Rifaximin's Effect on Covert Hepatic Encephalopathy With SIBO and Gastrointestinal Dysmotility
NCT ID: NCT04244877
Last Updated: 2025-12-24
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
WITHDRAWN
Clinical Phase
PHASE3
Study Classification
INTERVENTIONAL
Study Start Date
2021-09-15
Study Completion Date
2023-12-01
Brief Summary
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Small Intestinal Bacterial Overgrowth (SIBO) is a common and increasingly recognized disorder in cirrhosis (30% to 73%). One of the most important predisposing factors of SIBO is small bowel dysmotility. Multiple studies have shown that the presence of SIBO is strongly linked to the pathogenesis of Minimal Hepatic Encephalopathy (MHE) also known as Covert Hepatic Encephalopathy (CHE). Consequently, altering and modulating the intestinal microbiota with ammonia-lowering agents and Rifaximin has been the target treatment strategy in CHE. The aim of this study is to determine the therapeutic effect of Rifaximin on patients with CHE and underlying SIBO while assessing the influence of Rifaximin on small bowel motility. In this prospective interventional study, 40 patients with liver cirrhosis will be screened for Covert Hepatic Encephalopathy (CHE) using neuro-psychometric tests. Patients diagnosed with CHE will undergo breath test (BT) for SIBO screening. Afterwards, wireless motility capsule (The SmartPill) will be performed in all patients with a positive BT. Thereafter, the cirrhotic patients diagnosed with CHE and SIBO will receive Rifaximin 550 mg PO twice daily for eight weeks. At the end of treatment, neuro-psychometric tests will be repeated to evaluate the therapeutic effect on CHE. In addition, BT and SmartPill will be repeated at the completion of the Rifaximin treatment period to assess the effect on small bowel motility. All collected clinical parameters at the end of the study will be compared to baseline values.
Detailed Description
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Small intestinal bacterial overgrowth (SIBO) is a common and an increasingly recognized disorder in liver cirrhosis, correlating with its severity. The prevalence of SIBO, assessed by the quantification of the bacterial density in the small intestinal aspirate, ranges from 30% to 73%. Multiple physiological derangements leading to SIBO appear in cirrhosis from decreased secretion of gastric acid, impaired mucosal immune response to decreased bile acid, and more importantly, intestinal dysmotility. The latter remains the most common predisposing factor in the pathogenesis of bacterial overgrowth. A recent pilot study using a wireless motility capsule (the SmartPill) demonstrated that patients with cirrhosis have significant delays in small bowel transit that is more pronounced in those with more severe liver disease. Altered small bowel motility in cirrhosis has been attributed to autonomic dysfunction, altered levels of circulating neuropeptides and the effects of inflammatory mediators on gut muscle and the enteric nervous system.
Hepatic Encephalopathy (HE) is a spectrum of neuro-cognitive impairment in cirrhosis that range from abnormal neuropsychiatric testing without clinical evidence of disease (Minimal Hepatic Encephalopathy\[MHE\]) to varying degrees of overt clinical findings: Overt Hepatic Encephalopathy (OHE). MHE is found in 30-84% of patients with liver cirrhosis. The neuro-cognitive deficit noted in MHE could predispose patient to impaired quality of life (QOL) which translates into lower QOL scores, higher risk of falls, driving problems and difficulties maintaining employment. Previous studies have shown that SIBO is prevalent and strongly linked to the pathogenesis of MHE. Consequently, altering and modulating the intestinal microbiota with ammonia-lowering and gut-selective agents has been the target treatment strategy. Multiple prior studies have evaluated Rifaximin efficacy in MHE and have shown improvements across a variety of study clinical end points including neuropsychiatric and QOL tests. However, the precise mechanism of action of Rifaximin in MHE is unclear. The proposed mechanisms by which Rifaximin may lead to improvement of MHE may be beyond the bactericidal/bacteriostatic effect, resulting in changes in bacterial metabolic function/virulence, to an anti-inflammatory and immune-modulatory effect.
