Efficacy and Safety of Rifaximin With NAC in IBS-D

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

Sponsors

Lead Sponsor: Cedars-Sinai Medical Center

Collaborator: Bausch Health Ireland Limited

Source Cedars-Sinai Medical Center
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.

Overall Status Not yet recruiting
Start Date September 2020
Completion Date June 2021
Primary Completion Date December 2020
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Change in stool form and in stool frequency 12 months
Change in abdominal pain 12 months
Secondary Outcome
Measure Time Frame
Change in urgency 12 months
Changes in bloating 12 months
Changes of Hydrogen on lactulose hydrogen breath test 12 months
Enrollment 45
Condition
Intervention

Intervention Type: Drug

Intervention Name: Rifaximin

Description: Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

Other Name: xifaxan

Intervention Type: Drug

Intervention Name: N-acetylcysteine

Description: N-acetylcysteine (NAC) is a clinically approved mucolytic agent.

Arm Group Label: Traveler's diarrhea dose + NAC

Other Name: NAC

Intervention Type: Drug

Intervention Name: Placebo

Description: 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.

Arm Group Label: Traveler's diarrhea dose + placebo

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: 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

Gender: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Mark Pimentel, MD Study Director Cedars-Sinai Medical Center
Overall Contact

Last Name: MAST Program

Phone: (310) 423-0617

Email: [email protected]

Location
Facility: Contact: Investigator: Cedars-Sinai Medical Center Christine Chang, RN 310-423-7068 [email protected] Nipaporn Pichetshote, MD Principal Investigator
Location Countries

United States

Verification Date

September 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Cedars-Sinai Medical Center

Investigator Full Name: Nipaporn Pichetshote

Investigator Title: Assistant Medical Director, GI Motility Clinic

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Standard dose for IBS-D

Type: Active Comparator

Description: Rifaximin 550 mg

Label: Traveler's diarrhea dose + placebo

Type: Placebo Comparator

Description: Rifaximin 200 mg + placebo

Label: Traveler's diarrhea dose + NAC

Type: Experimental

Description: Rifaximin 200 mg plus N-acetylcysteine (NAC) 600 mg days

Study Design Info

Allocation: Randomized

Intervention Model: Factorial Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov