The Efficacy of PX0612 In The Treatment Of Irritable Bowel Syndrome: A Randomized, Double-Blind Placebo Controlled Clinical Trial
Phase: NA
Conditions: Irritable Bowel Syndrome With Diarrhea
Sponsor: Pharmabiotix Inc

The Efficacy of Symbion™ In The Treatment Of Irritable Bowel 
Syndrome: A Randomized, Double-Blind Placebo Controlled 
Clinical Trial  
Protocol number:  01-PBI-2012 
 
 
 
A Study Sponsored by Pharmabiotix Inc  
Pharmabiotix, Inc. 
7114 Casa Loma Ave. 
Dallas. Texas 75214 
214-327-4712 (phone) 
214-327-2813 (fax) 
 
 
A Study Conducted By The Northern Alberta Clinical Trials And Research 
Center (NACTRC) 
 
 
Sponsor CEO 
Mark L. Cobb 
 
Medical Lead 
Dr. Richard N Fedorak, MD, FRCPC, FRCP (London) 
Associate Vice President (Research) 
University of Alberta 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 4April 2018 

Symbion™ In The Treatment Of Irritable Bowel Syndrome: 
 
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BACKGROUND AND RATIONALE: 
 
Irritable Bowel Syndrome (IBS) is a functional illness, which is characterized by 
abdominal pain or discomfort associated with change in bowel habits and characteristics 
of disrupted defecation (1). IBS is one of the most common gastrointestinal (GI) 
disorders with one tenth to one fifth of the general adult population, with female 
predominance, reporting IBS symptoms (1).  
 
IBS is associated with a huge financial burden represented by direct medical cost and 
loss of productivity associated absenteeism of work (2), as well as deterioration of the 
individual’s quality of life both socially and professionally (3). 
 
Nearly 15% of the North American population is suffering from IBS representing one of 
the highest rates in the world (4). One of the major problems associated with IBS is that 
there is no approved medication to treat IBS, the treatment that the IBS patient receives 
aims to address his/her concerns and relief his/her symptoms (5). 
 
What Are Probiotics? 
Probiotics are living microscopic organisms, or microorganisms, that scientific research 
has shown to benefit your health. Most often they are bacteria, but they may also be 
other organisms such as yeasts. In some cases they are similar, or the same, as the 
“good” bacteria already in your body, particularly those in your gut. 
 
The most common probiotic bacteria come from two groups, Lactobacillus or 
Bifidobacterium, although it is important to remember that there are many other types 
of bacteria that are also classified as probiotics (eg, Streptococcus, E. coli). Each group of 
bacteria has different species, and each species has different strains. This is important to 
remember because different strains have different benefits for different parts of your 
body. For example, Lactobacillus casei Shirota has been shown to support the immune 
system and to help food move through the gut, but Lactobacillus bulgaricus may help 
relieve symptoms of lactose intolerance, a condition in which people can’t digest the 
lactose found in most milk and dairy products. In general, not all probiotics are the 
same. They don’t all work the same way.  
 
Scientists are still sorting out exactly how probiotics work, but there are a few 
possibilities: 
• They may stick to the gut wall and prevent harmful bacteria from attaching there 
and growing. 
• They may boost your immune system by producing antibodies for certain 
viruses. 
• They may produce substances that prevent infection. 
• They may send signals to your cells to strengthen the mucus in your intestine 
and help it act as a barrier against infection. 

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• They may inhibit or destroy toxins released by certain “bad” bacteria that can 
make you sick. 
• They may produce B vitamins necessary for metabolizing the food you eat, 
warding off anemia caused by deficiencies in B-6 and B-12, and maintaining 
healthy skin and a healthy nervous system.  
 