The investigators hypothesize that Rifaximin may have an additional effect on small bowel motility that may be independent of its effect on bacterial overgrowth. The effect may not be necessarily through changes in patient's microbiome but rather through a pro-motility mechanism. The investigators intend to test this hypothesis by comparing the motility at baseline in cirrhotic patients with MHE and clinically significant portal hypertension, before and after treatment of SIBO with Rifaximin.
Aims:
1. To determine the therapeutic effect of Rifaximin on patients with CHE and underlying SIBO and as it is related to small bowel motility.
2. To determine the effect of Rifaximin on small bowel motility by using the SmartPill.
Study Design:
This is a prospective and interventional study. It will be conducted at the Gastroenterology and Hepatology outpatient clinics of MetroHealth Medical Center/Case Western Reserve University. Approximately 40 patients with liver cirrhosis will be assessed for eligibility by their hepatologist. Eligible patients will be referred to an expert psychologist for neuro-psychometric testing to confirm CHE. Then the patients with diagnosed with CHE will undergo Glucose Hydrogen Breath Test (BT) for SIBO screening. Subsequently, wireless motility capsule (the SmartPill) for motility testing will be performed in all patients with positive BT. Thereafter, cirrhotic patients diagnosed with both CHE and SIBO will be prescribed Rifaximin 550 mg PO twice daily for eight weeks. At the end of the treatment period, neuro-psychometric tests will be repeated to evaluate the therapeutic effect on CHE. In addition, BT and the SmartPill will be repeated at the completion of the treatment period with Rifaximin in order to assess the effect on small bowel motility.
Hepatic Encephalopathy (HE) is a spectrum of neuro-cognitive impairment in cirrhosis that range from abnormal neuropsychiatric testing without clinical evidence of disease (Minimal Hepatic Encephalopathy\[MHE\]) to varying degrees of overt clinical findings: Overt Hepatic Encephalopathy (OHE). MHE is found in 30-84% of patients with liver cirrhosis. The neuro-cognitive deficit noted in MHE could predispose patient to impaired quality of life (QOL) which translates into lower QOL scores, higher risk of falls, driving problems and difficulties maintaining employment. Previous studies have shown that SIBO is prevalent and strongly linked to the pathogenesis of MHE. Consequently, altering and modulating the intestinal microbiota with ammonia-lowering and gut-selective agents has been the target treatment strategy. Multiple prior studies have evaluated Rifaximin efficacy in MHE and have shown improvements across a variety of study clinical end points including neuropsychiatric and QOL tests. However, the precise mechanism of action of Rifaximin in MHE is unclear. The proposed mechanisms by which Rifaximin may lead to improvement of MHE may be beyond the bactericidal/bacteriostatic effect, resulting in changes in bacterial metabolic function/virulence, to an anti-inflammatory and immune-modulatory effect.
The investigators hypothesize that Rifaximin may have an additional effect on small bowel motility that may be independent of its effect on bacterial overgrowth. The effect may not be necessarily through changes in patient's microbiome but rather through a pro-motility mechanism. The investigators intend to test this hypothesis by comparing the motility at baseline in cirrhotic patients with MHE and clinically significant portal hypertension, before and after treatment of SIBO with Rifaximin.
Aims:
1. To determine the therapeutic effect of Rifaximin on patients with CHE and underlying SIBO and as it is related to small bowel motility.
2. To determine the effect of Rifaximin on small bowel motility by using the SmartPill.
Study Design:
This is a prospective and interventional study. It will be conducted at the Gastroenterology and Hepatology outpatient clinics of MetroHealth Medical Center/Case Western Reserve University. Approximately 40 patients with liver cirrhosis will be assessed for eligibility by their hepatologist. Eligible patients will be referred to an expert psychologist for neuro-psychometric testing to confirm CHE. Then the patients with diagnosed with CHE will undergo Glucose Hydrogen Breath Test (BT) for SIBO screening. Subsequently, wireless motility capsule (the SmartPill) for motility testing will be performed in all patients with positive BT. Thereafter, cirrhotic patients diagnosed with both CHE and SIBO will be prescribed Rifaximin 550 mg PO twice daily for eight weeks. At the end of the treatment period, neuro-psychometric tests will be repeated to evaluate the therapeutic effect on CHE. In addition, BT and the SmartPill will be repeated at the completion of the treatment period with Rifaximin in order to assess the effect on small bowel motility.
Conditions
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Cirrhosis, Liver
Minimal Hepatic Encephalopathy
Small Intestinal Bacterial Overgrowth
Gastrointestinal Motility Disorder
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Rifaximin
Rifaximin 550 mg by mouth twice daily for eight weeks.
Group Type
EXPERIMENTAL
Rifaximin
Intervention Type
DRUG
Drug: Rifaximin tablet
Interventions
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Rifaximin
Drug: Rifaximin tablet
Intervention Type
DRUG
Other Intervention Names
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Xifaxan
Eligibility Criteria
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Inclusion Criteria
1. Cirrhosis patients between 18-89 years of age, without prior transjugular intrahepatic portosystemic shunt (TIPS) placement or prior overt hepatic encephalopathy.
2. Cirrhosis diagnosed on the basis of liver biopsy, liver stiffness measurement (Fibroscan) or radiological study.
3. CHE diagnosis using pre-defined criteria \[two of the following should be abnormal as compared to healthy controls: number connection test A/B (NCT-A/B), Digit Symbol Test (DST), or Block Design Test (BDT)\] at least 2 months prior to the start of the study (beyond 2 standard deviation of normal). Testing will be carried out by a trained psychologist.
2. Cirrhosis diagnosed on the basis of liver biopsy, liver stiffness measurement (Fibroscan) or radiological study.
3. CHE diagnosis using pre-defined criteria \[two of the following should be abnormal as compared to healthy controls: number connection test A/B (NCT-A/B), Digit Symbol Test (DST), or Block Design Test (BDT)\] at least 2 months prior to the start of the study (beyond 2 standard deviation of normal). Testing will be carried out by a trained psychologist.
Exclusion Criteria
1. Known allergy to rifaximin / rifabutin / rifampin.
2. Use of antibiotics within last 6 weeks
3. Use of lactulose / lactitol, probiotics, L-ornithine- L -aspartate, zinc, metronidazole, or neomycin, within last 6 weeks
4. Use of any drug known to affect gastro-intestinal motility within the previous 2 to 4 weeks (such as, Reglan, Erythromycin, or Domeperidone)
5. Use of drugs such as opiates and antidepressants (except stable doses of selective serotonin re-uptake inhibitors)
6. Patients deemed higher risk for capsule retention including a history of esophageal stricture or Zenker's diverticulum, partial or complete bowel obstruction, known fistulas, known large or numerous diverticula and dementia
7. Diseases associated with poor gastrointestinal motility such as uncontrolled diabetes (A1c \> 8%), rheumatological disorders (such as scleroderma and mixed connective tissue disorders \[MCT\])
8. History of gastrointestinal tract or abdominal surgery
9. Spontaneous peritonitis or other severe infections
10. Colonoscopy or enema treatment within 4 weeks
11. Hepatic encephalopathy with clinical signs
12. Inability to complete neuropsychiatric testing due to hearing loss, poor vision, etc.
13. Poorly compliant patients
14. Rifaximin - Pregnancy Category C- There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. Female study subjects of childbearing potential must have a negative pregnancy test and agree to use an acceptable method of contraception throughout the study. Participants that are breastfeeding are excluded.
15. Decompensated cirrhosis (i.e., history of variceal bleeding or ascites)
16. Total bilirubin = 2mg/dL or albumin \< 3.5g/dL or international normalized ratio (INR) \> 1.7
17. Patients with a calculated glomerular filtration rate (GFR) \< 60mL/min/1.73m2
18. Patients with severe hepatic impairment (Child-Pugh score \> 7)
19. Patients with untreated viral hepatitis
20. No prior episode of overt HE, not on therapy for overt HE, not on any psycho- active medications apart from stable doses of selective serotonin re-uptake inhibitors.
21. No concurrent use of P-glycoprotein inhibitors (e.g., cyclosporine)
22. Current abuse of alcohol or illicit drugs
2. Use of antibiotics within last 6 weeks
3. Use of lactulose / lactitol, probiotics, L-ornithine- L -aspartate, zinc, metronidazole, or neomycin, within last 6 weeks
4. Use of any drug known to affect gastro-intestinal motility within the previous 2 to 4 weeks (such as, Reglan, Erythromycin, or Domeperidone)
5. Use of drugs such as opiates and antidepressants (except stable doses of selective serotonin re-uptake inhibitors)
6. Patients deemed higher risk for capsule retention including a history of esophageal stricture or Zenker's diverticulum, partial or complete bowel obstruction, known fistulas, known large or numerous diverticula and dementia
7. Diseases associated with poor gastrointestinal motility such as uncontrolled diabetes (A1c \> 8%), rheumatological disorders (such as scleroderma and mixed connective tissue disorders \[MCT\])
8. History of gastrointestinal tract or abdominal surgery
9. Spontaneous peritonitis or other severe infections
10. Colonoscopy or enema treatment within 4 weeks
11. Hepatic encephalopathy with clinical signs
12. Inability to complete neuropsychiatric testing due to hearing loss, poor vision, etc.
13. Poorly compliant patients
14. Rifaximin - Pregnancy Category C- There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. Female study subjects of childbearing potential must have a negative pregnancy test and agree to use an acceptable method of contraception throughout the study. Participants that are breastfeeding are excluded.
15. Decompensated cirrhosis (i.e., history of variceal bleeding or ascites)
16. Total bilirubin = 2mg/dL or albumin \< 3.5g/dL or international normalized ratio (INR) \> 1.7
17. Patients with a calculated glomerular filtration rate (GFR) \< 60mL/min/1.73m2
18. Patients with severe hepatic impairment (Child-Pugh score \> 7)
19. Patients with untreated viral hepatitis
20. No prior episode of overt HE, not on therapy for overt HE, not on any psycho- active medications apart from stable doses of selective serotonin re-uptake inhibitors.
21. No concurrent use of P-glycoprotein inhibitors (e.g., cyclosporine)
22. Current abuse of alcohol or illicit drugs
Minimum Eligible Age
18 Years
Maximum Eligible Age
89 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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MetroHealth Medical Center
OTHER
Sponsor Role
lead
Responsible Party
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RONNIE FASS
Director, Division of Gastroenterology and Hepatology
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Ronnie Fass, MD
Role: PRINCIPAL_INVESTIGATOR
Metrohealth Medical Center/Case Western Reserve University
Countries
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United States
References
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Bauer TM, Schwacha H, Steinbruckner B, Brinkmann FE, Ditzen AK, Kist M, Blum HE. Diagnosis of small intestinal bacterial overgrowth in patients with cirrhosis of the liver: poor performance of the glucose breath hydrogen test. J Hepatol. 2000 Sep;33(3):382-6. doi: 10.1016/s0168-8278(00)80273-1.
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BACKGROUND
Giannelli V, Di Gregorio V, Iebba V, Giusto M, Schippa S, Merli M, Thalheimer U. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014 Dec 7;20(45):16795-810. doi: 10.3748/wjg.v20.i45.16795.
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BACKGROUND
Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver. Pathophysiological and clinical implications. J Hepatol. 2013 May;58(5):1020-7. doi: 10.1016/j.jhep.2012.11.023. Epub 2012 Nov 23. No abstract available.
