Hepatic EncephalopathyPhase 2NCT00281502
The Role of Bacterial Overgrowth and Delayed Intestinal Transit in Hepatic Encephalopathy
A Phase 2 study testing Rifaximin (drug) in people with Hepatic Encephalopathy and Hepatitis C, run by Weill Medical College of Cornell University at 1 site in United States.
Trial summary
The study will be conducted in two phases. Phase A will evaluate the contribution of bacterial overgrowth and colonic inertia to development of Hepatic Encephalopathy (HE)in 50 ambulatory subjects with HE and hepatitis C cirrhosis. This phase will include a Screening and Evaluation Visit. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis
- What is being tested?
- Rifaximin (drug)
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2005to Dec 2012
- 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
Phase A Inclusion Criteria:
- Subject is 18 to 70 years of age, inclusive.
- Subject has cirrhosis due to chronic HCV infection as documented by:
- Subject has evidence of hepatic encephalopathy as evidenced by:
- Neuro-psychometric Testing (Number Connection Test, Trails Test, etc.)
- Subject is non-azotemic (creatinine <1.5mg/dL) and ambulatory at screening.
- Subject has cirrhosis due to chronic HCV as documented by: pathologic or clinical and radiographic evidence of cirrhosis with a positive HCV RNA PCR level.
Phase A Exclusion Criteria:
- Subject has received active interferon therapy within 2 weeks of enrollment.
- Subject is pregnant or lactating.
- Subject has a life expectancy of less than 100 days.
- Subject has a history of alcohol abuse within 6 months of enrollment.
- Subject has active gastrointestinal bleeding at time of enrollment.
- Subject has used an agent that alters intestinal motility, eg, methadone, cholestyramine, tricyclic antidepressants.
- Subject is unable to take oral medication.
- Subject has used neomycin or other antibiotic within 2 weeks of enrollment or is actively using lactulose at time of enrollment.
- Subject is taking or has hypersensitivity or allergy to rifaximin or rifampin.
- Subject requires long term antibiotic therapy (eg, Lyme Disease, tuberculosis).
- Subject has known or suspected alcohol abuse or illicit drug use within 1 year of enrollment.
- Subject has participated in an investigational drug or device study within the 30 days prior to randomization.
- Subject has received rifaximin within the last 30 days.
- Subject has concomitant disease or condition that could interfere with, or for which treatment could interfere with the conduct of the study, or could in the opinion of the investigator increase the risk of AEs for the subject's participation in the study.
- Subject is unwilling or unable to comply with the study protocol for any other reason.
- Subject has been diagnosed with other forms of liver disease, including those with HIV and HBV co-infection, as determined by history, serological parameters, and histology when available.
- Subject has been diagnosed with a major psychiatric illness, chronic renal and/or respiratory insufficiency, intercurrent infections, treatment with sedatives within 7 days of enrollment.
- Subject shows presence of intestinal obstruction or inflammatory bowel disease, antacids or cathartics within the 12h before study start; antibiotics during 7 days before start of dosing; or treated with encephalopathy-causing agents.
- Subjects with bad vision or neurological diseases since they could have difficulty completing the neuropsychological assessments.
Phase B Inclusion Criteria
- Subject successfully participated in and continues to meet all eligibility criteria required in Phase A of the study based on completion of tests, Breath Tests, and Radiological Marker.
- Subject has a Number Connection Test score >50 sec at time of enrollment.
Phase B Exclusion Criteria
- A subject will not be eligible for inclusion in Phase B if (s)he meets any of the exclusion criteria for Phase A of the study.
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
New York Presbyterian Hospital: Weill Medical College of Cornell University
New York, New York, 10021
Sam Sigal, M.D., 212-746-4129, shs2015@med.cornell.edu
Sam Sigal, M.D.
About this study
Official title: The Role of Bacterial Overgrowth and Delayed Intestinal Transit in Hepatic Encephalopathy. Phase A: Breath Testing and Colonic Transit in Hepatic Encephalopathy. Phase B: A Randomized Double Blind, Placebo Controlled Trial of Rifaximin for Hepatic Encephalopathy
The study will be conducted in two phases. Phase A will evaluate the contribution of bacterial overgrowth and colonic inertia to development of Hepatic Encephalopathy (HE)in 50 ambulatory subjects with HE and hepatitis C cirrhosis. This phase will include a Screening and Evaluation Visit.
Phase B will evaluate the effect of rifaximin on bacterial outgrowth and severity of HE in 20 of the subjects enrolled in Phase A who have a somewhat greater degree of encephalopathy.
Read more
The purpose of this study is to evaluate the following:
- the relationship between bacterial overgrowth and the presence and severity of HE in patients with hepatitis C cirrhosis;
- the effectiveness and tolerability of rifaximin relative to placebo in treatment of HE associated with hepatitis C cirrhosis;
- the relationship between bacterial overgrowth and the presence and severity of HE before and after rifaximin treatment.
Read the detailed description
Hepatic encephalopathy is a frequent and occasionally refractory complication of cirrhosis and is associated with impaired quality of life. Its severity may not correlate with other parameters of liver dysfunction. Although multiple pathogenic mechanisms for the condition have been proposed, most include the participation of bacterial toxins, especially ammonia, produced in the gastrointestinal tract. Treatment options for hepatic encephalopathy at this time are limited to lactulose and neomycin. Lactulose is frequently poorly tolerated, and many patients are non-compliant with its use. In patients with renal insufficiency in whom hepatic encephalopathy is frequently problematic, use of neomycin is contraindicated due to ototoxicity and nephrotoxicity.
Autonomic dysfunction is common in patients with cirrhosis and could contribute to the development of hepatic encephalopathy by impairment of intestinal motility, leading to bacterial overgrowth and colonic inertia.
The following questions will be addressed:
- Is impaired intestinal transit and bacterial overgrowth associated with the presence and severity of hepatic encephalopathy?
50 patients will undergo a detailed clinical evaluation for severity of liver disease, hepatic encephalopathy and assessment of intestinal transit and bacterial overgrowth with radiographic marker study and breath test analysis. Multivariate analysis will then be performed to determine the relationship of intestinal transit and evidence of bacterial overgrowth with the presence and severity of hepatic encephalopathy.
- Does treatment with rifaximin improve bacterial overgrowth and hepatic encephalopathy?
20 patients from the above population with significant encephalopathy will be randomized to receive either rifaximin or placebo. Post-treatment evaluation for severity of hepatic encephalopathy and breath test analysis for bacterial overgrowth will then be performed. The effect of treatment on changes in hepatic encephalopathy and bacterial overgrowth and the relationship between changes in bacterial overgrowth and severity of hepatic encephalopathy will also be assessed.
Phase A Endpoints: Degree of bacterial overgrowth and its correlation with the grade of hepatic encephalopathy (if present).
Phase B Endpoints: To demonstrate improvement in degree of HE with treatment of Rifaximin
Efficacy Endpoints The primary efficacy endpoint for Phase B of the study will be the change from baseline in the proportion of patients with no HE, minimal HE (no symptoms, abnormal psychometric testing), mild persistent HE (mild symptoms), and persistent Stage II HE (presence of asterixis, history of hospitalization for spontaneous Stage III or IV HE).
Secondary efficacy endpoints for Phase B will be the following:
To demonstrate improvement in intestinal transit time for patients (based on Lactulose Hydrogen Breath Test) To demonstrate improvement in bacterial overgrowth, improved insomnia, flatulence, and quality of life.
To demonstrate that rifaximin improved patients' symptoms of insomnia, flatulence, and quality of life measure with the degree of bacterial overload and the impaired intestinal transit time.
- Conditions
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis
- Being tested
- Rifaximin (drug)
- Keywords
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis, Bacterial Overgrowth
- Medical subject headings
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifaximin (drug)Drug
Also called Xifaxan
Rifaximin 400mg three (3) times daily
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase A: Degree of bacterial overgrowth and its correlation with the grade of hepatic encephalopathy (if present)
Measured: 3 months
Phase B: Improvement in the psychometric scores and proportion of patients who change of HE stage
Measured: 3 months
Secondary outcomes (5)
Improved Intestinal transit time
Measured: 3 months
Improvement in bacterial overgrowth
Measured: 3 months
Improved insomnia
Measured: 3 months
Improved flatulence
Measured: 3 months
Improved quality of life.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jan 2006 (estimated)
- Study startDec 2005
- Primary completionDec 2012 (estimated)
- Study completionDec 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- 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
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Collaborators
- Bausch Health Americas, Inc.
- Investigators
- Sam Sigal, M.D., Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00281502
- Sponsor's protocol ID
- Salix-RifaxPSE-BactOvrGrwth-01
- Status last verified
- Nov 2010
- First submitted
- 20 Jan 2006
- Last updated
- 5 Nov 2010
- Results posted
- No
- Data monitoring committee
- No
Publications
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21. doi: 10.1053/jhep.2002.31250.
PubMed 11870389Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci. 2003 Aug;48(8):1622-6. doi: 10.1023/a:1024784327783.
PubMed 12924658Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol. 2000 May;32(5):748-53. doi: 10.1016/s0168-8278(00)80243-3.
PubMed 10845661Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998 Jul;28(1):45-9. doi: 10.1002/hep.510280108.
PubMed 9657095Amodio P, Del Piccolo F, Marchetti P, Angeli P, Iemmolo R, Caregaro L, Merkel C, Gerunda G, Gatta A. Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology. 1999 Jun;29(6):1662-7. doi: 10.1002/hep.510290619.
PubMed 10347105Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999 May;30(5):890-5. doi: 10.1016/s0168-8278(99)80144-5.
PubMed 10365817
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of Bacterial Overgrowth and Delayed Intestinal Transit in Hepatic Encephalopathy. Phase A: Breath Testing and Colonic Transit in Hepatic Encephalopathy. Phase B: A Randomized Double Blind, Placebo Controlled Trial of Rifaximin for Hepatic Encephalopathy
- ClinicalTrials.gov ID
- NCT00281502
- Acronym / sponsor ID
- Salix-RifaxPSE-BactOvrGrwth-01
- Conditions
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis
- Keywords
- Hepatic Encephalopathy, Hepatitis C, Liver Cirrhosis, Bacterial Overgrowth
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Collaborators
- Bausch Health Americas, Inc.
- Study start
- Dec 2005
- Primary completion
- Dec 2012 (estimated)
- Study completion
- Dec 2012 (estimated)
- First posted
- 24 Jan 2006 (estimated)
- 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.
The study will be conducted in two phases. Phase A will evaluate the contribution of bacterial overgrowth and colonic inertia to development of Hepatic Encephalopathy (HE)in 50 ambulatory subjects with HE and hepatitis C cirrhosis. This phase will include a Screening and Evaluation Visit.
Phase B will evaluate the effect of rifaximin on bacterial outgrowth and severity of HE in 20 of the subjects enrolled in Phase A who have a somewhat greater degree of encephalopathy.
The purpose of this study is to evaluate the following:
- the relationship between bacterial overgrowth and the presence and severity of HE in patients with hepatitis C cirrhosis;
- the effectiveness and tolerability of rifaximin relative to placebo in treatment of HE associated with hepatitis C cirrhosis;
- the relationship between bacterial overgrowth and the presence and severity of HE before and after rifaximin treatment.
Detailed description
Hepatic encephalopathy is a frequent and occasionally refractory complication of cirrhosis and is associated with impaired quality of life. Its severity may not correlate with other parameters of liver dysfunction. Although multiple pathogenic mechanisms for the condition have been proposed, most include the participation of bacterial toxins, especially ammonia, produced in the gastrointestinal tract. Treatment options for hepatic encephalopathy at this time are limited to lactulose and neomycin. Lactulose is frequently poorly tolerated, and many patients are non-compliant with its use. In patients with renal insufficiency in whom hepatic encephalopathy is frequently problematic, use of neomycin is contraindicated due to ototoxicity and nephrotoxicity.
Autonomic dysfunction is common in patients with cirrhosis and could contribute to the development of hepatic encephalopathy by impairment of intestinal motility, leading to bacterial overgrowth and colonic inertia.
