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

• ClinicalTrials.gov Identifier: NCT00298038
• Recruitment Status: Completed
• First Posted: March 1, 2006
• Results First Posted: August 14, 2019
• Last Update Posted: September 18, 2019
• Sponsor: Bausch Health Americas, Inc.
• Information provided by (Responsible Party): Bausch Health Americas, Inc.

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).

Condition or disease	Intervention/treatment	Phase
Hepatic Encephalopathy	Drug: Rifaximin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 299 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: December 19, 2005
• Actual Primary Completion Date: August 15, 2008
• Actual Study Completion Date: August 15, 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rifaximin; 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.	Drug: Rifaximin; Oral; Other Name: Xifaxan®
Placebo Comparator: Placebo; 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.	Drug: Placebo; Oral

Outcome Measures

Primary Outcome Measures :

1. Time To The First Breakthrough Overt HE Episode [ Time Frame: Baseline up to 6 Months (168 days) ]
   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 :

1. Time To First HE-related Hospitalization [ Time Frame: Baseline up to 6 months ]
   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.
2. Time To Any Increase From Baseline In Conn Score [ Time Frame: Baseline up to 6 months ]
   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.
3. Time To Any Increase From Baseline In Asterixis Grade [ Time Frame: Baseline up to 6 months ]
   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.
4. Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment [ Time Frame: Baseline, 6 months (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).
5. Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment [ Time Frame: Baseline, Month 6 (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.

Eligibility Criteria

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

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

Contacts and Locations

Sponsors and Collaborators

Bausch Health Americas, Inc.

Investigators

• Study Director: Lindsey Mathew; Bausch Health Companies

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Bausch Health Americas, Inc.
• ClinicalTrials.gov Identifier: NCT00298038
• Other Study ID Numbers: RFHE3001
• First Posted: March 1, 2006
• Results First Posted: August 14, 2019
• Last Update Posted: September 18, 2019
• Last Verified: September 2019

Additional relevant MeSH terms:

Hepatic Encephalopathy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Metabolic Diseases; Rifaximin; Anti-Bacterial Agents; Anti-Infective Agents; Gastrointestinal Agents