Hepatic EncephalopathyPhase 3NCT00298038

A 6-month Efficacy, Safety, and Tolerability Study of Rifaximin In Preventing Hepatic Encephalopathy

A Phase 3 study testing Rifaximin in people with Hepatic Encephalopathy, run by Bausch Health Americas, Inc..

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Trial summary

The purpose of this study is to determine if the study drug is safe and effective in preventing hepatic encephalopathy (HE). Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Hepatic Encephalopathy
What is being tested?: Rifaximin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 299 participants
Where: No sites listed yet
Study dates: 19 Dec 2005to 15 Aug 2008
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

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 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Must sign an Informed Consent Form
In remission from past HE
Uses appropriate birth control measures
More than or equal to 18 years of age
Must have potential to benefit from treatment
Recent prior HE episodes

Show all 10Show fewer

Capable and willing to comply with all study procedures
Participant has personal support available
Has a certain Model End Stage Liver Disease (MELD) score
Recent transjugular intrahepatic portosystemic shunt (TIPS) placement or revision

Who cannot join

Significant medical conditions, medical conditions that may impact study participation, or Investigator decision not to include
Allergies to the study drug or similar drugs
Laboratory abnormalities
Recent participation in another clinical trial
History of non-compliance
Pregnant or at risk of pregnancy, or is lactating

Show all 15Show fewer

Recent alcohol consumption
Active bacterial or viral Infections
Bowel issues
Active malignancy
On a prohibited medication
Liver transplant expected in near term
Lactulose intolerance
Participant shows presence of intestinal obstruction or has inflammatory bowel disease
Ongoing or recent GI bleed

About this study

Official title: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy, Safety and Tolerability of Rifaximin 550 mg BID For 6 Months In Preventing Hepatic Encephalopathy

The purpose of this study is to determine if the study drug is safe and effective in preventing hepatic encephalopathy (HE).

Conditions: Hepatic Encephalopathy
Being tested: Rifaximin, Placebo
Medical subject headings: Hepatic Encephalopathy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RifaximinDrug
Also called Xifaxan®
Oral
PlaceboDrug
Oral

Study groups in NCT00298038
Study group	Role	What they receive
Rifaximin	Experimental	Participants were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for 6 months or until a breakthrough episode of hepatic encephalopathy or another reason for discontinuation. Receives: Drug: Rifaximin
Placebo	Placebo comparator	Participants were administered a single matching placebo tablet 2 times per day (approximately every 12 hours) for 6 months or until a breakthrough episode of hepatic encephalopathy or another reason for discontinuation. Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Time To The First Breakthrough Overt HE Episode
Time to a breakthrough overt HE episode was the duration (number of days) from time of first dose of study drug to the first breakthrough overt HE episode. A breakthrough overt HE episode was defined as an increase of Conn score from Grade 0 or 1 to ≥2, or an increase in Conn and asterixis score of 1 grade each for those participants who entered the study with a Conn score of 0. Participants who completed the study and did not experience a breakthrough overt HE episode were censored at the time of their 6-month visit. Participants who terminated early for reasons other than a breakthrough overt HE episode were contacted at 6 months from randomization to determine if they had experienced a breakthrough overt HE event or other outcome. Participants without breakthrough overt HE were censored at the time of last contact or death, whichever was earlier. The number of events of a first breakthrough overt HE episode during the treatment interval is presented.
Measured: Baseline up to 6 Months (168 days)

Secondary outcomes (5)

Time To First HE-related Hospitalization
Time to first HE-related hospitalization is defined as the duration (number of days) between the first dose of study drug and the date of first HE-related hospitalization. Participants who discontinued prior to hospitalization due to HE and prior to completion of the 6-month treatment period were censored at the time of discontinuation. The number of participants with their first HE-related hospitalization per interval is presented. The number of events of the first HE-related hospitalization during the treatment interval is presented.
Measured: Baseline up to 6 months
Time To Any Increase From Baseline In Conn Score
Time to any increase in Conn score (mental state grade) was computed as the number of days from the first dose of study drug to the initial occurrence of an increase from baseline in Conn score. Conn score range: Grade 0 (no behavioral abnormality) to Grade 4 (coma; unable to test mental state). Participants who discontinued prior to experiencing an increase in Conn score and prior to completion of the 6-month treatment period were censored at the time of discontinuation. The number of events of the initial occurrence of an increase from baseline in Conn score during the treatment interval is presented.
Measured: Baseline up to 6 months
Time To Any Increase From Baseline In Asterixis Grade
Time to any increase in asterixis grade was computed as the number of days from the first dose of study drug to the initial occurrence of an increase from baseline in asterixis grade. Asterixis (flapping tremor) was determined with the participant holding both arms and forearms extended with wrists dorsiflexed and fingers open for ≥30 seconds per standard practice. Asterixis grade range: Grade 0 (no abnormal movement) to Grade 4 (almost continuous flapping motions). Participants who discontinued prior to experiencing an increase in asterixis grade and prior to completion of the 6-month treatment period were censored at the time of discontinuation. The number of events of the initial occurrence of an increase from baseline in asterixis grade during the treatment interval is presented.
Measured: Baseline up to 6 months
Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment
The 29-item Chronic Liver Disease Questionnaire (CLDQ) questionnaire consists of the following domains: fatigue, activity, emotional function, abdominal symptoms, systemic symptoms, and worry. Participants ranked their level of fatigue by using a 7-point scale from the worst response (1, high degree of fatigue) to the best response (7, minimal fatigue).
Measured: Baseline, 6 months (End Of Treatment)
Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment
Venous blood samples (10 mL) were collected at Baseline/Randomization (Day 0) and Days 28, 84, and 168. Baseline value was the last available value prior to first dose of study drug, and end of treatment value was the last available post-baseline value during the treatment period.
Measured: Baseline, Month 6 (End Of Treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

19 Dec 200515 Aug 2008

First posted1 Mar 2006 (estimated)
Study start19 Dec 2005
Primary completion15 Aug 2008
Study completion15 Aug 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (4)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 Bausch Health Americas, Inc.The 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 3
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 299 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00298038
Sponsor's protocol ID: RFHE3001
Status last verified: Sep 2019
First submitted: 28 Feb 2006
Last updated: 18 Sep 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2023 Jul 19;7(7):CD011585. doi: 10.1002/14651858.CD011585.pub2.
PubMed 37467180
Flamm SL, Mullen KD, Heimanson Z, Sanyal AJ. Rifaximin has the potential to prevent complications of cirrhosis. Ther Adv Gastroenterol. 2018 Sep 28;11:1756284818800307. doi: 10.1177/1756284818800307. eCollection 2018.
PubMed 30283499
Sanyal A, Younossi ZM, Bass NM, Mullen KD, Poordad F, Brown RS, Vemuru RP, Mazen Jamal M, Huang S, Merchant K, Bortey E, Forbes WP. Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011 Oct;34(8):853-61. doi: 10.1111/j.1365-2036.2011.04808.x. Epub 2011 Aug 17.
PubMed 21848797
Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. doi: 10.1056/NEJMoa0907893.
PubMed 20335583

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Effect of Mini-Program Monitoring on Hepatic Encephalopathy in Post-TIPS Patients
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Daridorexant for Sleep Disturbance in Adults With Liver Cirrhosis
Liver Cirrhosis, Sleep Disturbance
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Equivalence of Electronic vs Paper-based PHES in Diagnosing Hepatic Encephalopathy
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Recruiting
4D-Flow MRI Assessment of Portal Hypertension and TIPS Outcomes in Cirrhosis
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Active, not recruitingPhase 1/2
RTX001 Autologous Engineered Macrophages for Liver Cirrhosis
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All Hepatic Encephalopathy trials

Study at a glance

From the registry record, last updated by the sponsor on 18 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy, Safety and Tolerability of Rifaximin 550 mg BID For 6 Months In Preventing Hepatic Encephalopathy
ClinicalTrials.gov ID: NCT00298038
Acronym / sponsor ID: RFHE3001
Conditions: Hepatic Encephalopathy
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 299 participants (actual)
Lead sponsor: Bausch Health Americas, Inc.Industry (pharma, biotech, devices)
Study start: 19 Dec 2005 (actual)
Primary completion: 15 Aug 2008 (actual)
Study completion: 15 Aug 2008 (actual)
First posted: 1 Mar 2006 (estimated)
Results: Posted 14 Aug 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The purpose of this study is to determine if the study drug is safe and effective in preventing hepatic encephalopathy (HE).

