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Efficacy and Safety of Rifaximin With NAC in IBS-D

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04557215
Recruitment Status : Recruiting
First Posted : September 21, 2020
Last Update Posted : December 4, 2020
Bausch Health Ireland Limited
Information provided by (Responsible Party):
Nipaporn Pichetshote, 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.

Condition or disease Intervention/treatment Phase
Irritable Bowel Syndrome With Diarrhea Drug: Rifaximin Drug: N-acetylcysteine Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : November 13, 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diarrhea

Arm Intervention/treatment
Active Comparator: Standard dose for IBS-D
Rifaximin 550 mg
Drug: Rifaximin
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Other Name: xifaxan

Placebo Comparator: Traveler's diarrhea dose + placebo
Rifaximin 200 mg + placebo
Drug: Rifaximin
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Other Name: xifaxan

Drug: Placebo
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.

Experimental: Traveler's diarrhea dose + NAC
Rifaximin 200 mg plus N-acetylcysteine (NAC) 600 mg days
Drug: Rifaximin
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Other Name: xifaxan

Drug: N-acetylcysteine
N-acetylcysteine (NAC) is a clinically approved mucolytic agent.
Other Name: NAC

Primary Outcome Measures :
  1. Change in stool form and in stool frequency [ Time Frame: 12 months ]
    Change in stool form and in stool frequency from baseline, as determined from stool diary data comparing Rifaximin alone vs rifaximin and NAC

  2. Change in abdominal pain [ Time Frame: 12 months ]
    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 severe pain to capture abdominal pain score.

Secondary Outcome Measures :
  1. Change in urgency [ Time Frame: 12 months ]
    Change in urgency from baseline, as determined from weekly average VAS scores, relative to Rifaximin alone. VAS scale allows subject to choose 0 for no urgency to 100 severe urgency to capture urgency score.

  2. Changes in bloating [ Time Frame: 12 months ]
    Changes in bloating from baseline, as determined from weekly average VAS scores, relative to Rifaximin alone. VAS scale allows subject to choose 0 for no bloating to 100 severe bloating to capture bloating score.

  3. Changes of Hydrogen on lactulose hydrogen breath test [ Time Frame: 12 months ]
    Reduction of Hydrogen on lactulose hydrogen breath test (LHBT) from baseline, relative to Rifaximin alone

Other Outcome Measures:
  1. Changes in microbiome profile [ Time Frame: 12 months ]
    Changes in microbiome profiles from baseline, as determined by 16S rRNA gene sequencing

  2. Normalization of stool scores from baseline [ Time Frame: 12 months ]
    Normalization of Bristol stool scores from baseline to standardize stool photos using artificial intelligence (Dieta app).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04557215

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Contact: MAST Program (310) 423-0617

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United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Christine Chang, RN    310-423-7068   
Principal Investigator: Nipaporn Pichetshote, MD         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Bausch Health Ireland Limited
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Study Director: Mark Pimentel, MD Cedars-Sinai Medical Center
Thompson WG. The functional gasterointestinal bowel disorders. In: Drossman DA, editor. The functional gaterointestinal disorders. Boston: Little, Brown; 1994. p. pp-117-134.
The burden of gasterointestinal diseases. In: American Gastroenterological Association; 2001; Bethesda, MD; 2001.
Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393

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Responsible Party: Nipaporn Pichetshote, Assistant Medical Director, GI Motility Clinic, Cedars-Sinai Medical Center Identifier: NCT04557215    
Other Study ID Numbers: 550
First Posted: September 21, 2020    Key Record Dates
Last Update Posted: December 4, 2020
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nipaporn Pichetshote, Cedars-Sinai Medical Center:
Irritable Bowel Syndrome with Diarrhea
Additional relevant MeSH terms:
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Irritable Bowel Syndrome
Pathologic Processes
Signs and Symptoms, Digestive
Colonic Diseases, Functional
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Antiviral Agents
Anti-Infective Agents
Respiratory System Agents
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Anti-Bacterial Agents
Gastrointestinal Agents