Common Uses For Probiotics 
Probiotics are most often used to promote digestive health. Because there are different 
kinds of probiotics, it is important to find the right one for the specific health benefit 
you seek. Researchers are still studying which probiotic should be used for which health 
or disease state. Nevertheless, probiotics have been shown to help regulate the 
movement of food through the intestine. They also may help treat digestive disease, 
something of much interest to gastroenterology scientists. Some of the most common 
uses for probiotics include the treatment of the following: 
 
Irritable Bowel Syndrome (IBS).  IBS is a disorder of movement in the gut. People who 
have IBS may have diarrhea, constipation, or alternating bouts of both. IBS is not caused 
by injury or illness. Often the only way doctors can diagnose it is to rule out other 
conditions through testing. 
 
Probiotics, particularly Bifidobacterium infantis, Sacchromyces boulardii, Lactobacillus 
plantarum and combination probiotics may help regulate how often people with IBS 
have bowel movements. Probiotics may also help relieve bloating from gas. Research is 
continuing to determine which probiotics are best to treat IBS.  
 
Symbion 
Symbion ™ is a probiotic which is composed of the following ingredients contained in a 
veggie capsule, being one dose: 
 
Bacillus coagulans 
200 million colony forming units 
  33.34mg 
Bacillus subtilis 
100 million colony forming units 
    16.67mg 
Enterococcus faecium 
100 million colony forming units 
    16.67mg 
Fructo-
oligosacharride  
a nutrient for the packaged 
product            
600.0mg 
                                                                                        Total            666.68 mg 
 
Bacillus coagulans is a non-pathogenic, Gram positive, spore forming bacteria that 
produces lactic acid. Though not normally found in the gut. Bacillus coagulans strains 
have been used as general nutritional supplements and agents to control constipation 
and diarrhea in humans and animals. 
 

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Bacillus subtilis is a Gram-positive, endospore-forming soil bacteria comprising aerobic 
and a few facultatively anaerobic rod shaped bacteria. Bacillus subtilis was historically 
used to treat dysentery. 
Enterococcus faecium is a facultative (growing with or without oxygen) anaerobic, Gram 
positive cocci that produces lactic acid. The Enterococcus faecium strain is a natural 
inhabitant of the mammalian GI tract. 
 
Historically Lactobacilli and Bifidobacteria associated with food have been considered 
safe. Many probiotic bacteria are normal commensals of the mammalian gut flora and 
their established safe use over decades in a diversity of foods and dietary supplement 
products worldwide support this safety conclusion. 
  
Many IBS patients who used Symbion™ as a dietary supplement to help rebalancing 
their gastrointestinal flora reported resolution of their IBS symptoms. The large number 
of positive anecdotal reports to Pharmabiotix Inc. suggest that Symbion™ may be of 
benefit if made into a medicinal drug to treat IBS (6). Therefore there is a need for 
further investigation to confirm these findings. 
 
 
STUDY OBJECTIVES: 
 
Primary objective: 
To compare the effect of Symbion™  (PXO612) to placebo, administered over 12 weeks, 
in IBS-Diarrhea patients; on bowel movements using patient’s reported stool frequency 
(number of stools)    
Secondary Objectives: 
To compare the effect of Symbion™  (PXO612) to placebo; using the patient's rating for 
IBS symptoms based on the assessment of the overall symptoms relief (calculated at 
each visit by summing the following reported symptoms scores): 
o Stool frequency (number of stools/day) 
o Abdominal pain (on a scale of 0-4) 
o Stool consistency (on a scale of 1-7)  
o Straining (yes (1) or no (0)) 
o Urgency (yes (1) or no (0)) 
o Feeling of incomplete defecation (yes (1) or no (0)) 
o Bloating (yes (1) or no (0)) 
o Passage of mucus (yes (1) or no (0) )  
 
To evaluate 
• Changes in abdominal pain/discomfort, stool consistency, stool frequency, 
straining or urgency, feeling of incomplete defecation, passage of mucus and 
bloating or feeling of abdominal distention over the study period 

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• Changes in upper GI symptoms (i.e. heartburn, early satiety, postprandial 
fullness, sensation of prolonged digestion, nausea and vomiting) over the study 
period 
• Changes in the patient’s assessment of their quality of life using SF-36 
• Sub group analysis regarding: gender  
 
