The Safety/Efficacy of Rifaximin With/Without Lactulose in Participants With A History of Recurrent Hepatic Encephalopathy

A Multicenter, Randomized, Open-Label, Active-Controlled, Trial to Evaluate the Safety and Efficacy of Rifaximin 550 mg With and Without Lactulose in Subjects With a History of Recurrent Overt Hepatic Encephalopathy

The purpose of the study is to evaluate if rifaximin alone or rifaximin plus lactulose delays the onset of hepatic encephalopathy (HE) in participants with cirrhosis who have had a previous episode of HE.

Study Overview

• Status: Completed
• Conditions: Hepatic Encephalopathy; Cirrhosis
• Intervention / Treatment: Drug: Rifaximin; Drug: Lactulose

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Banner Research
  • California
    • Coronado, California, United States, 92118
      • Southern California Liver Centers
    • Fresno, California, United States, 93721
      • UCSF/Fresno - CRMC
    • La Jolla, California, United States, 92037
      • UCSD Clinical & Translational Research Institute
    • Long Beach, California, United States, 90822
      • Salix Site
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • Riverside, California, United States, 92501
      • Salix Site
    • San Diego, California, United States, 92103
      • Salix Site
    • San Francisco, California, United States, 94115
      • Salix Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
    • Englewood, Colorado, United States, 80113
      • South Denver GI
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University Of Florida Hepatology
    • Tampa, Florida, United States, 33605
      • Tampa General Medical Group
  • Georgia
    • Macon, Georgia, United States, 31201
      • Gastroenterology Associates
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Salix Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Des Moines, Iowa, United States, 50309-1453
      • Central Iowa Hospital Corp
  • Louisiana
    • Jefferson, Louisiana, United States, 70124
      • Salix Site
    • Monroe, Louisiana, United States, 71201
      • Delta Research Partners, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202-2165
      • The Center for Liver and Biliary Disease
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital Division of Gastroenterology & Hepatology
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3285
      • Univ. of Nebraska Medical Center
  • New York
    • New York, New York, United States, 10016
      • New York University Medical Center
    • New York, New York, United States, 10016
      • Concorde Medical Group PLLC
    • New York, New York, United States, 10016
      • Salix Site
    • New York, New York, United States, 10032
      • Columbia University Medical Ctr. Center for Liver Disease & Transplantation
    • Rochester, New York, United States, 14642
      • University of Rochester Strong Memorial Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Asheville Gastroenterology Associates, PA
    • Chapel Hill, North Carolina, United States, 27599-7584
      • UNC School of Medicine/Division of Gastroenterology and Hepatology
    • Charlotte, North Carolina, United States, 28204
      • Carolina Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Nazh Zuhdi Transplant Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstien Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Research Specialists of Texas
    • Houston, Texas, United States, 77090
      • Amcare Research Inc
    • Odessa, Texas, United States, 79761
      • Salix Site
    • San Antonio, Texas, United States, 78215
      • Alamo Medical Research
    • San Antonio, Texas, United States, 78229
      • Methodist Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • VCU/MCV Health Systems
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital & Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or non-pregnant, non-lactating females greater than or equal to (≥) 18 years old.
• In remission from demonstrated overt HE (Conn score 0 or 1).
• Have had one or more episodes of overt HE associated with cirrhosis within 6 months prior to screening visit (Day -7 to -1).
• Participant has a close family member or other personal contact who is familiar with the participant's HE and can provide continuing oversight to the participant and is willing to perform as caregiver for the participant during the conduct of the trial.

Exclusion Criteria:

