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Rifaximin's Effect on Covert Hepatic Encephalopathy in Cirrhosis Patients With Small Intestinal Bacterial Overgrowth and Gastrointestinal Dysmotility

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ClinicalTrials.gov Identifier: NCT04244877
Recruitment Status : Not yet recruiting
First Posted : January 28, 2020
Last Update Posted : January 28, 2020
Sponsor:
Information provided by (Responsible Party):
Ronnie Fass, MD, MetroHealth Medical Center

Tracking Information
First Submitted Date  ICMJE December 27, 2019
First Posted Date  ICMJE January 28, 2020
Last Update Posted Date January 28, 2020
Estimated Study Start Date  ICMJE March 2020
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2020)
Comparing the effects of Rifaximin on patients with covert hepatic encephalopathy (CHE) and SIBO using neuropsychometric test (NST) and glucose hydrogen breath test (BT) after 8 weeks of Rifaximin. [ Time Frame: 8 weeks ]
The percent of subjects with improvement on Portosystemic Encephalopathy Syndrome test (PSE) after taking Rifaximin for 8 weeks. The percent of subjects who test negative on glucose breath test (BT) after treatment with Rifaximin.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2020)
Improvement in small bowel motility in subjects taking Rifaximin [ Time Frame: 8 weeks ]
The percent of patients with improvement in small bowel motility as measured by the SmartPill after taking Rifaximin for 8 weeks
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rifaximin's Effect on Covert Hepatic Encephalopathy in Cirrhosis Patients With Small Intestinal Bacterial Overgrowth and Gastrointestinal Dysmotility
Official Title  ICMJE Evaluation of the Therapeutic Effect of Rifaximin on Covert Hepatic Encephalopathy With Underlying Small Intestinal Bacterial Overgrowth and Gastrointestinal Dysmotility in Liver Cirrhosis Patients
Brief Summary 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 three times daily for 2 weeks and then be treated with Rifaximin 550 mg PO twice daily for 6 more 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

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 three times daily for 2 weeks and then Rifaximin 550 mg PO twice daily for 6 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cirrhosis, Liver
  • Minimal Hepatic Encephalopathy
  • Small Intestinal Bacterial Overgrowth
  • Gastrointestinal Motility Disorder
Intervention  ICMJE Drug: Rifaximin
Drug: Rifaximin tablet
Other Name: Xifaxan
Study Arms  ICMJE Experimental: Rifaximin
Rifaximin 550 mg by mouth three time daily for two weeks followed immediately with Rifaximin 550 mg by mouth two times daily for six weeks.
Intervention: Drug: Rifaximin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 27, 2020)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Cirrhosis patients between 18-70years 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.
  4. 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.

Exclusion Criteria:

  1. Known allergy to rifaximin / rifabutin / rifampin.
  2. Current or recent (<6 months) abuse of alcohol or illicit drugs
  3. Use of antibiotics within last 6 weeks
  4. Use of lactulose / lactitol, probiotics, L-ornithine- L -aspartate, zinc, metronidazole, or neomycin, within last 6 weeks
  5. Use of any drug known to affect gastro-intestinal motility within the previous 2 to 4 weeks (such as, Reglan, erythromycin, or domperidone)
  6. Use of drugs such as opiates and antidepressants (except stable doses of selective serotonin re-uptake inhibitors)
  7. Diarrhea or abdominal distention
  8. Patients deemed higher risk for capsule retention including a history of esophageal stricture or Zenker's diverticulum, partial or complete bowel obstruction, known fistula, known large or numerous diverticula and dementia
  9. Diseases associated with poor gastrointestinal motility such as cardiac and pulmonary dysfunction, renal insufficiency, diabetes, rheumatological disorders (such as scleroderma and mixed connective tissue disorders)
  10. History of gastrointestinal tract or abdominal surgery
  11. Spontaneous peritonitis or other severe infections
  12. Colonoscopy or enema treatment within 4 weeks
  13. Hepatic encephalopathy with clinical signs
  14. Inability to complete neuropsychiatric testing due to hearing loss, poor vision, etc.
  15. Poorly compliant patients
  16. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ronnie Fass, MD 216-778-3145 rfass@metrohealth.org
Contact: Sara Ghoneim, MD 2167770498 sghoneim@metrohealth.org
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04244877
Other Study ID Numbers  ICMJE IRB17-00550
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ronnie Fass, MD, MetroHealth Medical Center
Study Sponsor  ICMJE Ronnie Fass, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ronnie Fass, MD Metrohealth Medical Center/Case Western Reserve University
PRS Account MetroHealth Medical Center
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP