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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hepatic Encephalopathy, Cirrhosis

Intervention / Treatment
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* Drug: Rifaximin
* Drug: Lactulose


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin 550 mg BID<br>Participants will receive rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks. | Drug: Rifaximin<br>* Rifaximin will be administered per the dose and schedule specified in the arms.<br>* Other names: Xifaxan®;|
| Experimental: Rifaximin 550 mg BID + Lactulose<br>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<br>* Rifaximin will be administered per the dose and schedule specified in the arms.<br>* Other names: Xifaxan®;Drug: Lactulose<br>* Laculose will be administered per the schedule specified in the respective arm.<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Failure, Hepatic Insufficiency, Liver Diseases, Brain Diseases, Rifaximin, Cirrhosis