METHODS: 
 
Design:  
Randomized double-blind placebo controlled study 
 
Setting: 
The Northern Alberta Clinical Trials and Research Centre (NACTRC), Edmonton, Alberta, 
Canada 
  
Participants: 
Inclusion criteria: 
• Male or female 
• 18 - 65 years old  
• Signed informed consent 
• Mild to moderate (using Functional Bowel Disorder Severity Index (FBDSI)) IBS-
Diarrhea patient: 
o IBS definition will be based on Rome criteria; 
   The symptoms of IBS must persist for at least 3 months and must include: 
1. Abdominal pain or discomfort which is relieved by defecation, and/or 
associated with a change in frequency of stool and/or consistency of 
stool 
2. At least two of the following, at least a quarter of occasions or days 
(25%): 
A. Altered stool frequency (> 3 bowel movements/day or < 3 
bowel movements/week) 
B. Altered stool form (lumpy/hard or loose/watery stools) 
C. Altered stool passage (straining, urgency or feeling of 
incomplete evacuation) 
D. Passage of mucus 
E. Bloating or feeling of abdominal distention 
 
o Diarrhea is defined as having loose watery stools at least three times per 
day  
 
Exclusion criteria: 
The patient will be excluded from the study if:  

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• Assessment by the treating investigator showed an evidence for cardiovascular, 
respiratory, urogenital, gastrointestinal/hepatic, hematologic/immunologic, 
head, ears, eyes, nose and throat, dermatologic/psychiatric, allergy, major 
surgery or other diseases as revealed by history, physical examination and 
existing laboratory assessments which may interfere with the administration or 
assessment of study medication. This should be confirmed by a pre-study 
medical examination performed 2 weeks prior the study. 
• Pregnant or lactating 
• Females at child bearing age will be excluded unless they are using acceptable 
birth control measures (i.e. implants, injectables, combined oral contraceptives, 
some intrauterine contraceptive devices, sexual abstinence or a vasectomized 
partner)  
• Patients requiring treatments with non-permitted medication (i.e. 5-HT3 
antagonist, spasmolytics, anticholinergics, cholestyramine, anti-flatulence 
agents, metoclopramide, gastric-anti secretory agents (proton pump inhibitors; 
for indications other than Gastroesophageal  Reflux Disease (GERD)), narcotics, 
anti-diarrheal drugs, and systemic steroids) 
• Patients requiring the use of antibiotics either in medicine form of natural (e.g. 
grapefruit seed extract, olive leaf extract, oil of oregano, colloidal silver and 
highly concentrated garlic preparations) 
• Exercise and the use of complementary and alternative medicine for IBS 
symptoms (i.e. peppermint oil, cognitive behavior therapy) during the study 
should be maintained at the same level prior to the study. 
• Patients exceeding the treatment limits of permitted medication [(more than 2 
days/week during the study period): alginate, antacids and analgesics (limited to 
acetaminophen ≤ 1000 mg/day, acetylsalicylic acid or NSAIDS no more than 2 
tablets/day), (stable dose throughout the study period, anti-depressants (must 
be on a stable dose > 3 months), fiber supplements, psyllium hydrophilic 
mucilloid, gastric anti secretory agents (only for GERD patients who are on a 
stable dose > 3 months; patients should be able to differentiate between IBS and 
GERD symptoms), acetylsalicylic acid ≤ 325 mg/day, sedatives.  Deliverance 
medications: Mild laxatives only if necessary.]. Any other medications can be 
used without limits based on the clinical judgment of the treating investigator. 
• Being in another clinical trial 4 weeks before entering the study  
• Constipated IBS patients 
• IBS-Diarrhea patients with un-treated lactose intolerance 
• Regular use of probiotics or using other probiotics during the course of the study 
• Patients allergic to milk or soy products 
• Patients using catheters  
• Patients presented with rectal bleeding, weight loss, iron deficiency anemia, 
nocturnal symptoms and a family history of colorectal cancer, inflammatory 
bowel disease and celiac spruce  

