Use of Novel Prebiotic Fiber for Targeted Dietary Management of Irritable Bowel Syndrome (Nutrabiotix Phase II)

The investigators will conduct an 18-week (2-week initial run-in phase, 12-week treatment
phase, and 4-week follow up phase), 2-arm, randomized, double-blind, controlled Phase 2
trial in 120 subjects with IBS-C. A 2-week run in will be completed in order to ensure the
stability of baseline symptom scores and to ensure that all study subjects have the required
symptom severity to fulfill the inclusion criteria before randomization and beginning the
treatment. The investigators selected a 12-week treatment phase because of the adequacy of
this length of time to clinically see the impact of fiber supplementation (as seen in the
investigators Phase I trial), and because of the 12-week duration requirement of the FDA for
all therapeutic intervention/agents for treatment of IBS. The 4-week follow up phase is to
determine the sustainability of the effects of therapy and to obtain further safety
data.Potential study subjects will be identified though the Rush University Medical Center
(RUMC) clinical databases; advertisements on the RUMC clinical trials and GI websites, RUMC
Facebook and other social media sites; and IRB approved flyers placed in the GI clinic and
throughout the medical center. All potential candidates will be interviewed on the phone by
a clinical coordinator using a structured checklist, at which time the study requirements
will also be explained. Subjects will be asked for food allergies, including artificial
sweeteners such as sucralose and ascelfame K. Subjects will also be informed that the fiber
is made out of corn or psyllium and not other grains. However, it can't be guaranteed that
it is free of other food allergy-related contaminants. Also, subjects will be asked to limit
intake of foods containing more than 3 grams of prebiotics. A list of these foods will be
provided.

Those who are eligible and are willing to participate will be invited for the first study
visit. Five visits will be required from each subject.

Visit 1: After the subject has reviewed and signed the informed consent form, the
investigators will check to see if they are eligible for this study by a physical exam,
questionnaires and a blood test. A physician or their assistant will do a physical exam and
take the subjects vitals (such as height, weight, waist circumference and blood pressure).

The Subject Information Form will be an administered questionnaire related to their health,
disease, and their family medical history. They will then have 2½ tablespoons of blood drawn
by a certified nurse or medical assistant. They will be reminded in advance to fast 12 hours
prior to their research visit. The blood tests include: CBC, CMP, CRP, TSH, INR, fasting
lipid profile and HbA1c. The subject will be given a 3-day food diary and a 14-day IBS
symptom diary to complete before their next visit. They will also be provided with stool
collection supplies and instructions to take home. When blood test results are available,
those who do not fit the criteria will be called within 7 days after Visit 1 stating that
they are ineligible. Among these blood tests, the fasting lipid profile results will be
given to the subject after their participation in the study and after completion of the
study. The rest of the results will be given to the subject at their next visit. If they
continue to be a candidate in this study based on blood results, the potential subjects will
fill out the 3-day food diary, continue to fill out the 14-day IBS symptom diary, and
complete the stool collection the day before or the morning of Visit 2. The subject will be
advised to not keep the stool at room temperature longer than 5 hours. If they anticipate it
to be longer than 5 hours before their visit time, then the stool will be kept in the
freezer. Both of the diaries and the stool sample are to be brought to Visit 2, which is 2
weeks after their Visit 1. Visit 1 will be about 3 hours in length.

Visit 2: The subject will give the study coordinator their 3-day food diary, 14-day IBS
symptom diary, and stool sample. They will provide the date of stool collection, as well as
the method of storing the sample. The physician will review their 14-day IBS symptom diary
and confirm their eligibility. If they continue to be eligible, the physician will do a
physical exam and take their vitals (such as weight, waist circumference and blood
pressure). The subject will then be asked to fill out a series of questionnaires relating to
their diet (VioScreen Food Frequency Questionnaire), IBS symptoms (IBS-Quality of Life
questionnaire [IBS-QoL] and IBS Questionnaire by Whorwell and Francis), sleeping/circadian
patterns (2 NIH sleep questionnaires, Munich Chronotype Questionnaire, Lark/Hummingbird/Owl
questionnaire, food timing questionnaire), the Expectancy and Credibility Questionnaire, and
the 34-item tool asking about their GI symptoms and severity. The subject will then be
randomized into one of the two groups. Depending on which group they are randomized to, they
will be provided with a 6-week supply of NTX-1 OR psyllium fiber products in an identical
appearing sachet along with instructions for taking the fiber. They will be provided with a
3-day food diary and a daily and weekly IBS symptom diary to fill out prior to Visit 3. This
visit will be about 3 hours in length. The next visit will be 6 weeks after Visit 2.