The following questions will be addressed:
- Is impaired intestinal transit and bacterial overgrowth associated with the presence and severity of hepatic encephalopathy?
50 patients will undergo a detailed clinical evaluation for severity of liver disease, hepatic encephalopathy and assessment of intestinal transit and bacterial overgrowth with radiographic marker study and breath test analysis. Multivariate analysis will then be performed to determine the relationship of intestinal transit and evidence of bacterial overgrowth with the presence and severity of hepatic encephalopathy.
- Does treatment with rifaximin improve bacterial overgrowth and hepatic encephalopathy?
20 patients from the above population with significant encephalopathy will be randomized to receive either rifaximin or placebo. Post-treatment evaluation for severity of hepatic encephalopathy and breath test analysis for bacterial overgrowth will then be performed. The effect of treatment on changes in hepatic encephalopathy and bacterial overgrowth and the relationship between changes in bacterial overgrowth and severity of hepatic encephalopathy will also be assessed.
Phase A Endpoints: Degree of bacterial overgrowth and its correlation with the grade of hepatic encephalopathy (if present).
Phase B Endpoints: To demonstrate improvement in degree of HE with treatment of Rifaximin
Efficacy Endpoints The primary efficacy endpoint for Phase B of the study will be the change from baseline in the proportion of patients with no HE, minimal HE (no symptoms, abnormal psychometric testing), mild persistent HE (mild symptoms), and persistent Stage II HE (presence of asterixis, history of hospitalization for spontaneous Stage III or IV HE).
Secondary efficacy endpoints for Phase B will be the following:
To demonstrate improvement in intestinal transit time for patients (based on Lactulose Hydrogen Breath Test) To demonstrate improvement in bacterial overgrowth, improved insomnia, flatulence, and quality of life.
To demonstrate that rifaximin improved patients' symptoms of insomnia, flatulence, and quality of life measure with the degree of bacterial overload and the impaired intestinal transit time.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| Rifaximin (drug)Also: XifaxanRifaximin 400mg three (3) times daily | Drug | – |
Primary outcome
Phase A: Degree of bacterial overgrowth and its correlation with the grade of hepatic encephalopathy (if present)
Time frame: 3 months
Phase B: Improvement in the psychometric scores and proportion of patients who change of HE stage
Time frame: 3 months
5 secondary outcomes
Improved Intestinal transit time
Time frame: 3 months
Improvement in bacterial overgrowth
Time frame: 3 months
Improved insomnia
Time frame: 3 months
Improved flatulence
Time frame: 3 months
Improved quality of life.
Time frame: 3 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2010.
- Background: PubMed 11870389Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21. doi: 10.1053/jhep.2002.31250.
- Background: PubMed 12924658Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci. 2003 Aug;48(8):1622-6. doi: 10.1023/a:1024784327783.
- Background: PubMed 10845661Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol. 2000 May;32(5):748-53. doi: 10.1016/s0168-8278(00)80243-3.
- Background: PubMed 9657095Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998 Jul;28(1):45-9. doi: 10.1002/hep.510280108.
- Background: PubMed 10347105Amodio P, Del Piccolo F, Marchetti P, Angeli P, Iemmolo R, Caregaro L, Merkel C, Gerunda G, Gatta A. Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology. 1999 Jun;29(6):1662-7. doi: 10.1002/hep.510290619.
- Background: PubMed 10365817Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodes J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999 May;30(5):890-5. doi: 10.1016/s0168-8278(99)80144-5.
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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.
Sam Sigal, M.D. principal investigator
Weill Medical College of Cornell University
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 Rifaximin (drug) in people with Hepatic Encephalopathy and Hepatitis C, run by Weill Medical College of Cornell University 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?
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: status not confirmed, as of the sponsor's last update on 5 Nov 2010. 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. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sam Sigal, M.D. (646 962-5483, shs2015@med.cornell.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase A: Degree of bacterial overgrowth and its correlation with the grade of hepatic encephalopathy (if present) (time frame: 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00281502, which also lists 6 linked publications.
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 5 Nov 2010.