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• Patients over 50 diagnosed with Irritable Bowel Syndrome who have not had a 
colonoscopy in the last 5 years  
• Patients who have allergies for the active ingredients or any of the exepients 
• Patients presented with any immune-compromised condition (such as AIDS, 
lymphoma, long term corticosteroid treatment) 
• Patients presented with nausea, vomiting and fever   
 
 
Patient withdrawal from the study: 
All patients are free to withdraw from the study at any time with or without providing a 
reason for their withdrawal. 
 
Drop-outs are the patients who decide to leave the study before the planned finishing 
time for whatever reason. Withdrawals are the drop-outs who are withdrawn from the 
study for the following reasons: 
• Cannot tolerate the adverse events 
• Lack of efficacy 
• Insufficient compliance  
• Protocol violation 
 
Since the analysis will be conducted on ‘Intention to Treat’ basis, the last available data 
from the drop-outs will be carried forward in the analysis. 
 
 
Screening and Recruitment:  
 
Figure 1 below describes the overall study design: 
 
Pre-study
run in
(without any 
treatment)
treatment period (drug/placebo)
(day)
(week)
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
-14
1
29
57
85
V
1
V
2
V
3
V
4
V
5
V = patients visit
Figure 1:  Overall Study Design
 
The study will be seeking to recruit IBS patients via advertising through local radio 
stations, local news papers and flyers. 

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Visit 1: ‘Run- In’ And Recruitment visit. Week -2: 
Interested potential participants will be asked to contact NACTRAC where they will 
undergo a thorough assessment of their fitness for inclusion into the study including 
determination of their status as an IBS-Diarrhea patient using the following criteria: 
• IBS-Diarrhea patient: 
o IBS definition will be based on Rome criteria; 
   The symptoms of IBS must persist for at least 3 months and must include: 
1. Abdominal pain or discomfort which is relieved by defecation, and/or 
associated with a change in frequency of stool and/or consistency of 
stool 
2. At least two of the following, at least a quarter of occasions or days 
(25%): 
a. Altered stool frequency (> 3 bowel movements/day or < 3 
bowel movements/week) 
b. Altered stool form (lumpy/hard or loose/watery stools) 
c. Altered stool passage (straining, urgency or feeling of 
incomplete evacuation) 
d. Passage of mucus 
e. Bloating or feeling of abdominal distention 
 
o Diarrhea is defined as having loose watery stools at least three times per 
day  
 
The potential participants will also undergo the following assessments/procedure: 
• Informed consent 
• Medical history 
• Demographic data 
• Physical examination 
• Upper GI symptoms 
• Relationship between bowel motions and IBS symptoms 
• Baseline complaints 
• Concomitant medications 
• Pregnancy test 
 
 
Patients who meet the inclusion criteria will be asked to come back to NACTRC after 14 
days. These 14 days are going to be used as ‘run-in’ period where patients are going to 
undergo the following: 
• Asked to stop the non-permitted medications immediately. 
• Asked to follow the following dietary recommendations: 
1. Eliminate or greatly reduce sugars from their diet. This includes refined 
sugar, brown sugar, syrups, molasses, agave, cane juice and honey. As 

