Trial Outcomes & Findings for A 6-month Efficacy, Safety, and Tolerability Study of Rifaximin In Preventing Hepatic Encephalopathy (NCT NCT00298038)

Last Updated: 2019-09-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

299 participants

Primary outcome timeframe

Baseline up to 6 Months (168 days)

Results posted on

2019-09-18

Participant Flow

Participants were to be withdrawn from the study after experiencing a breakthrough overt hepatic encephalopathy (HE) episode.

Participant milestones

Participant milestones
Measure	Rifaximin Participants were administered a single rifaximin 550 milligrams (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.	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.
Overall Study STARTED	140	159
Overall Study Received At Least 1 Dose Of Study Drug	140	159
Overall Study COMPLETED	88	66
Overall Study NOT COMPLETED	52	93

Reasons for withdrawal

Reasons for withdrawal
Measure	Rifaximin Participants were administered a single rifaximin 550 milligrams (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.	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.
Overall Study Lost to Follow-up	0	1
Overall Study Liver Transplant	0	1
Overall Study Protocol Violation	1	3
Overall Study Death	6	3
Overall Study Withdrawal by Subject	6	9
Overall Study Adverse Event	8	7
Overall Study Breakthrough overt HE episode	28	69
Overall Study Noncompliance	1	0
Overall Study Cocaine Abuse	1	0
Overall Study Severe Gastrointestinal Bleed	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.	Total n=299 Participants Total of all reporting groups
Age, Continuous	55.5 years STANDARD_DEVIATION 9.57 • n=99 Participants	56.8 years STANDARD_DEVIATION 9.18 • n=107 Participants	56.2 years STANDARD_DEVIATION 56.0 • n=206 Participants
Sex: Female, Male Female	65 Participants n=99 Participants	52 Participants n=107 Participants	117 Participants n=206 Participants
Sex: Female, Male Male	75 Participants n=99 Participants	107 Participants n=107 Participants	182 Participants n=206 Participants

PRIMARY outcome

Timeframe: Baseline up to 6 Months (168 days)

Population: Randomized participants who received at least 1 dose of study drug (ITT population). Assuming censored cases were at risk for half of the interval for onset of breakthrough HE episode, the censored cases only counted for half in figuring number at risk. Numbers at risk were rounded up to whole integers.

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Time To The First Breakthrough Overt HE Episode 0 to <28 Days	13 events	20 events
Time To The First Breakthrough Overt HE Episode 28 to <56 Days	4 events	23 events
Time To The First Breakthrough Overt HE Episode 56 to <84 Days	6 events	14 events
Time To The First Breakthrough Overt HE Episode 84 to <140 Days	7 events	10 events
Time To The First Breakthrough Overt HE Episode 140 to <168 Days	1 events	6 events
Time To The First Breakthrough Overt HE Episode ≥168 Days	0 events	0 events

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Time To First HE-related Hospitalization 0 to <28 Days	4 events	11 events
Time To First HE-related Hospitalization 28 to <56 Days	4 events	12 events
Time To First HE-related Hospitalization 56 to <84 Days	4 events	7 events
Time To First HE-related Hospitalization 84 to 140 Days	5 events	4 events
Time To First HE-related Hospitalization 140 to <168 Days	2 events	2 events
Time To First HE-related Hospitalization ≥168 Days	0 events	0 events

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Time To Any Increase From Baseline In Conn Score 0 to <28 Days	17 events	26 events
Time To Any Increase From Baseline In Conn Score 28 to <56 Days	5 events	21 events
Time To Any Increase From Baseline In Conn Score 56 to <84 Days	9 events	15 events
Time To Any Increase From Baseline In Conn Score 84 to <140 Days	5 events	10 events
Time To Any Increase From Baseline In Conn Score 140 to <168 Days	0 events	5 events
Time To Any Increase From Baseline In Conn Score ≥168 Days	1 events	0 events

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Time To Any Increase From Baseline In Asterixis Grade 0 to <28 Days	13 events	20 events
Time To Any Increase From Baseline In Asterixis Grade 28 to <56 Days	7 events	15 events
Time To Any Increase From Baseline In Asterixis Grade 56 to <84 Days	7 events	4 events
Time To Any Increase From Baseline In Asterixis Grade 84 to <140 Days	3 events	6 events
Time To Any Increase From Baseline In Asterixis Grade 140 to <168 Days	1 events	4 events
Time To Any Increase From Baseline In Asterixis Grade ≥168 Days	1 events	1 events

SECONDARY outcome

Timeframe: Baseline, 6 months (End Of Treatment)

Population: Randomized participants who received at least 1 dose of study drug (ITT population) and able to complete the questionnaire at the applicable time point.

