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Rifamycin in Minimal Hepatic Encephalopathy

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ClinicalTrials.gov Identifier: NCT04082780
Recruitment Status : Recruiting
First Posted : September 9, 2019
Last Update Posted : February 12, 2020
Sponsor:
Information provided by (Responsible Party):
Hunter Holmes Mcguire Veteran Affairs Medical Center

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : September 1, 2019
Estimated Primary Completion Date : September 15, 2020
Estimated Study Completion Date : November 15, 2020


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 Name: Aemcolo

Placebo Comparator: Placebo
Placebo PO two times a day for 30 days
Other: Placebo
Placebo arm




Primary Outcome Measures :
  1. Cirrhosis Dysbiosis Ratio of stool microbiota [ Time Frame: 30 days ]
    Comparing this ratio in rifamycin compared to placebo groups (Lachnospiraceae + Ruminococcaceae + Clostridium Cluster XIV + Veillonellaceae / Enterobacteriaceae + Bacteroidaceae)


Secondary Outcome Measures :
  1. Psychometric hepatic encephalopathy score (PHES) composite score ranges from -15 to +5 [ Time Frame: 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.

  2. EncephalApp Stroop OffTime+OnTime is the total time taken to complete 5 runs in Off and 5 runs in On state. [ Time Frame: 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.

  3. Sickness Impact Profile total score is the total score determined after all 12 domains are scored [ Time Frame: 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.

  4. Sickness Impact Profile psychosocial score is the score of the psychosocial part of the SIP [ Time Frame: 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.

  5. Sickness Impact Profile physical score is the score of the physical part of the SIP [ Time Frame: 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.

  6. Pittsburgh sleep quality index [ Time Frame: 30 days ]
    Validated questionnaire for sleep quality. Investigators will compare this in rifamycin compared to placebo groups

  7. Serious adverse events (Hospitalizations, death, prolongation of hospitalizations) [ Time Frame: 30 days ]
    Investigators will compare this in rifamycin compared to placebo groups

  8. Serious adverse events (Hospitalizations, death, prolongation of hospitalizations) [ Time Frame: 37 days ]
    Investigators will compare this in rifamycin compared to placebo groups

  9. Adverse events related to rifamycin [ Time Frame: 30 days ]
    Investigators will compare this in rifamycin compared to placebo groups

  10. Adverse events related to rifamycin [ Time Frame: 37 days ]
    Investigators will compare this in rifamycin compared to placebo groups

  11. Systemic exposure of rifamycin in the blood [ Time Frame: Baseline ]
    AUC of rifamycin levels in the 6 hourly blood collection time-points post rifamycin ingestion will be studied on day 1

  12. Systemic exposure of rifamycin in the blood [ Time Frame: 15 days ]
    Spot plasma level of rifamycin will be analyzed

  13. Systemic exposure of rifamycin in the urine [ Time Frame: Baseline ]
    AUC of rifamycin levels in the 6 hours urine collection post rifamycin ingestion will be studied on day 1

  14. Systemic exposure of rifamycin in the urine [ Time Frame: 15 days ]
    Spot urine level of rifamycin will be analyzed

  15. Endotoxin levels in serum using LAL assay [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups

  16. Calprotectin levels in stool [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups

  17. Serum IL-6 levels [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups

  18. Serum IL-1beta levels [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups

  19. Fecal bile acid levels [ Time Frame: 30 days ]
    Using LC/MS. Investigators will compare these in rifamycin compared to placebo groups

  20. Serum bile acid levels [ Time Frame: 30 days ]
    Using GC/MS. Investigators will compare these in rifamycin compared to placebo groups

  21. Microbiota diversity using Shannon index [ Time Frame: 30 days ]
    Stool microbiota diversity. Investigators will compare these in rifamycin compared to placebo groups ranges widely from 0-20

