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

Primary Purpose

Hepatic Encephalopathy, Cirrhosis

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Rifaximin
Lactulose
Sponsored by
Bausch Health Americas, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatic Encephalopathy focused on measuring Liver Failure, Hepatic Insufficiency, Liver Diseases, Brain Diseases, Rifaximin, Cirrhosis

Eligibility Criteria

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

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.

Sites / Locations

  • Banner Research
  • Southern California Liver Centers
  • UCSF/Fresno - CRMC
  • UCSD Clinical & Translational Research Institute
  • Salix Site
  • Inland Empire Liver Foundation
  • Salix Site
  • Salix Site
  • Salix Site
  • University of Colorado Denver
  • South Denver GI
  • University of Florida Hepatology
  • Tampa General Medical Group
  • Gastroenterology Associates
  • Salix Site
  • Indiana University
  • Central Iowa Hospital Corp
  • Salix Site
  • Delta Research Partners, LLC
  • The Center for Liver and Biliary Disease
  • Brigham and Women's Hospital Division of Gastroenterology & Hepatology
  • Mayo Clinic
  • Kansas City Research Institute
  • St. Louis University
  • Univ. of Nebraska Medical Center
  • Concorde Medical Group PLLC
  • New York University Medical Center
  • Salix Site
  • Columbia University Medical Ctr. Center for Liver Disease & Transplantation
  • University of Rochester Strong Memorial Hospital
  • Asheville Gastroenterology Associates, PA
  • UNC School of Medicine/Division of Gastroenterology and Hepatology
  • Carolina Medical Center
  • Integris Nazh Zuhdi Transplant Institute
  • Albert Einstien Medical Center
  • Research Specialists of Texas
  • Amcare Research Inc
  • Salix Site
  • Alamo Medical Research
  • Methodist Hospital
  • University of Utah Hospital
  • VCU/MCV Health Systems
  • University of Wisconsin Hospital & Clinics

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Rifaximin 550 mg BID

Rifaximin 550 mg BID + Lactulose

Arm Description

Participants will receive rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Number of Participants Who Died Due to Any Reason

Full Information

First Posted
April 16, 2013
Last Updated
September 6, 2019
Sponsor
Bausch Health Americas, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01842581
Brief Title
The Safety/Efficacy of Rifaximin With/Without Lactulose in Participants With A History of Recurrent Hepatic Encephalopathy
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Completed
Study Start Date
January 8, 2013 (Actual)
Primary Completion Date
December 17, 2014 (Actual)
Study Completion Date
December 17, 2014 (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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Encephalopathy, Cirrhosis
Keywords
Liver Failure, Hepatic Insufficiency, Liver Diseases, Brain Diseases, Rifaximin, Cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
222 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rifaximin 550 mg BID
Arm Type
Experimental
Arm Description
Participants will receive rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.
Arm Title
Rifaximin 550 mg BID + Lactulose
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rifaximin
Other Intervention Name(s)
Xifaxan®
Intervention Description
Rifaximin will be administered per the dose and schedule specified in the arms.
Intervention Type
Drug
Intervention Name(s)
Lactulose
Intervention Description
Laculose will be administered per the schedule specified in the respective arm.
Primary Outcome Measure Information:
Title
Number of Participants Reporting a First Breakthrough HE Episode
Description
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.
Time Frame
From randomization (Day 1) up to Day 170
Secondary Outcome Measure Information:
Title
Number of Participants Who Were Hospitalized Due to HE Episode
Description
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.
Time Frame
From randomization (Day 1) up to Day 170
Title
Number of Participants Who Died Due to Any Reason
Time Frame
From randomization (Day 1) up to end of study (Day 186)
Other Pre-specified Outcome Measures:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
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.
Time Frame
From randomization (Day 1) up to end of study (Day 186)
Title
Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170
Description
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.
Time Frame
Baseline, Day 170
Title
Change From Baseline in Critical Flicker Frequency (CFF) at Day 170
Description
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.
Time Frame
Baseline, Day 170

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lindsey Mathew
Organizational Affiliation
Bausch Health Americas, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Banner Research
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
Southern California Liver Centers
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
UCSF/Fresno - CRMC
City
Fresno
State/Province
California
ZIP/Postal Code
93721
Country
United States
Facility Name
UCSD Clinical & Translational Research Institute
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
Salix Site
City
Long Beach
State/Province
California
ZIP/Postal Code
90822
Country
United States
Facility Name
Inland Empire Liver Foundation
City
Rialto
State/Province
California
ZIP/Postal Code
92377
Country
United States
Facility Name
Salix Site
City
Riverside
State/Province
California
ZIP/Postal Code
92501
Country
United States
Facility Name
Salix Site
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
Salix Site
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
University of Colorado Denver
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
South Denver GI
City
Englewood
State/Province
Colorado
ZIP/Postal Code
80113
Country
United States
Facility Name
University of Florida Hepatology
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0277
Country
United States
Facility Name
Tampa General Medical Group
City
Tampa
State/Province
Florida
ZIP/Postal Code
33605
Country
United States
Facility Name
Gastroenterology Associates
City
Macon
State/Province
Georgia
ZIP/Postal Code
31201
Country
United States
Facility Name
Salix Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Central Iowa Hospital Corp
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50309-1453
Country
United States
Facility Name
Salix Site
City
Jefferson
State/Province
Louisiana
ZIP/Postal Code
70124
Country
United States
Facility Name
Delta Research Partners, LLC
City
Monroe
State/Province
Louisiana
ZIP/Postal Code
71201
Country
United States
Facility Name
The Center for Liver and Biliary Disease
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21202-2165
Country
United States
Facility Name
Brigham and Women's Hospital Division of Gastroenterology & Hepatology
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Kansas City Research Institute
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64131
Country
United States
Facility Name
St. Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Univ. of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-3285
Country
United States
Facility Name
Concorde Medical Group PLLC
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Salix Site
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Columbia University Medical Ctr. Center for Liver Disease & Transplantation
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Rochester Strong Memorial Hospital
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Asheville Gastroenterology Associates, PA
City
Asheville
State/Province
North Carolina
ZIP/Postal Code
28801
Country
United States
Facility Name
UNC School of Medicine/Division of Gastroenterology and Hepatology
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7584
Country
United States
Facility Name
Carolina Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
Integris Nazh Zuhdi Transplant Institute
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
Albert Einstien Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19141
Country
United States
Facility Name
Research Specialists of Texas
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Amcare Research Inc
City
Houston
State/Province
Texas
ZIP/Postal Code
77090
Country
United States
Facility Name
Salix Site
City
Odessa
State/Province
Texas
ZIP/Postal Code
79761
Country
United States
Facility Name
Alamo Medical Research
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
Methodist Hospital
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Utah Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
VCU/MCV Health Systems
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
University of Wisconsin Hospital & Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

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

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