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sugars play a major role in the overgrowth of small intestinal bacterial 
and other pathogens such as fungi. 
2. Avoid known trigger foods, such as fatty fried foods and spicy foods, and 
additionally any foods that the patient has a known allergy or 
intolerance to, such as tomatoes, eggs, etc. 
3. Eat processed foods only in moderation 
• No study treatment will be given 
• Diaries will be issued for each patient with a detailed explanation on its use. 
Diaries will include the overall subjective assessment of the following (based 
on the recommendations of the Rome committee on treatment trials (7)):)  
1. Stool frequency (number of stools/day) 
2. Abdominal pain [on a scale of 0-4 (0 is none, 1 mild, 2 moderate, 3 severe 
and 4 is incapacitating)] 
3. Stool consistency [on a scale of 1-7 according to the Bristol stool form 
scale (1 is separate hard lumps, 2 is sausage shaped but lumpy, 3 is like a 
sausage or a snake but with cracks on the surface, 4 is like a sausage or a 
snake, smooth and soft, 5 is soft blobs with clear-cut edges, 6 is fluffy 
pieces with ragged edges, a mushy stool and 7 is watery, no solid pieces)] 
4. Straining (yes (1) or no (0) question) 
5. Urgency (yes (1) or no (0) question) 
6. Feeling of incomplete defecation (yes (1) or no (0) question) 
7. Bloating (yes (1) or no (0) question) 
8. Passage of mucus (yes (1) or no (0) question) 
9. Any medication taken for bowel movement (either for diarrhea or 
constipation)  
10. Food frequency and kind to assess the ingestion of potential symptom-
exacerbating foods 
 
Visit 2: Baseline visit. Week 0: 
At baseline visit patients will be excluded if: 
• The patient developed any of the exclusion criteria mentioned earlier 
• The patient did not complete the diary adequately 
• The patient rated his/her abdominal pain as incapacitating at least twice during 
the ‘run-in’ period 
• The patient reported not having abdominal pain/discomfort for more than 50% 
of the ‘run-in’ period 
• The patient did not have a bowel movement for more than 4 days (either 
consecutive or non-consecutive) during the ‘run-in’ period 
 
Excluded patients will be replaced within the study. If the patient is fit to be in the study 
he/she will be randomized into either of the study groups on the following basis: 
 

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The patients are going to be randomized (on 1:1 basis) via a centralized secure website 
to ensure allocation concealment into either the ‘intervention’ group or the ‘placebo’ 
group. Both the patients and the treating investigators are going to be blinded to the 
treatment. 
 
Patients in the ‘intervention’ group will receive PXO612 which is a probiotic composed 
of the following ingredients contained in a veggie capsule, being one dose: 
 
Bacillus coagulans 
200 million colony forming units 
   33.34mg 
Bacillus subtilis 
100 million colony forming units 
     16.67mg 
Enterococcus faecium 
100 million colony forming units 
     16.67mg 
Fructo-
oligosacharride  
a nutrient for the packaged 
product            
 600.0mg 
                                                                                        Total             668.68 mg 
 
Bacillus coagulans is a non-pathogenic, Gram positive, spore forming bacteria that 
produces lactic acid. Though not normally found in the gut. Bacillus coagulans strains 
have been used as general nutritional supplements and agents to control constipation 
and diarrhea in humans and animals. 
 
Bacillus subtilis is a Gram-positive, endospore-forming soil bacteria comprising aerobic 
and a few facultatively anaerobic rod shaped bacteria. Bacillus subtilis was historically 
used to treat dysentery. 
 
Enterococcus faecium is a facultative (growing with or without oxygen) anaerobic, Gram 
positive cocci that produces lactic acid. The Enterococcus faecium strain is a natural 
inhabitant of the mammalian GI tract. 
 
Patients in the ‘placebo’ group will receive the placebo capsules. The main ingredient in 
the placebo capsule is Di-Calcium Phosphate 
 
 
After the randomization the treating investigator will review the patient’s diary and the 
patients will undergo the following: 
 
• Bowel movements (stool frequency) will be assessed at each visit using the 
patient's reported stool frequency/day 
• The overall symptoms relief will be calculated at each visit by summing the 
following reported symptoms scores (based on the recommendations of the 
Rome committee on treatment trials (7)): 
o Stool frequency (number of stools/day) 
o Abdominal pain (on a scale of 0-4) 
o Stool consistency (on a scale of 1-7)  

