Only 
water will be allowed until midnight before the test. Subjects cannot chew gum during this time 
of fasting.  
All subjects will be asked to brush their teeth or use mouthwash (not swallowed) and refrain 
from smoking cigarettes on the morning of the test.  
 
Test Administration: 
All subjects will provide a baseline end expiratory breath sample at the start of the test.  
They will then be provided a syrup containing 10 g of lactulose syrup after which breath samples 
will be collected every 15 minutes exactly for 120 minutes.  
 
Sample Analysis: 
Samples will be analyzed using a gas chromatograph capable of measuring hydrogen (H2), 
methane (CH4) and carbon dioxide (CO2). The CO2 will be used to correct for alveolar sampling 
error. The H2 and CH4 will be plotted on a graph with time on the x-axis and gas concentration in 
ppm on the y-axis.  
 
 
 
 
 
 


32 
 
Appendix 3:  Stool Diary 
 
See next page.  


33 
 
Daily Diary
Subject Number: _________________
If you had no bowel movements today, please check this box:
no bowel movements today.
Describe the consistency of bowel 
movement
Describe the Ease of Passage of bowel 
movement
Did you feel like you completely  
       emptied your bowels?
Date:  _ _ / _ _ / 20 _ _
  
 
 
 
 
 
 
 
 
 
 
  
1
hard lumps 
 
  
1
no straining needed 
  
  
1
n
o 
 
 
 
 
 
 
  
2
lumpy sausage
2
mild straining
2
yes
3
cracked sausage
3
moderate straining
4
smooth sausage
4
severe straining
  
 
 
 
 
 
 
 
 
 
 
  
5
soft lumps 
 
  
5
very severe straining 
  
 
 
 
 
 
 
 
 
  
6
mushy
  
  
  
  
  
  
  
  
  
  
  
  
7
watery 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
am
1
hr.
min
pm
am
2
hr.
min
pm
am
3
hr.
min
pm
am
4
hr.
min
pm
(If more than 4…continue on reverse of this page) 


34 
 
Appendix 4:  Bristol Stool Chart 
 
 


35 
 
Appendix 5: Assessment of rectal sensitivity using graded balloon distention 
 
 
A standard non-latex rectal balloon (Mui Scientific, Mississauga, Ontario, Canada) will used for 
assessment of rectal sensitivity. After lubrication the balloon will be inserted into the rectum and 
will be advanced for 5 cm. The balloon will be inflated by 20 cc and pull back until sphincter 
resistance is appreciated. At this point the catheter will be advance 3cm and will be deflated. 
Following a 20 second hiatal, every minute the balloon will be inflated by 10 cc in 10 seconds. 
Patient will be asked about the sensation after 10 seconds.  Patients will be blinded from the 
balloon volume or whether the balloon is inflated. The balloon will be deflated and inflated with 
10cc incremental volumes until the first sensation, first sensation of urge, normal sensation of 
urge and severe sensation of urge is appreciated (see scale below). When these points are 
achieved, the balloon pressure will also be recorded (Posey 8199 Manometer, Arcadia, CA, 
USA). The maximum inflated volume will be 200 cc. 
 
 


36 
 
Appendix 6:  Weekly Questionnaire 
BOWEL SYMPTOMS QUESTIONNAIRE  
Week #: _____ 
Day #: _____ 
                                                                                                                     
DATE: ________________                                                                     CODE: 
_____________ 
AGE: _________________ 
SEX:  _________________ 
HEIGHT: ______________ 
WEIGHT: ______________ 
INSTRUCTIONS:  For each symptom indicated, please mark a vertical line on the scale that 
best represents the symptom severity that you experienced during the past one week. 
 
                     EXAMPLE:   
 
 
 
 
 
 
 
1.  Bloating 
                        
 
 
2.  Excess Gas 
 
 
 
3.  Incomplete Evacuation (feeling that all your stool has NOT come out) 
 
 
 
 
 
4.  Abdominal Pain 
0
10
0
0
10
10
No Symptom 
0
10
Severe Symptom


37 
 
 
5.  Constipation 
 
 
 
6.  Diarrhea 
 
 
 
7.  Urgency 
 
 
 
 
8.  Mucous from rectum 
 
 
 
 
9.  Straining during bowel movement 
 
 
 
 
10.  Fatigue 
 
 
 
 
 
11. Overall improvement of your IBS symptoms 
 
 
 
 
 
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10