Efficacy and Safety of Rifaximin With NAC in IBS-D
Efficacy and Safety of Rifaximin With NAC in IBS-D
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.
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.
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:

 1. 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.

 2. 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:

 1. Double barrier methods (condom with spermicidal jelly or a diaphragm with
 spermicide),

 2. Hormonal methods (e. g. oral contraceptives, patches or medroxyprogesterone
 acetate),

 3. An intrauterine device (IUD) with a documented failure rate of less than 1% per
 year.

 4. Abstinence or partner(s) with a vasectomy may be considered an acceptable method
 of contraception at the discretion of the investigator.

 5. 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