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o Straining (yes (1) or no (0)) 
o Urgency (yes (1) or no (0)) 
o Feeling of incomplete defecation (yes (1) or no (0)) 
o Bloating (yes (1) or no (0)) 
o Passage of mucus (yes (1) or no (0)) 
• Subjective assessment of the upper GI symptoms [frequency of vomiting per 
week, heartburn, early satiety, postprandial fullness, sensation of prolonged 
digestion and nausea on a scale of 0-4 (0 is none, 1 mild, 2 moderate, 3 severe 
and 4 is incapacitating)]  
• Quality of life assessment using SF-36 
• Any medication being taken by the patient 
 
➢ At the end of each visit the patients will be provided with the drug or placebo 
supply that would be enough for them until the next visit. 
 
➢ Patients will be asked to keep filling their diary as requested over the study 
period; as their diary will be reviewed at each visit by the treating investigator. 
 
Visits 3, 4 and 5. Weeks 4, 8 and 12: 
If the patient developed any of the exclusion criteria during the course of the study 
he/she will be withdrawn from the study 
 
Bowel movements (stool frequency) will be assessed at each visit (3, 4 and 5) using the 
patient's reported stool frequency/day. 
 
The overall symptoms relief will be calculated at each visit (3, 4 and 5) by summing the 
following reported symptoms scores (based on the Rome criteria): 
1. Stool frequency (number of stools/day) 
 
2. Abdominal pain (on a scale of 0-4) 
3. Stool consistency (on a scale of 1-7)  
4. Straining (yes (1) or no (0)) 
5. Urgency (yes (1) or no (0)) 
6. Feeling of incomplete defecation (yes (1) or no (0)) 
7. Bloating (yes (1) or no (0)) 
8. Passage of mucus (yes (1) or no (0)) 
 
The following subjective information is going to be collected at visits 3 and 4: 
• Subjective assessment of upper GI symptoms [frequency of vomiting per week, 
heartburn, early satiety, postprandial fullness, sensation of prolonged digestion 
and nausea on a scale of 0-4 (0 is none, 1 mild, 2 moderate, 3 severe and 4 is 
incapacitating)]  
• Compliance with the treatment (using pill count) 

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• Adverse events 
• Any non-study medication 
 
At visit 5 the patient will undergo the following: 
• Compliance assessment (using pill count) 
• Subjective assessment of the upper GI symptoms [frequency of vomiting per 
week, heartburn, early satiety, postprandial fullness, sensation of prolonged 
digestion and nausea on a scale of 0-4 (0 is none, 1 mild, 2 moderate, 3 severe 
and 4 is incapacitating)]  
• Quality of life assessment using SF-36 
• A Functional Bowel Disorder Severity Index (FBDSI) evaluation 
• Adverse events assessment 
• Any non-study medication 
 
Dosing regimen: 
The patients will start taking 1 capsule per day with any meal. At the beginning of week 
3, they will take one capsule with breakfast and one with their evening meal. At 
beginning of week 7, they will take one in morning, one at lunch and one at the evening 
meal. The patients will be asked to keep their sugar intake to a minimum. 
 
Outcomes: 
Primary outcome: 
The primary outcome is the difference in change in the bowel movements (stool 
frequency) between the 'intervention' group and the 'placebo' group over the study 
period. Secondary outcomes: 
• Difference in the overall symptoms relief between the ‘intervention’ group and 
the ‘placebo’ group over the study period 
• Differences in abdominal pain/discomfort, stool consistency, stool frequency, 
straining, urgency, bloating, feeling of incomplete defecation and passage of 
mucus between the ‘intervention’ group and the ‘placebo’ group over the study 
period 
• Differences in upper GI symptoms (i.e. heartburn, early satiety, postprandial 
fullness, sensation of prolonged digestion, nausea and vomiting) between the 
‘intervention’ group and the ‘placebo’ group over the study period 
• Differences in quality of life using SF-36 between the ‘intervention’ group and 
the ‘placebo’ group over the study period 
• Changes in severity of IBS symptoms as determined by pre- and post-study FBDSI 
scores 
 
 
Sample Size:  
Using the information from Dolin (2009) (approximate reduction of 0.47 in the bowel 
movements in the placebo group versus 0.8 in the treatment group), power of 80% and 

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95% confidence interval. 78 patients (39 in each group) are required to be able to detect 
a minimum of 0.33 difference in change in the bowel movements between the 
'intervention' group and the 'placebo' group over the study period.  
 
