Efficacy and Safety of Rifaximin With NAC in IBS-D

Irritable Bowel Syndrome With Diarrhea Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04557215
• Other study ID #: 550
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 13, 2020
• Est. completion date: October 30, 2022

Study information

• Verified date: March 2023
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: October 30, 2022
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diarrhea
• Irritable Bowel Syndrome
• Irritable Bowel Syndrome With Diarrhea
• Syndrome

Intervention

Drug:
• Rifaximin
Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
• N-acetylcysteine
N-acetylcysteine (NAC) is a clinically approved mucolytic agent.
• 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.

Locations

Country	Name	City	State
United States	Cedars-Sinai Medical Center	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center	Bausch Health Ireland Limited

Country where clinical trial is conducted

United States, 

References & Publications (49)

Bassotti G, Villanacci V, Maurer CA, Fisogni S, Di Fabio F, Cadei M, Morelli A, Panagiotis T, Cathomas G, Salerni B. The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut. 2006 Jan;55(1):41-6. doi: 10.1136/gut.2005.073197. Epub 2005 Jul 24. — View Citation

Cuoco L, Salvagnini M. Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin. Minerva Gastroenterol Dietol. 2006 Mar;52(1):89-95. — View Citation

Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence mechanisms at supra- and sub-inhibitory concentrations. J Chemother. 2008 Apr;20(2):186-94. doi: 10.1179/joc.2008.20.2.186. — View Citation

Ermund A, Schutte A, Johansson ME, Gustafsson JK, Hansson GC. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am J Physiol Gastrointest Liver Physiol. 2013 Sep 1;305(5):G341-7. doi: 10.1152/ajpgi.00046.2013. Epub 2013 Jul 5. — View Citation

Eshraghi A, Maldonado-Arocho FJ, Gargi A, Cardwell MM, Prouty MG, Blanke SR, Bradley KA. Cytolethal distending toxin family members are differentially affected by alterations in host glycans and membrane cholesterol. J Biol Chem. 2010 Jun 11;285(24):18199-207. doi: 10.1074/jbc.M110.112912. Epub 2010 Apr 12. — View Citation

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. — View Citation

Frisk A, Lebens M, Johansson C, Ahmed H, Svensson L, Ahlman K, Lagergard T. The role of different protein components from the Haemophilus ducreyi cytolethal distending toxin in the generation of cell toxicity. Microb Pathog. 2001 Jun;30(6):313-24. doi: 10.1006/mpat.2000.0436. — View Citation

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. — View Citation

Giamarellos-Bourboulis EJ, Pyleris E, Barbatzas C, Pistiki A, Pimentel M. Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage. BMC Gastroenterol. 2016 Jul 11;16(1):67. doi: 10.1186/s12876-016-0484-6. — View Citation

Ji S, Park H, Lee D, Song YK, Choi JP, Lee SI. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol. 2005 Mar;20(3):381-6. doi: 10.1111/j.1440-1746.2005.03574.x. — View Citation

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. — View Citation

Johansson ME, Sjovall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):352-61. doi: 10.1038/nrgastro.2013.35. Epub 2013 Mar 12. — View Citation

Lackner JM, Gudleski GD, Zack MM, Katz LA, Powell C, Krasner S, Holmes E, Dorscheimer K. Measuring health-related quality of life in patients with irritable bowel syndrome: can less be more? Psychosom Med. 2006 Mar-Apr;68(2):312-20. doi: 10.1097/01.psy.0000204897.25745.7c. — View Citation

Leite GGS, Morales W, Weitsman S, Celly S, Parodi G, Mathur R, Sedighi R, Barlow GM, Rezaie A, Pimentel M. Optimizing microbiome sequencing for small intestinal aspirates: validation of novel techniques through the REIMAGINE study. BMC Microbiol. 2019 Nov 1;19(1):239. doi: 10.1186/s12866-019-1617-1. — View Citation

Lembo A, Pimentel M, Rao SS, Schoenfeld P, Cash B, Weinstock LB, Paterson C, Bortey E, Forbes WP. Repeat Treatment With Rifaximin Is Safe and Effective in Patients With Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterology. 2016 Dec;151(6):1113-1121. doi: 10.1053/j.gastro.2016.08.003. Epub 2016 Aug 13. — View Citation

Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012 Jul;10(7):712-721.e4. doi: 10.1016/j.cgh.2012.02.029. Epub 2012 Mar 15. — View Citation

Lupascu A, Gabrielli M, Lauritano EC, Scarpellini E, Santoliquido A, Cammarota G, Flore R, Tondi P, Pola P, Gasbarrini G, Gasbarrini A. Hydrogen glucose breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel syndrome. Aliment Pharmacol Ther. 2005 Dec;22(11-12):1157-60. doi: 10.1111/j.1365-2036.2005.02690.x. — View Citation

Majewski M, McCallum RW. Results of small intestinal bacterial overgrowth testing in irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med Sci. 2007;52:139-42. — View Citation

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. — View Citation

Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, Perona M. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 2005 Jul;129(1):98-104. doi: 10.1053/j.gastro.2005.04.012. — View Citation

Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A Review on Various Uses of N-Acetyl Cysteine. Cell J. 2017 Apr-Jun;19(1):11-17. doi: 10.22074/cellj.2016.4872. Epub 2016 Dec 21. — View Citation

Neal KR, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a six year follow up study. Gut. 2002 Sep;51(3):410-3. doi: 10.1136/gut.51.3.410. — View Citation

Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol. 2004 Sep;99(9):1774-8. doi: 10.1111/j.1572-0241.2004.30435.x. — View Citation