• Participant has been diagnosed with human immunodeficiency virus (HIV) as determined by medical history.
• History of tuberculosis infection.
• Participant has been diagnosed with chronic respiratory insufficiency.
• Participant has been diagnosed with a current infection for which they are currently taking oral or parenteral antibiotics.
• Renal insufficiency requiring routine dialysis.
• Participant has an active spontaneous bacterial peritonitis(SBP) infection.
• Intestinal obstruction or inflammatory bowel disease.
• Participant has active malignancy within the last 5 years prior to screening visit, except basal cell carcinoma of the skin, or if female, in situ cervical carcinoma that has been surgically excised.
• Current gastrointestinal (GI) bleeding or has a history of a GI hemorrhage of sufficient severity to require hospitalization and a transfusion of ≥2 units of blood within 3 months prior to screening visit.
• Participant is anemic, as defined by a hemoglobin of less than (<) 8 grams/deciliter (g/dL).
• Scheduled to receive a liver transplant within 1 month of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rifaximin 550 mg BID; Participants will receive rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.	Drug: Rifaximin; Rifaximin will be administered per the dose and schedule specified in the arms.; Other Names: Xifaxan®
Experimental: Rifaximin 550 mg BID + Lactulose; Participants will receive rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose will be self-titrated by the participant to produce 2 to 3 soft stools per day.	Drug: Rifaximin; Rifaximin will be administered per the dose and schedule specified in the arms.; Other Names: Xifaxan®; Drug: Lactulose; Laculose will be administered per the schedule specified in the respective arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting a First Breakthrough HE Episode	A breakthrough HE episode was defined as an increase of the Conn score to Grade greater than or equal to (≥) 2 (ie, 0 or 1 to ≥ 2). Conn score is widely used as a measure of mental state in HE. The scale used in Conn scoring system include: Grade 0=No personality or behavioral abnormality; Grade 1=Trivial lack of awareness, euphoria, or anxiety; shortened attention span, impairment of addition or subtraction; Grade 2=Lethargy, disorientation for time, obvious personality change, inappropriate behaviour; Grade 3=Somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behaviour; Grade 4=Coma, unable to test mental state. The time to the first breakthrough HE episode was defined as the duration between the date of first dose of study drug and the date of first breakthrough HE episode. Number of participants reporting a first breakthrough HE episode during randomization to Month 6 is presented.	From randomization (Day 1) up to Day 170

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Were Hospitalized Due to HE Episode	An HE-related hospitalization was defined as a hospitalization directly resulting from HE, or when HE events occurred during hospitalization. The time to first HE-related hospitalization was defined as the duration between the date of first dose of study drug and the date of first HE-related hospitalization. Number of participants who were hospitalized due to HE episode during randomization to Month 6 is presented.	From randomization (Day 1) up to Day 170
Number of Participants Who Died Due to Any Reason		From randomization (Day 1) up to end of study (Day 186)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAE was defined as an AE that occurred from first dose of study drug until last dose of study drug plus 5 days (for non-fatal AEs) or plus 30 days (for fatal AEs).A summary of non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	From randomization (Day 1) up to end of study (Day 186)
Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170	CLDQ was used to measure health-related quality of life. CLDQ includes 29 items in the following 6 domains: abdominal symptoms (3 items), fatigue (5 items), systemic symptoms (5 items), activity (3 items), emotional function (8 items), and worry (5 items). All items were measured on a 7-point Likert scale, ranging from 0 to 6 with higher values indicating better quality of life. Each domain score of CLDQ was calculated as the mean of the responses of items in that domain. Overall CLDQ score was obtained by adding scores for each item and dividing by the total number of items. Overall CLDQ score ranged from 0 (most impairment) to 6 (least impairment) with higher scores indicating better quality of life. If at least half of the items were non-missing for a domain, mean values of the non-missing items for that domain were used as imputed values for missing values. If more than half of the items in a domain were missing, no values were imputed and domain score was considered as missing.	Baseline, Day 170
Change From Baseline in Critical Flicker Frequency (CFF) at Day 170	The critical flicker frequency (CFF), a validated assessment of neurological function was assessed using a specialized CFF instrument. The CFF is the frequency at which the participant observes a constant light transition to a flickering light and was measured in Hertz. The CFF was measured on a continuous scale and was the mean of 8 separate fusion-to-flicker transition tests performed in rapid succession. Increases in CFF results represent improvement in neurological function in participants with HE.	Baseline, Day 170

Collaborators and Investigators

• Sponsor: Bausch Health Americas, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2013
• Primary Completion (Actual): December 17, 2014
• Study Completion (Actual): December 17, 2014

Study Registration Dates

• First Submitted: April 16, 2013
• First Submitted That Met QC Criteria: April 24, 2013
• First Posted (Estimate): April 29, 2013

Study Record Updates

• Last Update Posted (Actual): September 9, 2019
• Last Update Submitted That Met QC Criteria: September 6, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Cirrhosis; Liver Diseases; Brain Diseases; Rifaximin; Liver Failure; Hepatic Insufficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Brain Diseases, Metabolic; Fibrosis; Hepatic Encephalopathy; Brain Diseases; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin; Lactulose
• Other Study ID Numbers: RFHE4044