Clinical trial NCT04244877: Rifaximin's Effect on Covert Hepatic Encephalopathy With SIBO and Gastrointestinal Dysmotility
Official title: Evaluation of the Therapeutic Effect of Rifaximin on Covert Hepatic Encephalopathy With Underlying Small Intestinal Bacterial Overgrowth and Gastrointestinal Dysmotility in Liver Cirrhosis Patients
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Cirrhosis, Liver
Minimal Hepatic Encephalopathy
Small Intestinal Bacterial Overgrowth
Gastrointestinal Motility Disorder
Lead sponsor: MetroHealth Medical Center
Sponsor class: OTHER
First posted: 2020-01-28
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 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: 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.

Eligibility criteria: 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.

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

Primary outcomes:
measure: 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.
timeFrame: 8 weeks
Secondary outcomes:
measure: Improvement in small bowel motility in subjects taking Rifaximin
timeFrame: 8 weeks
Other outcomes:
Locations:
Study officials:
affiliation: Metrohealth Medical Center/Case Western Reserve University
name: Ronnie Fass, MD
role: PRINCIPAL_INVESTIGATOR
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