Efficacy and Safety of Rifaximin With NAC in IBS-D

Study Overview
=================
Brief Summary
-----------------
Randomized, prospective proof of concept, double-blind, single site clinical trial to determine the efficacy of combined rifaximin and N-acetylcysteine (NAC) therapy vs. rifaximin alone in decreasing clinical symptoms in subjects with IBS-D.

Detailed Description
-----------------
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, affecting 11% of the world's population, and accounting for 50% of all gastrointestinal office visits. IBS can be a chronic, long-term condition, with up to 57% of subjects who otherwise had normal bowel function continuing to have altered bowel function for at least 6 years after recovering from the initial acute illness. As a result, the health care costs of IBS have been estimated at over $30 billion per year. Further, this results in serious quality of life implications, which have been likened to diabetes or heart disease, in young adults who should otherwise be productive and healthy. IBS is characterized by abdominal pain, cramping and bloating, accompanied by altered bowel habits. The major forms of IBS are diarrhea-predominant (IBS-D), constipation-predominant (IBS-C) and mixed IBS (IBS-M). There is significant bacterial involvement in IBS, particularly IBS-D. IBS-D can be precipitated by acute gastroenteritis, which is caused by infection with bacterial pathogens such as Escherichia coli, Salmonella, Shigella and Campylobacter jejuni. In addition, there is now overwhelming evidence that small intestinal bacterial overgrowth (SIBO) contributes to the symptoms of IBS-D. Therefore, antibiotic treatment has become a mainstay in the treatment of IBS. Of these, rifaximin is the only antibiotic currently approved by the FDA for the treatment of IBS-D. Rifaximin is an oral, broad-spectrum antimicrobial agent that is minimally absorbed (99.6% retained in the gut), targets the gastrointestinal tract, and associated with a low risk of clinically relevant bacterial antibiotic resistance. It is generally recognized as having no side effects in blinded comparisons that differ from placebo. In two identically designed, phase 3, double-blind, placebo-controlled trials of patients with IBS-D, 40.7% of patients treated with rifaximin 550 mg 3 times daily for 2 weeks experienced adequate relief of global IBS symptoms, compared with 31.7% of patients treated with placebo (P<0.001). In addition, a greater percentage of rifaximin-treated than placebo-treated patients reported durable improvement in IBS-D symptoms for at least 10 weeks post-treatment. It is well known that treatment of IBS-D with rifaximin is effective and now FDA-approved. However, only 44% of subjects improved with rifaximin treatment. Although what is unique about rifaximin is its 'one-and-done' treatment effect, this is only seen in 36% of subjects who respond to this drug. As such, there is room for improvement with rifaximin. In recent studies, we have shown that the most predominant bacteria in the bacterial overgrowth associated with IBS are E. coli and Klebsiella. Rifaximin is highly effective in treating these two organisms. However, we have since learned that the majority of these excessive organisms in IBS are found in the small intestinal mucus layer. Since rifaximin is not soluble in mucus, it cannot penetrate and affect bacteria within the mucus layer. Our hypothesis that the addition of a mucolytic like N-acetylcysteine (NAC) will allow the penetration of rifaximin into the mucus by first solubilizing rifaximin and secondly liquifying the mucus. This may allow for two important effects. One is a reduction in the necessary dose of rifaximin necessary to treat IBS, and the other is improved efficacy. Both of these will be tested in this trial. In this study, we propose to test whether combining rifaximin with a clinically approved mucolytic agent, NAC, can result in improvement in stool form and reduction in stool frequency, as well as improved relief of clinical symptoms, in subjects with IBS-D.

Official Title
-----------------
Evaluation of the Efficacy and Safety of Rifaximin in Combination With N-acetylcysteine (NAC) in Adult Patients With Irritable Bowel Syndrome With Diarrhea

Conditions
-----------------
Irritable Bowel Syndrome With Diarrhea

Intervention / Treatment
-----------------
* Drug: Rifaximin
* Drug: N-acetylcysteine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects aged 18-75 years old inclusive Onset of clinical symptoms for IBS-D occurring at least 6 months and, in order to progress to treatment phase, meet the following: Has abdominal pain, on average, ≥1 day per week in previous 3 months, associated with ≥2 of the following: (1) Related to defecation, (2) Associated with a change in stool frequency, or (3) Associated with a change in form (appearance) of stool. Fits Rome IV criteria for IBS with diarrhea (IBS-D), which is defined by >25% of abnormal bowel movements with Bristol stool form types 6 or 7 (loose, watery stool) and <25% of abnormal bowel movements with Bristol stool form types 1 or 2 (hard, lumpy stool). Colonoscopy must have been completed within the past 10 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 All subjects (male and female) shall 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), 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. 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. Exclusion Criteria: Use of any oral antibiotics in the last two months Subjects with history of intestinal surgery (except appendectomy or cholecystectomy) Subjects with known pelvic floor dysfunction Pregnancy Nursing mothers Poorly controlled/uncontrolled significant medical condition that would interfere with study procedures History of bowel obstruction History of inflammatory bowel disease or celiac disease History of HIV Cirrhosis IBS-C/chronic idiopathic constipation Poorly controlled diabetes or thyroid disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose for IBS-D<br>Rifaximin 550 mg | Drug: Rifaximin<br>* Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.<br>* Other names: xifaxan;|
| Placebo Comparator: Traveler's diarrhea dose + placebo<br>Rifaximin 200 mg + placebo | Drug: Rifaximin<br>* Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.<br>* Other names: xifaxan;Drug: Placebo<br>* An inactive substance or treatment that looks the same as, and is given in the same way as, an active drug or intervention/treatment being studied.<br>|
| Experimental: Traveler's diarrhea dose + NAC<br>Rifaximin 200 mg plus N-acetylcysteine (NAC) 600 mg days | Drug: Rifaximin<br>* Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.<br>* Other names: xifaxan;Drug: N-acetylcysteine<br>* N-acetylcysteine (NAC) is a clinically approved mucolytic agent.<br>* Other names: NAC;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Stool Form | Change in stool form from baseline, as determined from stool diary data comparing Rifaximin alone vs rifaximin and NAC The Bristol Stool Chart, the minimum value is 1 (means constipation) and maximum value is 7 (means diarrhea). The change between two time points is reported baseline and 4 weeks after cessation of treatment (at 6 weeks) | value at 6 weeks minus value at baseline | 
| Change in Abdominal Pain | Change in severity of abdominal pain from baseline, as determined from weekly average visual analog scale (VAS) scores, relative to Rifaximin alone. VAS scores allows subject to choose 0 for no pain to 100 pain as bad as it could possibly be. The Visual Analogue Scale (VAS) measures pain intensity. The VAS consists of a 10cm line, with two end points representing 0 no pain and 100 pain as bad as it could possibly be The change between two time points is reported baseline and 4 weeks after cessation of treatment (at 6 weeks) | value at 6 weeks minus value at baseline | 
| Change in Stool Frequency | Change in stool frequency from baseline, as determined from diary data comparing Rifaximin alone vs Rifaximin and NAC determined from daily stool diary data The change in bowel movements/day between two time points is reported baseline and 4 weeks after cessation of treatment (at 6 weeks) | value at 6 weeks minus value at baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Irritable Bowel Syndrome with Diarrhea, IBS-D, Rifaximin, N-acetylcysteine, NAC