  22. Salivary dysbiosis ratio [ Time Frame: 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:
  1. Handgrip strength [ Time Frame: 30 days ]
    Jamar hand dynanometer; Investigators will compare these in rifamycin compared to placebo groups

  2. Body Muscle composition [ Time Frame: 30 days ]
    InBody assessment; Investigators will compare these in rifamycin compared to placebo groups

  3. Brain MR Spectroscopy in Anterior cingulate cortex [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol

  4. Brain MR Spectroscopy in posterior gray matter [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol

  5. Brain MR Spectroscopy in right parietal white matter [ Time Frame: 30 days ]
    Investigators will compare these in rifamycin compared to placebo groups and measure choline, glutamate/glutamine and myoinositol



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-75 years
  2. Cirrhosis defined by any one of the following

    1. Cirrhosis on liver biopsy or transient elastography
    2. Nodular liver on imaging
    3. Endoscopic or radiological evidence of varices in a patient with chronic liver disease
    4. Platelet count <150,000/mm3 and AST/ALT ratio >1 in a patient with chronic liver disease
  3. 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.
  4. 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.)
  5. Willing and able to participate, provide samples and complete follow-up
  6. Stable Liver function tests between 2-12 weeks prior to enrollment (can include the screening laboratory values details in exclusion criteria)

Exclusion Criteria:

  1. Unclear diagnosis of cirrhosis (does not meet the criteria outlined above)
  2. Child score >8
  3. 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.
  4. Unable to consent, follow for the study duration
  5. Normal performance on PHES
  6. Mini-mental status exam<2518
  7. Recent alcohol abuse (within 3 months)
  8. Recent illicit drug abuse (within 3 months) except marijuana
  9. Current use of psychoactive drugs apart from long-standing opioids or stable anti-depressant use.
  10. 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
  11. Currently on lactulose or rifaximin
  12. Current or recent invasive bacterial or fungal infections (<1 month)
  13. Allergic reactions to rifamycin, rifampin or rifaximin
  14. MELD >20
  15. TIPS placement
  16. Serum sodium<125
  17. On SBP prophylaxis
  18. Post-transplant cirrhosis
  19. Infections within 4 weeks
  20. End-stage organ failures: CHF with EF<25%, End-stage renal disease on dialysis, COPD on home oxygen
  21. Pregnancy (positive urine pregnancy test at screening)
  22. Current on statin therapy
  23. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04082780


Contacts
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Contact: JASMOHAN BAJAJ, MD 8046755802 jasmohan.bajaj@vcuhealth.org
Contact: Edith Gavis 8046755584 edith.gavis@va.gov

Locations
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United States, Virginia
Hunter Holmes McGuire VA Medical Center Recruiting
Richmond, Virginia, United States, 23249
Contact: Edith Gavis, RN    804-675-5584    edith.gavis@va.gov   
Contact: Jasmohan Bajaj, MD    8046755802    jasmohan.bajaj@vcuhealth.org   
Principal Investigator: Jasmohan S Bajaj, MD,MS         
Sponsors and Collaborators
Hunter Holmes Mcguire Veteran Affairs Medical Center
Investigators
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Principal Investigator: JASMOHAN BAJAJ Hunter Holmes McGuire Medical Center
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Responsible Party: Hunter Holmes Mcguire Veteran Affairs Medical Center
ClinicalTrials.gov Identifier: NCT04082780    
Other Study ID Numbers: BAJAJ0025
First Posted: September 9, 2019    Key Record Dates
Last Update Posted: February 12, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hunter Holmes Mcguire Veteran Affairs Medical Center:
brain MRI
cognitive testing
microbiota
metabolomics
pharmacokinetics
Additional relevant MeSH terms:
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Hepatic Encephalopathy
Liver Cirrhosis
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Liver Failure
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases
Brain Diseases, Metabolic
Metabolic Diseases
Rifamycins
Rifamycin SV
Anti-Bacterial Agents
Anti-Infective Agents
Antirheumatic Agents