A Phase 1/2 interventional study of Rifaximin and N-acetylcysteine in Irritable Bowel Syndrome With Diarrhea, sponsored by Cedars-Sinai Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2023-03-28.
Sponsored by Cedars-Sinai Medical Center · Phase 1/2, Interventional, and Treatment
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.
Cedars-Sinai Medical Center is the lead sponsor of 455 studies on the registry; 108 are open to participants now.
Of its 65 completed or terminated interventional studies of FDA-regulated products, 49 (75%) have results posted.
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Onset of clinical symptoms for IBS-D occurring at least 6 months and, in order to progress to treatment phase, meet the following:
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:
Exclusion Criteria:
Rifaximin 550 mg
Drug: Rifaximin
Rifaximin 200 mg + placebo
Drug: Rifaximin · Drug: Placebo
Rifaximin 200 mg plus N-acetylcysteine (NAC) 600 mg days
Drug: Rifaximin · Drug: N-acetylcysteine
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Also known as: xifaxan
N-acetylcysteine (NAC) is a clinically approved mucolytic agent.
Also known as: NAC
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.
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)
Time frame: 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)
Time frame: 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)
Time frame: value at 6 weeks minus value at baseline
| Milestone | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC |
|---|---|---|---|
| Started | 15 | 15 | 15 |
| Completed | 15 | 15 | 15 |
| Not completed | 0 | 0 | 0 |
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)
| score on a scale | Rifaximin 550 mg | Rifaximin 200 mg + Placebo | Rifaximin 200 mg Plus N-acetylcysteine (NAC) 600 mg Days |
|---|---|---|---|
| Change in Stool Form | -0.26 ± 0.69 | -0.45 ± 0.86 | -0.49 ± 0.72 |
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)
| units on a scale | Rifaximin 550 mg | Rifaximin 200 mg + Placebo | Rifaximin 200 mg Plus N-acetylcysteine (NAC) 600 mg Days |
|---|---|---|---|
| Change in Abdominal Pain | -5.43 ± 13.91 | -8.90 ± 21.42 | -5.59 ± 15.99 |
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)
| number of bowel movements | Rifaximin 550 mg | Rifaximin 200 mg + Placebo | Rifaximin 200 mg Plus N-acetylcysteine (NAC) 600 mg Days |
|---|---|---|---|
| Change in Stool Frequency | -0.04 ± 0.64 | -0.50 ± 1.50 | -0.24 ± 0.80 |
Collected over 6 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rifaximin 550 mg | 0/15 (0%) | 0/15 (0%) | 1/15 (6.7%) |
| Rifaximin 200 mg + Placebo | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) |
| Rifaximin 200 mg Plus N-acetylcysteine (NAC) 600 mg Days | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) |
| Event | Rifaximin 550 mg | Rifaximin 200 mg + Placebo | Rifaximin 200 mg Plus N-acetylcysteine (NAC) 600 mg Days |
|---|---|---|---|
| Bloating & ConstipationGastrointestinal disorders | 1/15 | 0/15 | 0/15 |
| Nausea and vomitingGastrointestinal disorders | 0/15 | 1/15 | 0/15 |
| Headache and nauseaGastrointestinal disorders | 0/15 | 1/15 | 0/15 |
| Burning in esophagusGastrointestinal disorders | 0/15 | 0/15 | 1/15 |
| urinary tract infectionInfections and infestations | 0/15 | 0/15 | 1/15 |
| Age, Categorical(Participants) | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 15 | 15 | 15 | 45 |
| >=65 years | 0 | 0 | 0 | 0 |
| Age, Continuous(years) | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC | Total |
|---|---|---|---|---|
| Mean | 48 ± 17 | 44 ± 14 | 47 ± 13 | 45.89 ± 15.03 |
| Sex: Female, Male(Participants) | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC | Total |
|---|---|---|---|---|
| Female | 10 | 12 | 7 | 29 |
| Male | 5 | 3 | 8 | 16 |
| Race (NIH/OMB)(Participants) | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 1 | 1 | 1 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 14 | 12 | 13 | 39 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 2 | 1 | 3 |
| Region of Enrollment(participants) | Standard Dose for IBS-D | Traveler's Diarrhea Dose + Placebo | Traveler's Diarrhea Dose + NAC | Total |
|---|---|---|---|---|
| United States | 15 | 15 | 15 | 45 |
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Studies of the drug tested here: Acetylcysteine