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

Primary Purpose

Hepatic Encephalopathy

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Rifaximin
Placebo
Sponsored by
Bausch Health Americas, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Hepatic Encephalopathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 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 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 Exclusion Criteria: 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 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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Rifaximin

    Placebo

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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.
    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.
    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.
    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).
    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.

    Full Information

    First Posted
    February 28, 2006
    Last Updated
    September 6, 2019
    Sponsor
    Bausch Health Americas, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00298038
    Brief Title
    A 6-month Efficacy, Safety, and Tolerability Study of Rifaximin In Preventing Hepatic Encephalopathy
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2019
    Overall Recruitment Status
    Completed
    Study Start Date
    December 19, 2005 (Actual)
    Primary Completion Date
    August 15, 2008 (Actual)
    Study Completion Date
    August 15, 2008 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Bausch Health Americas, Inc.

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hepatic Encephalopathy

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    299 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Rifaximin
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Rifaximin
    Other Intervention Name(s)
    Xifaxan®
    Intervention Description
    Oral
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Oral
    Primary Outcome Measure Information:
    Title
    Time To The First Breakthrough Overt HE Episode
    Description
    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.
    Time Frame
    Baseline up to 6 Months (168 days)
    Secondary Outcome Measure Information:
    Title
    Time To First HE-related Hospitalization
    Description
    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.
    Time Frame
    Baseline up to 6 months
    Title
    Time To Any Increase From Baseline In Conn Score
    Description
    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.
    Time Frame
    Baseline up to 6 months
    Title
    Time To Any Increase From Baseline In Asterixis Grade
    Description
    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.
    Time Frame
    Baseline up to 6 months
    Title
    Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment
    Description
    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).
    Time Frame
    Baseline, 6 months (End Of Treatment)
    Title
    Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment
    Description
    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.
    Time Frame
    Baseline, Month 6 (End Of Treatment)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 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 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 Exclusion Criteria: 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 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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Lindsey Mathew
    Organizational Affiliation
    Bausch Health Companies
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    30283499
    Citation
    Flamm SL, Mullen KD, Heimanson Z, Sanyal AJ. Rifaximin has the potential to prevent complications of cirrhosis. Therap Adv Gastroenterol. 2018 Sep 28;11:1756284818800307. doi: 10.1177/1756284818800307. eCollection 2018.
    Results Reference
    derived
    PubMed Identifier
    21848797
    Citation
    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.
    Results Reference
    derived
    PubMed Identifier
    20335583
    Citation
    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.
    Results Reference
    derived

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

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