Visit 3: The subject will give the study coordinator their 3-day food diary, the daily and
weekly IBS symptom diary, and any excess fiber product. The physician will review their IBS
symptom diary and ensure there are no significant adverse events. The physician will do a
physical exam and take their vitals (such as weight, waist circumference and blood
pressure). The subject will then be asked to fill out a series of questionnaires relating to
their IBS symptoms (IBS-Quality of Life questionnaire (IBS-QoL) and IBS Questionnaire by
Whorwell and Francis), sleeping/circadian patterns (2 NIH sleep questionnaires, Munich
Chronotype Questionnaire, Lark/Hummingbird/Owl questionnaire, food timing questionnaire),
the Expectancy and Credibility Questionnaire, and the 34-item tool asking about their GI
symptoms and severity. Next, they will have 2 tablespoons of blood drawn by a certified
nurse or medical assistant. The following blood tests will be done: CBC, CMP and CRP. The
subject will be reminded in advance to fast 12 hours prior to their research visit. A copy
of their blood test results will be given to them at their next visit. Next, they will be
given another 6-week supply of the fiber product, the 3-day food diary, a daily and weekly
IBS symptom diary to fill out prior to Visit 4 and stool collection supplies. They are asked
to collect stool as previously indicated and bring the stool to Visit 4; handling will be
identical to previous visit. This visit will be about 2 hours in length. The next visit will
be 6 weeks after their Visit 3.

Visit 4: The subject will give the study coordinator their 3-day food diary, the daily and
weekly IBS symptom diary, and any excess fiber product. The physician will review their IBS
symptom diary and ensure there are no significant adverse events. The physician will
complete a physical exam and take their vitals (such as weight, waist circumference and
blood pressure). The subject will then be asked to fill out a series of questionnaires
relating to their diet (VioScreen Food Frequency Questionnaire), IBS symptoms (IBS-Quality
of Life questionnaire (IBS-QoL) and IBS Questionnaire by Whorwell and Francis),
sleeping/circadian patterns (2 NIH sleep questionnaires, Munich Chronotype Questionnaire,
Lark/Hummingbird/Owl questionnaire, food timing questionnaire), the Expectancy and
Credibility Questionnaire, and the 34-item tool asking about their GI symptoms and severity.
They will then have 2½ tablespoons of blood drawn by a certified nurse or medical assistant.
Subjects will be reminded in advance to fast 12 hours prior to their research visit. The
blood tests include: CBC, CMP, CRP, TSH, INR, fasting lipid profile and HbA1c. Among these
blood tests, the fasting lipid profile results will be given to the subject after the
completion of the study. The rest of the results will be given to the subject at their next
visit. They will be provided with a 3-day food diary and a daily and weekly IBS symptom
diary to fill out prior to Visit 5. Visit 4 will be about 3 hours in length. The next visit
will be 4 weeks after their fourth visit, which is the subjects' last visit.

Visit 5: The subject will give the study coordinator their 3-day food diary and the daily
and weekly IBS symptom diary. The physician will review their IBS symptom diary and ensure
there are no significant adverse events. The physician will do a physical exam and take
their vitals (such as weight, waist circumference and blood pressure). The subject will then
be asked to fill out questionnaires relating to their IBS symptoms (IBS-Quality of Life
questionnaire (IBS-QoL) and IBS Questionnaire by Whorwell and Francis) and the 34-item tool
asking about their GI symptoms and severity. Next, they will have 2 tablespoons of blood
drawn by a certified nurse or medical assistant. Subjects will have been reminded in advance
to fast 12 hours prior to their research visit. The following blood tests will be done: CBC
and CMP. A copy of their blood test results, including the two fasting lipid profile tests,
will be given to the subject via e-mail or mail. This visit will be about 2 hours in length.

Inclusion - History

1. Between the ages of 18-75

2. Have recurrent abdominal pain or discomfort at least 3 days/month in the last 3
months

3. Have at least 2 of the following in the last 6 months:

1. Improvement of abdominal pain or discomfort with defecation

2. Onset of abdominal pain or discomfort associated with change in frequency of
stool

3. Onset of abdominal pain or discomfort associated with a change in
form/appearance of stool

4. Symptom onset at least 6 months prior to screening date

5. Willing to take study supplement three times a day and willing to comply with all
study procedures (i.e. swallow capsules)

6. Willing to stop taking over-the-counter laxatives after the 2 week screening period
(Ex: ex-lax, senna, miralax, milk of magnesia)

Inclusion - Screening Diary

7. Abdominal bloating/discomfort/pain (if either a, b, OR c is positive, then this meets
the criteria for #7)

1. A weekly average of worst abdominal bloating score of ≥ 3 during the screening
period on a 0-10 numeric rating scale

2. A weekly average of worst abdominal discomfort score of ≥ 3 during the screening
period on a 0-10 numeric rating scale

3. A weekly average of worst abdominal pain score of ≥ 3 during the screening
period on a 0-10 numeric rating scale

8. Bowel movements/stool consistency (if either a OR b is positive, then this meets the
criteria for #8)

1. Less than 3 spontaneous complete BM (SCBM) per week. (SCBM is defined as a BM
occurring in the absence of a laxative that is associated with a sense of
complete evacuation)