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 2

Arm	Type	Receives
Rifaximin	Experimental	Drug: RifaximinParticipants were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for 6 months or until a breakthrough episode of hepatic encephalopathy or another reason for discontinuation.
Placebo	Placebo comparator	Drug: PlaceboParticipants were administered a single matching placebo tablet 2 times per day (approximately every 12 hours) for 6 months or until a breakthrough episode of hepatic encephalopathy or another reason for discontinuation.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (10 listed)

Must sign an Informed Consent Form
In remission from past HE
Uses appropriate birth control measures
More than or equal to 18 years of age
Must have potential to benefit from treatment

Key exclusion criteria (15 listed)

Significant medical conditions, medical conditions that may impact study participation, or Investigator decision not to include
Allergies to the study drug or similar drugs
Laboratory abnormalities
Recent participation in another clinical trial
History of non-compliance

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
RifaximinAlso: Xifaxan®Oral	Drug	Rifaximin
PlaceboOral	Drug	Placebo

Primary outcome

Time To The First Breakthrough Overt HE Episode
Time frame: Baseline up to 6 Months (168 days)
Time to a breakthrough overt HE episode was the duration (number of days) from time of first dose of study drug to the first breakthrough overt HE episode. A breakthrough overt HE episode was defined as an increase of Conn score from Grade 0 or 1 to ≥2, or an increase in Conn and asterixis score of 1 grade each for those participants who entered the study with a Conn score of 0. Participants who completed the study and did not experience a breakthrough overt HE episode were censored at the time of their 6-month visit. Participants who terminated early for reasons other than a breakthrough overt HE episode were contacted at 6 months from randomization to determine if they had experienced a breakthrough overt HE event or other outcome. Participants without breakthrough overt HE were censored at the time of last contact or death, whichever was earlier. The number of events of a first breakthrough overt HE episode during the treatment interval is presented.

5 secondary outcomes

Time To First HE-related Hospitalization
Time frame: Baseline up to 6 months
Time To Any Increase From Baseline In Conn Score
Time frame: Baseline up to 6 months
Time To Any Increase From Baseline In Asterixis Grade
Time frame: Baseline up to 6 months
Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment
Time frame: Baseline, 6 months (End Of Treatment)
Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment
Time frame: Baseline, Month 6 (End Of Treatment)

Results and safety

Results posted to the registry on 14 Aug 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Rifaximin	140	88
Placebo	159	66

Primary outcome: Time To The First Breakthrough Overt HE Episode

Time frame: Baseline up to 6 Months (168 days). Number. Unit: events

Measure	Rifaximin n = 140	Placebo n = 159
0 to <28 Days	13	20
28 to <56 Days	4	23
56 to <84 Days	6	14
84 to <140 Days	7	10
140 to <168 Days	1	6
≥168 Days	0	0

Rifaximin vs Placebo: Hazard Ratio (HR): 0.421 (95% CI 0.276 to 0.641), p <0.0001, Cox proportional hazards model

Population analysed: Randomized participants who received at least 1 dose of study drug (ITT population). Assuming censored cases were at risk for half of the interval for onset of breakthrough HE episode, the censored cases only counted for half in figuring number at risk. Numbers at risk were rounded up to whole integers.

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: Baseline up to 6.5 months. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Rifaximin	51 of 140 (36.4%)	91 of 140 (65%)	Not reported
Placebo	63 of 159 (39.6%)	101 of 159 (63.5%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 37467180Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2023 Jul 19;7(7):CD011585. doi: 10.1002/14651858.CD011585.pub2.
Derived from this study: PubMed 30283499Flamm SL, Mullen KD, Heimanson Z, Sanyal AJ. Rifaximin has the potential to prevent complications of cirrhosis. Ther Adv Gastroenterol. 2018 Sep 28;11:1756284818800307. doi: 10.1177/1756284818800307. eCollection 2018.
Derived from this study: PubMed 21848797Sanyal A, Younossi ZM, Bass NM, Mullen KD, Poordad F, Brown RS, Vemuru RP, Mazen Jamal M, Huang S, Merchant K, Bortey E, Forbes WP. Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011 Oct;34(8):853-61. doi: 10.1111/j.1365-2036.2011.04808.x. Epub 2011 Aug 17.
Derived from this study: PubMed 20335583Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. doi: 10.1056/NEJMoa0907893.

Related trials for Hepatic Encephalopathy

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Equivalence of Electronic vs Paper-based PHES in Diagnosing Hepatic Encephalopathy
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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.

Lindsey Mathew study director

Bausch Health Companies

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Rifaximin in people with Hepatic Encephalopathy, run by Bausch Health Americas, Inc..

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 15 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 18 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Time To The First Breakthrough Overt HE Episode (time frame: Baseline up to 6 Months (168 days)). 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 NCT00298038, which also lists 4 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 18 Sep 2019.