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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01842581
Recruitment Status : Completed
First Posted : April 29, 2013
Results First Posted : September 9, 2019
Last Update Posted : September 9, 2019
Sponsor:
Information provided by (Responsible Party):
Bausch Health Americas, Inc.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Hepatic Encephalopathy Cirrhosis Drug: Rifaximin Drug: Lactulose Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 222 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 8, 2013
Actual Primary Completion Date : December 17, 2014
Actual Study Completion Date : December 17, 2014

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Arms and Interventions
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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 Name: 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 Name: Xifaxan®

Drug: Lactulose
Laculose will be administered per the schedule specified in the respective arm.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Reporting a First Breakthrough HE Episode [ Time Frame: From randomization (Day 1) up to Day 170 ]
    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 :
  1. Number of Participants Who Were Hospitalized Due to HE Episode [ Time Frame: From randomization (Day 1) up to Day 170 ]
    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.

  2. Number of Participants Who Died Due to Any Reason [ Time Frame: From randomization (Day 1) up to end of study (Day 186) ]

Other Outcome Measures:
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From randomization (Day 1) up to end of study (Day 186) ]
    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.

  2. Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 [ Time Frame: Baseline, 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.

  3. Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 [ Time Frame: Baseline, 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01842581


Locations
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Sponsors and Collaborators
Bausch Health Americas, Inc.
Investigators
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Study Director: Lindsey Mathew Bausch Health Americas, Inc.
More Information
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Responsible Party: Bausch Health Americas, Inc.
ClinicalTrials.gov Identifier: NCT01842581    
Other Study ID Numbers: RFHE4044
First Posted: April 29, 2013    Key Record Dates
Results First Posted: September 9, 2019
Last Update Posted: September 9, 2019
Last Verified: September 2019
Keywords provided by Bausch Health Americas, Inc.:
Liver Failure
Hepatic Insufficiency
Liver Diseases
 Brain Diseases
Rifaximin
Cirrhosis
Additional relevant MeSH terms:
Layout table for MeSH terms
Hepatic Encephalopathy
Brain Diseases
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Central Nervous System Diseases
Nervous System Diseases
Liver Failure
 Hepatic Insufficiency
Brain Diseases, Metabolic
Metabolic Diseases
Rifaximin
Lactulose
Anti-Bacterial Agents
Anti-Infective Agents
Gastrointestinal Agents