Study Results
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Recruitment Status
COMPLETED
Clinical Phase
PHASE1/PHASE2
Total Enrollment
45 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-11-13
Study Completion Date
2022-10-30
Brief Summary
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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.
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Detailed Description
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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.
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.
Conditions
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Irritable Bowel Syndrome With Diarrhea
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
FACTORIAL
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Standard dose for IBS-D
Rifaximin 550 mg
Group Type
ACTIVE_COMPARATOR
Rifaximin
Intervention Type
DRUG
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Traveler's diarrhea dose + placebo
Rifaximin 200 mg + placebo
Group Type
PLACEBO_COMPARATOR
Rifaximin
Intervention Type
DRUG
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Placebo
Intervention Type
DRUG
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.
Traveler's diarrhea dose + NAC
Rifaximin 200 mg plus N-acetylcysteine (NAC) 600 mg days
Group Type
EXPERIMENTAL
Rifaximin
Intervention Type
DRUG
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
N-acetylcysteine
Intervention Type
DRUG
N-acetylcysteine (NAC) is a clinically approved mucolytic agent.
Interventions
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Rifaximin
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
Intervention Type
DRUG
N-acetylcysteine
N-acetylcysteine (NAC) is a clinically approved mucolytic agent.
Intervention Type
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.
Intervention Type
DRUG
Other Intervention Names
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xifaxan
NAC
Eligibility Criteria
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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".
* 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
* 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
Minimum Eligible Age
18 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Bausch Health Ireland Limited
INDUSTRY
Sponsor Role
collaborator
Cedars-Sinai Medical Center
OTHER
Sponsor Role
lead
Responsible Party
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Bianca Chang
GI Motility Clinic
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Mark Pimentel, MD
Role: STUDY_DIRECTOR
Cedars-Sinai Medical Center
Locations
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Cedars-Sinai Medical Center
Los Angeles, California, United States
Site Status
Countries
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United States
References
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Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003 Feb;98(2):412-9. doi: 10.1111/j.1572-0241.2003.07234.x.
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Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012 May;57(5):1321-9. doi: 10.1007/s10620-012-2033-7. Epub 2012 Jan 20.
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Jiang ZD, DuPont HL. Rifaximin: in vitro and in vivo antibacterial activity--a review. Chemotherapy. 2005;51 Suppl 1:67-72. doi: 10.1159/000081991.
Reference Type
BACKGROUND
Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Ther. 2005 Apr;3(2):201-11. doi: 10.1586/14787210.3.2.201.
Reference Type
BACKGROUND
Fodor AA, Pimentel M, Chey WD, Lembo A, Golden PL, Israel RJ, Carroll IM. Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome. Gut Microbes. 2019;10(1):22-33. doi: 10.1080/19490976.2018.1460013. Epub 2018 Jul 18.
Reference Type
BACKGROUND
Pimentel M, Lembo A. Microbiome and Its Role in Irritable Bowel Syndrome. Dig Dis Sci. 2020 Mar;65(3):829-839. doi: 10.1007/s10620-020-06109-5.
Reference Type
BACKGROUND
Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R. Bowel Disorders. Gastroenterology. 2016 Feb 18:S0016-5085(16)00222-5. doi: 10.1053/j.gastro.2016.02.031. Online ahead of print.
Reference Type
BACKGROUND
Villanueva-Millan MJ, Leite G, Wang J, Morales W, Parodi G, Pimentel ML, Barlow GM, Mathur R, Rezaie A, Sanchez M, Ayyad S, Cohrs D, Chang C, Rashid M, Hosseini A, Fiorentino A, Weitsman S, Chuang B, Chang B, Pichetshote N, Pimentel M. Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes. Am J Gastroenterol. 2022 Dec 1;117(12):2055-2066. doi: 10.14309/ajg.0000000000001997. Epub 2022 Sep 6.
Reference Type
DERIVED
Pimentel M, Mathur R, Wang J, Chang C, Hosseini A, Fiorentino A, Rashid M, Pichetshote N, Basseri B, Treyzon L, Chang B, Leite G, Morales W, Weitsman S, Kraus A, Rezaie A. A Smartphone Application Using Artificial Intelligence Is Superior To Subject Self-Reporting When Assessing Stool Form. Am J Gastroenterol. 2022 Jul 1;117(7):1118-1124. doi: 10.14309/ajg.0000000000001723. Epub 2022 Mar 14.
Reference Type
DERIVED
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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550
Identifier Type: -
Identifier Source: org_study_id
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