Statistical Analyses: 
Interim Analysis 
An interim analysis will be conducted after a minimum of 20 patients in each study 
group have completed the trial. The interim analysis will include all safety and efficacy 
data. For the interim analysis, the study data will be unblinded to the biostatistician or 
sponsor representative. Trial success will be demonstrated if the change in bowel 
movements is statistically different at an alpha of 0.01. If it is not statistically significant 
at the interim, than recruitment will proceed as planned. 
 
All analysis will be conducted on ‘Intention to Treat’ basis. A comparison of baseline 
characteristics will be performed using t-tests or nonparametric Wilcoxon for 
continuous variables and chi-squared test for categorical variables. In order to account 
for any imbalance in baseline characteristics, test for differences in change in bowel 
movements  between the ‘intervention’ group and the ‘placebo’ group will be adjusted 
for using multiple regression models (or analysis of covariance models).  The problem of 
missing values will be checked for non-randomness and appropriate imputation 
methods will be applied when needed.   
 
Adverse events: 
Serious adverse event (SAE) or serious adverse reaction: any untoward medical 
occurrence that occur at any dose:  
• Results in death, 
• Is life threatening, (Note: the term life-threatening refers to an event/reaction in 
which the patient was at risk of death at the time of the event/reaction; it does 
not refer to an event/ reaction which hypothetically might have caused death if 
it were more severe) 
• Requires inpatient hospitalization or results in prolongation of existing 
hospitalization 
• Results in persistent or significant disability/ incapacity 
• Is a congenital anomaly/birth defect 
• Is a medically important event or reaction. Medical and scientific judgment 
should be exercised in deciding whether other situations should be considered 
serious, such as important medical events that might not be immediately life-
threatening or result in death or hospitalization, but might jeopardize the patient 
or might require intervention to prevent one of the other outcomes listed in the 
definition above. 
 
Related SAE: there is a reasonable possibility according to the treating investigator that 
the Product may have caused the event. 

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Unusual lack of efficacy: When a health product fails to produce the expected intended 
therapeutic effect.  
 
Adverse events will be collected and reported to the appropriate authorities through 
the appropriate channels. 
 
Patients will be withdrawn from the study if the suffered from any serious adverse 
events. 
 
 
 
 
 
References: 
1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 
2006; 130:1480-1491. 
2. Longstreth GF, Wilson A, Knight K, et al. Irritable bowel syndrome, health care, and costs: a U.S. 
managed care perspective. Am J Gastroenterol. 2003; 98: 600-607. 
3. Wilson A, Longstreth GF, Knight K, et al: Quality of life in managed care patients with irritable 
bowel syndrome. Manage Care Interface. 2004; 17: 24-28. 
4. Canadian Digestive Health Foundation. Irritable Bowel Syndrome; 2011. Available: 
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf (accessed Jan 2012). 
5. Drossman DA. Review article: An integrated approach to the irritable bowel syndrome. Aliment 
Pharmacol Ther. 1999; 13: (Suppl 2): 3-14. 
6. Pharmabiotix INC. Investigator brochure. 2011, 1-15.  
7. Schoenfeld p, Talley NJ. Measuring successful treatment of irritable bowel syndrome: is 
satisfactory relief enough? Am J Gastroenterol. 2006; 101: 1066-1068. 
8. Dolin BJ. Effects of a proprietary Bacillus Coagulans preparation on symptoms of diarrhea-
predominant irritable bowel syndrome. Methods Find Exp Clin Pharmacol. 2009; 31: 655-659