Ordog T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes. 2000 Oct;49(10):1731-9. doi: 10.2337/diabetes.49.10.1731. — View Citation

Oriano M, Terranova L, Teri A, Sottotetti S, Ruggiero L, Tafuro C, Marchisio P, Gramegna A, Amati F, Nava F, Franceschi E, Cariani L, Blasi F, Aliberti S. Comparison of different conditions for DNA extraction in sputum - a pilot study. Multidiscip Respir Med. 2019 Jan 31;14:6. doi: 10.1186/s40248-018-0166-z. eCollection 2019. — View Citation

Pickett CL, Whitehouse CA. The cytolethal distending toxin family. Trends Microbiol. 1999 Jul;7(7):292-7. doi: 10.1016/s0966-842x(99)01537-1. — View Citation

Pimentel M, Chatterjee S, Chow EJ, Park S, Kong Y. Neomycin improves constipation-predominant irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: subanalysis of a double-blind randomized controlled study. Dig Dis Sci. 2006 Aug;51(8):1297-301. doi: 10.1007/s10620-006-9104-6. Epub 2006 Jul 11. — View Citation

Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000 Dec;95(12):3503-6. doi: 10.1111/j.1572-0241.2000.03368.x. — View Citation

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. — View Citation

Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22-32. doi: 10.1056/NEJMoa1004409. — View Citation

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. — View Citation

Pimentel M, Morales W, Pokkunuri V, Brikos C, Kim SM, Kim SE, Triantafyllou K, Weitsman S, Marsh Z, Marsh E, Chua KS, Srinivasan S, Barlow GM, Chang C. Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model. Dig Dis Sci. 2015 May;60(5):1195-205. doi: 10.1007/s10620-014-3435-5. Epub 2014 Nov 26. — View Citation

Pimentel M, Morales W, Rezaie A, Marsh E, Lembo A, Mirocha J, Leffler DA, Marsh Z, Weitsman S, Chua KS, Barlow GM, Bortey E, Forbes W, Yu A, Chang C. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS One. 2015 May 13;10(5):e0126438. doi: 10.1371/journal.pone.0126438. eCollection 2015. — View Citation

Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006 Oct 17;145(8):557-63. doi: 10.7326/0003-4819-145-8-200610170-00004. — View Citation

Posserud I, Stotzer PO, Bjornsson ES, Abrahamsson H, Simren M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007 Jun;56(6):802-8. doi: 10.1136/gut.2006.108712. Epub 2006 Dec 5. — View Citation

Purdy D, Buswell CM, Hodgson AE, McALPINE K, Henderson I, Leach SA. Characterisation of cytolethal distending toxin (CDT) mutants of Campylobacter jejuni. J Med Microbiol. 2000 May;49(5):473-479. doi: 10.1099/0022-1317-49-5-473. — View Citation

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. — View Citation

Rumessen JJ. Ultrastructure of interstitial cells of Cajal at the colonic submuscular border in patients with ulcerative colitis. Gastroenterology. 1996 Dec;111(6):1447-55. doi: 10.1016/s0016-5085(96)70005-7. — View Citation

Sadowska AM, Verbraecken J, Darquennes K, De Backer WA. Role of N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006;1(4):425-34. doi: 10.2147/copd.2006.1.4.425. — View Citation

Shah ED, Basseri RJ, Chong K, Pimentel M. Abnormal breath testing in IBS: a meta-analysis. Dig Dis Sci. 2010 Sep;55(9):2441-9. doi: 10.1007/s10620-010-1276-4. Epub 2010 May 14. — View Citation

Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol. 2006 Feb;101(2):326-33. doi: 10.1111/j.1572-0241.2006.00458.x. — View Citation

Shenker BJ, Hoffmaster RH, Zekavat A, Yamaguchi N, Lally ET, Demuth DR. Induction of apoptosis in human T cells by Actinobacillus actinomycetemcomitans cytolethal distending toxin is a consequence of G2 arrest of the cell cycle. J Immunol. 2001 Jul 1;167(1):435-41. doi: 10.4049/jimmunol.167.1.435. — View Citation

Smith JL, Bayles DO. The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol. 2006 Oct-Dec;32(4):227-48. doi: 10.1080/10408410601023557. — View Citation

Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000 Dec;47(6):804-11. doi: 10.1136/gut.47.6.804. — View Citation

Streutker CJ, Huizinga JD, Campbell F, Ho J, Riddell RH. Loss of CD117 (c-kit)- and CD34-positive ICC and associated CD34-positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction. Am J Surg Pathol. 2003 Feb;27(2):228-35. doi: 10.1097/00000478-200302000-00012. — View Citation

The burden of gasterointestinal diseases. In: American Gastroenterological Association; 2001; Bethesda, MD; 2001.

Thompson WG. The functional gasterointestinal bowel disorders. In: Drossman DA, editor. The functional gaterointestinal disorders. Boston: Little, Brown; 1994. p. pp-117-134.

Torihashi S, Ward SM, Nishikawa S, Nishi K, Kobayashi S, Sanders KM. c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res. 1995 Apr;280(1):97-111. doi: 10.1007/BF00304515. — View Citation

Vanderwinden JM, Liu H, De Laet MH, Vanderhaeghen JJ. Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis. Gastroenterology. 1996 Aug;111(2):279-88. doi: 10.1053/gast.1996.v111.pm8690192. Erratum In: Gastroenterology 1996 Nov;111(5):1403. — View Citation

* Note: There are 49 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	value at 6 weeks minus value at baseline
Primary	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)	value at 6 weeks minus value at baseline
Primary	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)	value at 6 weeks minus value at baseline