2. Stool consistency of 1-2 on Bristol scale at least twice a week OR >25% of BM
for the week

Exclusion- Lab Results

1. Abnormalities in CBC (Hgb<12 g/dL, platelet count<100000, WBC<4000 or >10000)

2. Abnormal liver function tests (ALT, AST, alkaline phosphatase, or bilirubin >1.5
times normal range)

3. Abnormal renal function tests (BUN or creatinine >1.5 times normal range)

4. Low serum albumin (<3 g/dL)

5. Uncontrolled thyroid disease as evident from abnormal TSH level

6. High CRP (> 5), except those evaluated for IBD and IBD is ruled out through
colonoscopy, CT or additional tests

7. Insulin-requiring and/or poorly controlled diabetes (well-controlled diabetics with
HbA1c <7 may be enrolled)

Exclusion- History

8. Patient history of GI diseases (except for hemorrhoids or occasional (<3 times a
week) heartburn)

1. Inflammatory bowel disease (Ex: ulcerative colitis, crohn's disease, any
colitis)

2. Celiac disease

3. Colonic inertia (lazy/slow colon resulting in surgery, resection or daily
laxatives)

4. Diverticular stricture (narrowing of the colon)

9. Antibiotic use within last 4 weeks

10. Severe uncontrolled hypertension

11. Significant uncompensated cardiac or respiratory diseases (defined as requiring daily
medication for management of their diseases (Ex: on oxygen or can't walk))

12. Prior extensive intestinal resection

13. History of psychiatric hospitalization OR suicide attempt in the last 5 years

14. Drug and/or alcohol abuse

15. Plan to have a major change of their dietary habit during the following 5 months

16. Drug induced constipation (Ex: opiates)

17. Pregnant or lactating

18. Use of narcotic medications (pain killers, Ex: hydrocodone, methadone, morphine,
oxycodone or tramadol) or anticoagulant/antiplatelet agents (ex: heparin, warfarin ,
dabigitran., Coumadin)

19. If the subject is older than 50 years of age, subjects who have not had a colonoscopy
within last 7 years or CT colonography within last 5 years to rule out colon cancer

20. Alarm symptoms of colon cancer such as:

1. Weight loss (>10% unintentional loss of body weight in last 6 months)

2. Blood in the stool (except for clearly documented hemorrhoidal bleed OR
colonoscopy excluding colon cancer within the last year for blood in the stool)

3. Anemia (without a full work-up, including a colonoscopy or other tests deemed
important)

21. Continued chronic and daily use of prescription laxatives (Ex: Amitiza or Linzess/
linaclotide in the last month)

22. Loose or watery stools > than 3 times per week

23. History of fecal impaction requiring disimpaction in the last 3 months

24. History of laxative abuse (Ex: eating disorders)

25. Use of medications that affect gastrointestinal motility (i.e. resolor, domperidone,
reglan, cisapride, anticolonergic drugs, tricyclic antidepressant [Ex: Amitriptyline,
Amoxapine, anafranil, asendin, elavil, norpramin/desipramine, doxepin,
pamelor/nortriptyline, sinequan, surmontil/trimipramine, tofranil/imipramine or
vivactil/protriptyline]) SSRI's are OK

26. Documented untreated pelvic floor dysfunction

27. Colonic organic diseases such as:

1. Current colonic cancer or strictures

2. Connective tissue disease (ex: scleroderma, lupus)

3. Other neurological disorders leading to chronic constipation (Ex: Parkinson's or
multiple sclerosis)

28. Dietary intake exceptionally high in plant-based, high fiber foods, including those
following a strict vegetarian diet (high fiber foods: fruits, vegetables, beans,
whole grains, fortified foods)

29. Consumption of probiotics, prebiotics, or synbiotics without an appropriate 2-week
washout period (Ex: Activia, FiberOne products, probiotics supplements such as Align,
Pearls, or fiber/prebiotic supplements such as Metamucil, Benefiber, Citrucel, Fiber
Choice, Fiber Powder)

30. Intention of using fiber products during the study (other than the study supplement)

31. Known food allergies or hypersensitivities (Ex: the components of psyllium or NTX-1
(corn))

32. Have a colonoscopy done within the next 5 months

Exclusion- Screening Diary 32. Use of laxatives more than twice in the screening period
(The following are the ONLY laxatives the subject is allowed to use during the screening
period: Ex-lax, senna, miralax and milk of magnesia) 33. Have not completed 11 out of 14
days of symptoms diary at screening 34. Have an average daily IBS-C global symptom score
of <2 in the screening period 35. Average Bristol stool scale of more than 4 within the
screening period 36. Loose or watery stools with Bristol stool scale of 5 or greater for a
total of 6 or more days during the screening period 37. Use of fiber products during the
screening period