Rifamycin in Minimal Hepatic Encephalopathy

Sponsor

Hunter Holmes Mcguire Veteran Affairs Medical Center (U.S. Fed)

Overall Status

Recruiting

CT.gov ID

NCT04082780

Collaborator

(none)

Enrollment

Location

Arms

38.5

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized double-blind placebo-controlled trial of MHE in patients with cirrhosis using rifamycin SV-MMX 600mg BID vs placebo for 30 days with PK, safety, microbiota, brain function and brain MRI endpoints.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Encephalopathy Cirrhosis, Liver	Drug: Rifamycin SV MMX Other: Placebo	Phase 2

Detailed Description

Hepatic encephalopathy (HE) is a highly prevalent neuro-cognitive complication of cirrhosis characterized by cognitive dysfunction, and high rate of subsequent mortality and recurrence. HE also places a tremendous burden with a relentless increase in inpatient stay duration with charges topping $7244.7 million in 20092. There were almost 23,000 hospitalizations for HE in 2009 and far more patients with HE who are being managed as an outpatient in the US. In the NACSELD (North American Consortium for the Study of End-Stage Liver Disease) experience, HE in inpatients is an independent risk factor for mortality and the leading cause of readmissions in patients with cirrhosis.

HE has two major phases, covert or minimal HE (MHE), which is only recognized by specialized tests and overt HE (OHE), which is clinically obvious. OHE forms the tip of the iceberg, while MHE affects as many as 60% of tested patients with cirrhosis.

MHE is associated with changes in specific cognitive domains that result in altered health-related quality of life and daily function. This can promote the development of OHE, impair driving and employment, increase falls and is independently associated with a risk of hospitalizations and mortality.

There is an alteration of gut microbial composition and function (bile acid changes, endotoxemia and gut metabolic products) in cirrhosis, which worsens with disease progression with MHE and OHE. Current treatments for OHE are mostly focused on the gut, including lactulose and rifaximin. However, despite extracting a major toll on disease progression, there is no current guideline to treat MHE. Prior studies using lactulose and rifaximin have been performed in this setting with improvement in brain function, brain MRI changes and microbial function. However, these are still not standard of care.

Rifamycin SV MMX® 200 mg is a gut-specific antibiotic with a long track record of safety that has been FDA approved for the treatment of traveler's diarrhea. Unlike rifaximin, rifamycin-SV MMX mostly affects the colon, where the bacterial load is much larger than in the other parts of the GI tract. The impact of rifamycin on MHE has not been studied to date. This is a randomized double-blind placebo-controlled trial of MHE in patients with cirrhosis.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Patients will be randomized 1:1 into receiving rifamycin or placebo by a random number generator created by the McGuire VAMC Investigational pharmacy. These will be performed in blocks of 4.

Primary Purpose:

Treatment

Official Title:

A Double-Blind Randomized Placebo-Controlled Trial of Rifamycin in Minimal Hepatic Encephalopathy

Actual Study Start Date :

Sep 1, 2019

Anticipated Primary Completion Date :

Sep 15, 2022

Anticipated Study Completion Date :

Nov 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifamycin Rifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days	Drug: Rifamycin SV MMX Intervention arm Other Names: Aemcolo
Placebo Comparator: Placebo Placebo PO two times a day for 30 days	Other: Placebo Placebo arm

Arm

Intervention/Treatment

Experimental: Rifamycin

Rifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days

Drug: Rifamycin SV MMX

Intervention arm

Other Names:

Aemcolo

Placebo Comparator: Placebo

Placebo PO two times a day for 30 days

Other: Placebo

Placebo arm

Outcome Measures

Primary Outcome Measures

Cirrhosis Dysbiosis Ratio of stool microbiota [30 days]
Comparing this ratio in rifamycin compared to placebo groups (Lachnospiraceae + Ruminococcaceae + Clostridium Cluster XIV + Veillonellaceae / Enterobacteriaceae + Bacteroidaceae)