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BACKGROUND
Thalheimer U, De Iorio F, Capra F, del Mar Lleo M, Zuliani V, Ghidini V, Tafi MC, Caburlotto G, Gennari M, Burroughs AK, Vantini I. Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study. Eur J Gastroenterol Hepatol. 2010 Oct;22(10):1228-34. doi: 10.1097/MEG.0b013e32833b4b03.
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BACKGROUND
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BACKGROUND
Chander Roland B, Garcia-Tsao G, Ciarleglio MM, Deng Y, Sheth A. Decompensated cirrhotics have slower intestinal transit times as compared with compensated cirrhotics and healthy controls. J Clin Gastroenterol. 2013 Nov-Dec;47(10):888-93. doi: 10.1097/MCG.0b013e31829006bb.
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BACKGROUND
Maheshwari A, Thuluvath PJ. Autonomic neuropathy may be associated with delayed orocaecal transit time in patients with cirrhosis. Auton Neurosci. 2005 Mar 31;118(1-2):135-9. doi: 10.1016/j.autneu.2005.02.003.
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Fein BI, Holt PR. Hepatobiliary complications of total parenteral nutrition. J Clin Gastroenterol. 1994 Jan;18(1):62-6. doi: 10.1097/00004836-199401000-00015.
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Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998 Jul;28(1):45-9. doi: 10.1002/hep.510280108.
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BACKGROUND
Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007 Mar;22(1):125-38. doi: 10.1007/s11011-006-9042-1.
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Randolph C, Hilsabeck R, Kato A, Kharbanda P, Li YY, Mapelli D, Ravdin LD, Romero-Gomez M, Stracciari A, Weissenborn K; International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int. 2009 May;29(5):629-35. doi: 10.1111/j.1478-3231.2009.02009.x. Epub 2009 Mar 19.
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Simren M, Stotzer PO. Use and abuse of hydrogen breath tests. Gut. 2006 Mar;55(3):297-303. doi: 10.1136/gut.2005.075127.
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BACKGROUND
Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. Gastroenterol Hepatol (N Y). 2011 Dec;7(12):795-804.
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BACKGROUND
Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther. 2009 Jun 15;29(12):1273-81. doi: 10.1111/j.1365-2036.2009.03994.x. Epub 2009 Mar 6.
Reference Type
RESULT
Zhang Y, Feng Y, Cao B, Tian Q. Effects of SIBO and rifaximin therapy on MHE caused by hepatic cirrhosis. Int J Clin Exp Med. 2015 Feb 15;8(2):2954-7. eCollection 2015.
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RESULT
Gupta A, Dhiman RK, Kumari S, Rana S, Agarwal R, Duseja A, Chawla Y. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol. 2010 Nov;53(5):849-55. doi: 10.1016/j.jhep.2010.05.017. Epub 2010 Jul 17.
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RESULT
Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol. 2011 Feb;106(2):307-16. doi: 10.1038/ajg.2010.455. Epub 2010 Dec 14.
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RESULT
Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, Hafeezullah M, Bell DE, Sterling RK, Stravitz RT, Fuchs M, Luketic V, Sanyal AJ. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011 Feb;140(2):478-487.e1. doi: 10.1053/j.gastro.2010.08.061. Epub 2010 Sep 21.
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RESULT
Allampati S, Duarte-Rojo A, Thacker LR, Patidar KR, White MB, Klair JS, John B, Heuman DM, Wade JB, Flud C, O'Shea R, Gavis EA, Unser AB, Bajaj JS. Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp: A Multicenter US-Based, Norm-Based Study. Am J Gastroenterol. 2016 Jan;111(1):78-86. doi: 10.1038/ajg.2015.377. Epub 2015 Dec 8.
Reference Type
RESULT
Other Identifiers
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IRB17-00550
Identifier Type: -
Identifier Source: org_study_id