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).

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment Baseline	3.28 score on a scale Standard Deviation 1.326	3.34 score on a scale Standard Deviation 1.406
Mean Change From Baseline In Fatigue Domain Score On The CLDQ At End Of Treatment Change from Baseline	0.30 score on a scale Standard Deviation 1.262	0.11 score on a scale Standard Deviation 1.319

SECONDARY outcome

Timeframe: Baseline, Month 6 (End Of Treatment)

Population: Randomized participants who received at least 1 dose of study drug (ITT population) with evaluable venous ammonia data.

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.

Outcome measures

Outcome measures
Measure	Rifaximin n=140 Participants Participants were administered a single rifaximin 550 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.	Placebo n=159 Participants 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.
Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment Baseline	87.9 microgram per deciliter (ug/dL) Standard Deviation 47.76	92.1 microgram per deciliter (ug/dL) Standard Deviation 55.24
Mean Change From Baseline In Venous Ammonia Concentration At End Of Treatment Change from Baseline	-5.7 microgram per deciliter (ug/dL) Standard Deviation 46.77	-1.2 microgram per deciliter (ug/dL) Standard Deviation 60.98

Adverse Events

Rifaximin

Serious events: 51 serious events

Other events: 91 other events

Deaths: 0 deaths

Placebo

Serious events: 63 serious events

Other events: 101 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Director of Clinical Operations

Bausch Health Companies

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Please contact Sponsor directly for additional information.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rifaximin n=140 participants at risk Participants were administered a single rifaximin 550 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.	Placebo n=159 participants at risk 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.
Blood and lymphatic system disorders Anaemia	5.0% 7/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	3.8% 6/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Nausea	13.6% 19/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	13.2% 21/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Diarrhoea	10.7% 15/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	13.2% 21/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Ascites	10.7% 15/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	8.2% 13/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Abdominal pain	7.9% 11/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	8.2% 13/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Vomiting	5.7% 8/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	8.8% 14/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Abdominal distension	7.1% 10/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.9% 11/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Constipation	6.4% 9/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	5.7% 9/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Gastrointestinal disorders Abdominal pain upper	6.4% 9/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	5.0% 8/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
General disorders Pyrexia	5.7% 8/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	3.1% 5/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
General disorders Fatigue	12.1% 17/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	11.3% 18/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
General disorders Oedema peripheral	15.0% 21/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	8.2% 13/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
General disorders Asthenia	2.9% 4/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.9% 11/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Infections and infestations Nasopharyngitis	7.1% 10/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.3% 10/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Infections and infestations Urinary tract infection	4.3% 6/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	8.8% 14/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Musculoskeletal and connective tissue disorders Muscle spasms	9.3% 13/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.9% 11/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Musculoskeletal and connective tissue disorders Back pain	6.4% 9/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.3% 10/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Musculoskeletal and connective tissue disorders Arthralgia	6.4% 9/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	2.5% 4/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Nervous system disorders Headache	10.0% 14/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	10.7% 17/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Nervous system disorders Dizziness	12.9% 18/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	7.5% 12/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Psychiatric disorders Insomnia	7.1% 10/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.9% 11/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Psychiatric disorders Depression	7.1% 10/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	5.0% 8/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Respiratory, thoracic and mediastinal disorders Cough	7.1% 10/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.9% 11/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.4% 9/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	4.4% 7/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Skin and subcutaneous tissue disorders Pruritus	9.3% 13/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	6.3% 10/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Skin and subcutaneous tissue disorders Rash	5.0% 7/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	3.8% 6/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).
Nervous system disorders Hepatic encephalopathy	5.7% 8/140 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).	10.1% 16/159 • Baseline up to 6.5 months Randomized participants who received at least 1 dose of study drug (ITT population).