Hepatic EncephalopathyPhase 2RIVETNCT04082780
Rifamycin in Minimal Hepatic Encephalopathy
A Phase 2 study testing Rifamycin SV MMX in people with Hepatic Encephalopathy and Cirrhosis, Liver, run by Hunter Holmes Mcguire Veteran Affairs Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Hepatic Encephalopathy, Cirrhosis, Liver
- What is being tested?
- Rifamycin SV MMX
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2019to 28 Apr 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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 or EncephalApp Stroop - 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)
Who cannot join
- 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
Show all 22Show fewer
- 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)
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Hunter Holmes McGuire VA Medical Center
Richmond, Virginia, 23249
About this study
Official title: A Double-Blind Randomized Placebo-Controlled Trial of Rifamycin SV MXX in Minimal Hepatic Encephalopathy (RIVET Trial)
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.
Read the 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.
- Conditions
- Hepatic Encephalopathy, Cirrhosis, Liver
- Being tested
- Rifamycin SV MMX, Placebo
- Keywords
- brain MRI, cognitive testing, microbiota, metabolomics, pharmacokinetics
- Medical subject headings
- Hepatic Encephalopathy, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifamycin SV MMXDrug
Also called Aemcolo
Intervention arm
PlaceboOther
Placebo arm
| Study group | Role | What they receive |
|---|---|---|
| Rifamycin | Experimental | Rifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days Receives: Drug: Rifamycin SV MMX |
| Placebo | Placebo comparator | Placebo PO two times a day for 30 days Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cirrhosis Dysbiosis Ratio of stool microbiota
Comparing this ratio in rifamycin compared to placebo groups (Lachnospiraceae + Ruminococcaceae + Clostridium Cluster XIV + Veillonellaceae / Enterobacteriaceae + Bacteroidaceae)
Measured: 30 days
Secondary outcomes (19)
Psychometric hepatic encephalopathy score (PHES) composite score ranges from -15 to +5
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.
Measured: 30 days
EncephalApp Stroop OffTime+OnTime is the total time taken to complete 5 runs in Off and 5 runs in On state.
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.
Measured: 30 days
Sickness Impact Profile total score is the total score determined after all 12 domains are scored
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.
Measured: 30 days
Sickness Impact Profile psychosocial score is the score of the psychosocial part of the SIP
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.
Measured: 30 days
Sickness Impact Profile physical score is the score of the physical part of the SIP
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.
Measured: 30 days
Pittsburgh sleep quality index
Validated questionnaire for sleep quality. Investigators will compare this in rifamycin compared to placebo groups
Measured: 30 days
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Investigators will compare this in rifamycin compared to placebo groups
Measured: 30 days
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Investigators will compare this in rifamycin compared to placebo groups
Measured: 37 days
Adverse events related to rifamycin
Investigators will compare this in rifamycin compared to placebo groups
Measured: 30 days
Adverse events related to rifamycin
Investigators will compare this in rifamycin compared to placebo groups
Measured: 37 days
Systemic exposure of rifamycin in the blood
AUC of rifamycin levels in the 6 hourly blood collection time-points post rifamycin ingestion will be studied on day 1
Measured: Baseline
Systemic exposure of rifamycin in the blood
Spot plasma level of rifamycin will be analyzed
Measured: 15 days
Systemic exposure of rifamycin in the urine
AUC of rifamycin levels in the 6 hours urine collection post rifamycin ingestion will be studied on day 1
Measured: Baseline
Systemic exposure of rifamycin in the urine
Spot urine level of rifamycin will be analyzed
Measured: 15 days
Untargeted Metabolomics in serum using LC/MS
Investigators will compare these in rifamycin compared to placebo groups
Measured: 30 days
Calprotectin levels in stool
Investigators will compare these in rifamycin compared to placebo groups
Measured: 30 days
Untargeted Metabolomics in urine using LC/MS
Investigators will compare these in rifamycin compared to placebo groups
Measured: 30 days
Fecal bile acid levels
Using LC/MS. Investigators will compare these in rifamycin compared to placebo groups
Measured: 30 days
Microbiota diversity using Shannon index
Stool microbiota diversity. Investigators will compare these in rifamycin compared to placebo groups ranges widely from 0-20
Measured: 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Sep 2019
- Study start1 Sep 2019
- Primary completion28 Apr 2023
- Study completion28 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hunter Holmes Mcguire Veteran Affairs Medical Center
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- JASMOHAN BAJAJ, Principal investigator, Hunter Holmes McGuire Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04082780
- Sponsor's protocol ID
- BAJAJ0025
- Acronym
- RIVET
- Status last verified
- Sep 2023
- First submitted
- 22 Aug 2019
- Last updated
- 21 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind Randomized Placebo-Controlled Trial of Rifamycin SV MXX in Minimal Hepatic Encephalopathy (RIVET Trial)
- ClinicalTrials.gov ID
- NCT04082780
- Acronym / sponsor ID
- RIVET / BAJAJ0025
- Conditions
- Hepatic Encephalopathy, Cirrhosis, Liver
- Keywords
- brain MRI, cognitive testing, microbiota, metabolomics, pharmacokinetics
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Hunter Holmes Mcguire Veteran Affairs Medical CenterUS federal agency
- Study start
- 1 Sep 2019 (actual)
- Primary completion
- 28 Apr 2023 (actual)
- Study completion
- 28 Apr 2023 (actual)
- First posted
- 9 Sep 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Rifamycin | Experimental | Drug: Rifamycin SV MMXRifamycin-SV MMX 600 mg PO two times a day (1200 mg) for 30 days |
| Placebo | Placebo comparator | Other: PlaceboPlacebo PO two times a day for 30 days |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Age 18-75 years
- Cirrhosis defined by any one of the following
- 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 or EncephalApp Stroop - 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
Key exclusion criteria (22 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rifamycin SV MMXAlso: AemcoloIntervention arm | Drug | Rifamycin |
| PlaceboPlacebo arm | Other | Placebo |
Primary outcome
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)
19 secondary outcomes
Psychometric hepatic encephalopathy score (PHES) composite score ranges from -15 to +5
Time frame: 30 days
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
Sickness Impact Profile total score is the total score determined after all 12 domains are scored
Time frame: 30 days
Sickness Impact Profile psychosocial score is the score of the psychosocial part of the SIP
Time frame: 30 days
Sickness Impact Profile physical score is the score of the physical part of the SIP
Time frame: 30 days
Pittsburgh sleep quality index
Time frame: 30 days
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Time frame: 30 days
Serious adverse events (Hospitalizations, death, prolongation of hospitalizations)
Time frame: 37 days
Adverse events related to rifamycin
Time frame: 30 days
Adverse events related to rifamycin
Time frame: 37 days
Systemic exposure of rifamycin in the blood
Time frame: Baseline
Systemic exposure of rifamycin in the blood
Time frame: 15 days
Systemic exposure of rifamycin in the urine
Time frame: Baseline
Systemic exposure of rifamycin in the urine
Time frame: 15 days
Untargeted Metabolomics in serum using LC/MS
Time frame: 30 days
Calprotectin levels in stool
Time frame: 30 days
Untargeted Metabolomics in urine using LC/MS
Time frame: 30 days
Fecal bile acid levels
Time frame: 30 days
Microbiota diversity using Shannon index
Time frame: 30 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
JASMOHAN BAJAJ principal investigator
Hunter Holmes McGuire Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rifamycin SV MMX in people with Hepatic Encephalopathy and Cirrhosis, Liver, run by Hunter Holmes Mcguire Veteran Affairs Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cirrhosis Dysbiosis Ratio of stool microbiota (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2023.