The purpose of this study is to examine the effectiveness of using a combination of a drug, rifaximin and a dietary supplement, N-acetyl-L-cysteine (NAC), to treat patients with irritable bowel syndrome with diarrhea (IBS-D). Rifaximin is one of the standard treatments for IBS-D and is FDA approved. While rifaximin is safe and effective for treating symptoms in patients with IBS-D, many patients find that their symptoms may not completely resolve, or may come back after a period of time.

This research study is designed to test the investigational use of a combination of rifaximin and NAC. The combination of rifaximin and NAC is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of IBS-D, and the effects of taking both medications together are unknown. However, the two medications are approved for use separately, as detailed below.

Rifaximin is the only antibiotic approved by the FDA for the treatment of IBS-D. Rifaximin (at a dose of 550 mg by mouth three times daily for 14 days) is approved by the FDA for the treatment of IBS-D. Rifaximin (at a dose of 200 mg per mouth three times daily for 3 days) is FDA approved for the treatment of traveler's diarrhea. Rifaximin at a dose of 200 mg per mouth three times daily is not approved by the FDA for the treatment of IBS-D.

NAC is approved by the FDA to treat acetaminophen overdose (72-hour oral and 21-hour intravenous (IV) regimens), and for use in breaking up mucus in the lungs in patients with chronic obstructive pulmonary disease (COPD) and other lung conditions such as bronchitis. NAC is also available over-the-counter in 600 mg and 900 mg capsules as a dietary supplement, although over-the-counter use is not regulated by the FDA. This study will utilize the 600 mg dietary supplement capsules.

The Investigators want to know if using a combination of rifaximin and NAC will give better results in decreasing IBS-D symptoms than using rifaximin alone. As NAC is used to break up mucus in the lungs, and the Investigators want to see if this can also break up the mucus layer in the small intestine, and therefore potentially increase the effectiveness of rifaximin. The Investigators will be testing 2 doses to determine which dose is most effective.

participants are being asked to take part in this research study because participants were diagnosed with IBS-D.

This is a phase 2b, multi-center, randomized, double-blind, placebocontrolled study of rifaximin in patients with IBS-D. Eligible patients will be randomized (1:1:1) to receive RNIB21 containing rifaximin 66mg + NAC 560mg TID; RNIB21 containing rifaximin 132mg + NAC 560mg TID; or placebo TID. The study will consist of the following phases: Screening Phase; Treatment Phase (Days 1 to 14) which includes the Randomization Visit (Day 1) and visits at Week 1 (Day 7 ± 2) and Week 2 (Day 14 ± 2); and a Follow-up Phase including an End of Study visit at Week 14 (Day 98 ± 3). REDCap, a web-based reporting system will be utilized to capture daily patient reported outcomes as regards abdominal pain and stool consistency. A subset of participating sites will be designated as Pharmacokinetics sites. In a blinded fashion 24 patients (8 from each treatment arm) will participate in PK sampling in order to establish a PK profile and PK parameters for both rifaximin and NAC. Serial blood samples will be collected following first dose and last dose to establish the PK profiles after a single dose, and multiple doses. The primary evaluation period (PEP) will be the 28 days following the completion of therapy. The primary outcome for the study will be adequate relief of IBS symptoms based on FDA guidance during this period, specifically: the proportion of patients who are responders to treatment in both IBS-related abdominal pain AND stool consistency during the 4-week PEP. A patient will be considered a weekly responder if there is adequate relief in their IBS-related symptoms, which is defined as a 30% or greater improvement from their baseline in the weekly average of worst abdominal pain in past 24 hours score AND at least 50% reduction in the number of days in a week with at least one stool that has a consistency of type 6 or 7 compared with their baseline. Responders have to meet both abdominal pain and stool consistency criteria for at least 2 of 4 weeks of the PEP. Abdominal pain will be self-reported on a daily basis using an 11-point (0-10) pain scale. Stool consistency will be self-reported daily by patients based on the Bristol Stool Scale. A smartphone app which captures stool image will be used as an seondary endpoint, and compared to the patients' self-reports of stool consistency recorded on the BSS.

Inclusion Criteria:

1. Male or non-pregnant, non-lactating female patients ≥ 18 years of age

2. Diagnosed with IBS confirmed by the Rome IV criteria, with associated symptoms of diarrhea as noted below in 4(b).

3. Do not have adequate relief of IBS symptoms of abdominal pain, stool consistency or stool frequency

4. Have daily IBS symptom scores during screening as below:

   1. Weekly average score of worst daily abdominal pain >3.0 on a 0-10 point scale
   2. At least one stool with a consistency of Type 6 or 7 on the Bristol

Exclusion Criteria:

1. Present with the following symptoms of IBS with constipation:

   1. Less than 3 bowel movements a week,
   2. Hard or lumpy stools, and
   3. Excessive straining during a bowel movement.

2. History of inflammatory bowel disease, celiac disease, GI surgery (except cholecystectomy and/or appendectomy)

3. Evidence of active duodenal ulcer, gastric ulcer, diverticulitis, or active infectious gastroenteritis

4. Current diagnosis of asthma

5. Current user of NAC and/or rifaximin

6. Systemic antibiotic use in the last month

7. Not currently on a prokinetic drug

8. A significant medical condition including but not limited to hepatic, uncontrolled diabetes, renal, cardiovascular, pulmonary, uncontrolled thyroid disease. or psychiatric disease, which in the opinion of investigator precludes study participation