Secondary Outcome Measures

Psychometric hepatic encephalopathy score (PHES) composite score ranges from -15 to +5 [30 days]
Battery of 5 cognitive tests that yield a numeric composite score. Investigators will compare this score in rifamycin compared to placebo groups. Higher total score = better performance. Norms are at www.encephalapp.com, which are adjusted for age, gender and education status.
EncephalApp Stroop OffTime+OnTime is the total time taken to complete 5 runs in Off and 5 runs in On state. [30 days]
Cognitive test. Investigators will compare this score in rifamycin compared to placebo groups. High score = worse performance. Norms are at www.encephalapp.com, which are adjusted for age, gender and education status.
Sickness Impact Profile total score is the total score determined after all 12 domains are scored [30 days]
Validated questionnaire for health-related quality of life. Investigators will compare this score in rifamycin compared to placebo groups. There is no defined range but a higher score indicates worse QOL.
Sickness Impact Profile psychosocial score is the score of the psychosocial part of the SIP [30 days]
Validated questionnaire for health-related quality of life. Investigators will compare this score in rifamycin compared to placebo groups. There is no defined range but a higher score indicates worse QOL.
Sickness Impact Profile physical score is the score of the physical part of the SIP [30 days]
Validated questionnaire for health-related quality of life. Investigators will compare this score in rifamycin compared to placebo groups.There is no defined range but a higher score indicates worse QOL.
Pittsburgh sleep quality index [30 days]
Validated questionnaire for sleep quality. Investigators will compare this in rifamycin compared to placebo groups
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations) [30 days]
Investigators will compare this in rifamycin compared to placebo groups
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations) [37 days]
Investigators will compare this in rifamycin compared to placebo groups
Adverse events related to rifamycin [30 days]
Investigators will compare this in rifamycin compared to placebo groups
Adverse events related to rifamycin [37 days]
Investigators will compare this in rifamycin compared to placebo groups
Systemic exposure of rifamycin in the blood [Baseline]
AUC of rifamycin levels in the 6 hourly blood collection time-points post rifamycin ingestion will be studied on day 1
Systemic exposure of rifamycin in the blood [15 days]
Spot plasma level of rifamycin will be analyzed
Systemic exposure of rifamycin in the urine [Baseline]
AUC of rifamycin levels in the 6 hours urine collection post rifamycin ingestion will be studied on day 1
Systemic exposure of rifamycin in the urine [15 days]
Spot urine level of rifamycin will be analyzed
Endotoxin levels in serum using LAL assay [30 days]
Investigators will compare these in rifamycin compared to placebo groups
Calprotectin levels in stool [30 days]
Investigators will compare these in rifamycin compared to placebo groups
Serum IL-6 levels [30 days]
Investigators will compare these in rifamycin compared to placebo groups
Serum IL-1beta levels [30 days]
Investigators will compare these in rifamycin compared to placebo groups
Fecal bile acid levels [30 days]
Using LC/MS. Investigators will compare these in rifamycin compared to placebo groups
Serum bile acid levels [30 days]
Using GC/MS. Investigators will compare these in rifamycin compared to placebo groups
Microbiota diversity using Shannon index [30 days]
Stool microbiota diversity. Investigators will compare these in rifamycin compared to placebo groups ranges widely from 0-20
Salivary dysbiosis ratio [30 days]
Lachnospiraceae + Ruminococcaceae + Clostridium Cluster XIV + Veillonellaceae / Streptococcaceae will be calculated from the saliva.Investigators will compare these in rifamycin compared to placebo groups

Other Outcome Measures

Handgrip strength [30 days]
Jamar hand dynanometer; Investigators will compare these in rifamycin compared to placebo groups
Body Muscle composition [30 days]
InBody assessment; Investigators will compare these in rifamycin compared to placebo groups
Brain MR Spectroscopy in Anterior cingulate cortex [30 days]
Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol
Brain MR Spectroscopy in posterior gray matter [30 days]
Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol
Brain MR Spectroscopy in right parietal white matter [30 days]
Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18-75 years
Cirrhosis defined by any one of the following
Cirrhosis on liver biopsy or transient elastography
Nodular liver on imaging
Endoscopic or radiological evidence of varices in a patient with chronic liver disease
Platelet count <150,000/mm3 and AST/ALT ratio >1 in a patient with chronic liver disease
Women of childbearing age will need to be on accepted birth control for 10 days prior to entering study and 30 days after the end of the last dose of the study drug.
Cognitive impairment on PHES aggregate score [more than or greater than] -4SD - based on norms published in Allampati et al located at the website www.encephalapp.com17 (This is the accepted diagnosis of minimal HE.)
Willing and able to participate, provide samples and complete follow-up
Stable Liver function tests between 2-12 weeks prior to enrollment (can include the screening laboratory values details in exclusion criteria)

Exclusion Criteria:

Unclear diagnosis of cirrhosis (does not meet the criteria outlined above)
Child score >8
Increasing trend of ALT and AST in the 2-12 weeks prior to study inclusion (Baseline values established by at least two samples obtained at least 2 weeks and no more than 8-12 weeks apart) to account for disease related changes in liver enzymes and bilirubin while on study that may otherwise be inappropriately attributed to study drug. >20% increase in baseline serum AST, ALT, ALP and total bilirubin (TBL) will be considered an exclusion criterion.
Unable to consent, follow for the study duration
Normal performance on PHES
Mini-mental status exam<2518
Recent alcohol abuse (within 3 months)
Recent illicit drug abuse (within 3 months) except marijuana
Current use of psychoactive drugs apart from long-standing opioids or stable anti-depressant use.
Prior overt HE episodes defined as West-Haven Criteria grade 2 or higher in the past that required hospitalization or initiation of lactulose or rifaximin therapy
Currently on lactulose or rifaximin
Current or recent invasive bacterial or fungal infections (<1 month)
Allergic reactions to rifamycin, rifampin or rifaximin
MELD >20
TIPS placement
Serum sodium<125
On SBP prophylaxis
Post-transplant cirrhosis
Infections within 4 weeks
End-stage organ failures: CHF with EF<25%, End-stage renal disease on dialysis, COPD on home oxygen
Pregnancy (positive urine pregnancy test at screening)
Current on statin therapy
In the opinion of the PI, those who are unlikely to survive or remain without liver transplant for 6 weeks, or cannot adhere to the trial activities.