Trial Outcomes & Findings for The Safety/Efficacy of Rifaximin With/Without Lactulose in Participants With A History of Recurrent Hepatic Encephalopathy (NCT NCT01842581)

Last Updated: 2019-09-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

222 participants

Primary outcome timeframe

From randomization (Day 1) up to Day 170

Results posted on

2019-09-09

Participant Flow

A total of 222 participants with cirrhosis and in remission from demonstrated hepatic encephalopathy (HE) were enrolled and randomized in a 1:1 ratio to either Rifaximin 550 mg BID or Rifaximin 550 mg BID + Lactulose treatment arm.

Participant milestones

Participant milestones
Measure	Rifaximin 550 mg BID Participants received rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.	Rifaximin 550 mg BID + Lactulose Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Study STARTED	113	109
Overall Study Received at Least 1 Dose of Study Drug	113	108
Overall Study COMPLETED	69	79
Overall Study NOT COMPLETED	44	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Rifaximin 550 mg BID Participants received rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.	Rifaximin 550 mg BID + Lactulose Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Overall Study Adverse Event	6	4
Overall Study HE breakthrough	26	13
Overall Study Liver transplant	2	0
Overall Study Lost to Follow-up	2	5
Overall Study Withdrawal by Subject	5	7
Overall Study Other than specified	3	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.	Total n=221 Participants Total of all reporting groups
Age, Continuous	58.1 years STANDARD_DEVIATION 9.51 • n=5 Participants	58.8 years STANDARD_DEVIATION 9.49 • n=7 Participants	58.4 years STANDARD_DEVIATION 9.49 • n=5 Participants
Sex: Female, Male Female	44 Participants n=5 Participants	38 Participants n=7 Participants	82 Participants n=5 Participants
Sex: Female, Male Male	69 Participants n=5 Participants	70 Participants n=7 Participants	139 Participants n=5 Participants
Lactulose Usage Prior to First Dose Yes	100 Participants n=5 Participants	100 Participants n=7 Participants	200 Participants n=5 Participants
Lactulose Usage Prior to First Dose No	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization (Day 1) up to Day 170

Population: ITT population included all randomized participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Number of Participants Reporting a First Breakthrough HE Episode	28 Participants	15 Participants

SECONDARY outcome

Timeframe: From randomization (Day 1) up to Day 170

Population: ITT population included all randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Number of Participants Who Were Hospitalized Due to HE Episode	23 Participants	14 Participants

SECONDARY outcome

Timeframe: From randomization (Day 1) up to end of study (Day 186)

Population: Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Number of Participants Who Died Due to Any Reason	2 Participants	2 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization (Day 1) up to end of study (Day 186)

Population: Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	99 Participants	81 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Day 170

Population: ITT population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoint.

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.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 Baseline	4.13 units on a scale Standard Deviation 1.110	4.26 units on a scale Standard Deviation 1.197
Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 Change at Day 170	0.29 units on a scale Standard Deviation 0.860	0.08 units on a scale Standard Deviation 1.055

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rifaximin 550 mg BID n=113 Participants Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 Participants Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 Baseline	35.14 hertz Standard Deviation 7.767	34.64 hertz Standard Deviation 7.290
Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 Change at Day 170	1.09 hertz Standard Deviation 7.266	2.10 hertz Standard Deviation 6.699

Adverse Events

Rifaximin 550 mg BID

Serious events: 43 serious events

Other events: 68 other events

Deaths: 0 deaths

Rifaximin 550 mg BID + Lactulose

Serious events: 35 serious events

Other events: 53 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Director of Clinical Operations

Bausch Health Americas, Inc.

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 550 mg BID n=113 participants at risk Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	Rifaximin 550 mg BID + Lactulose n=108 participants at risk Participants received rifaximin 550 mg tablet orally BID with lactulose solution for 24 weeks. Lactulose dose was self-titrated to produce 2 to 3 soft stools per day.
Blood and lymphatic system disorders Anaemia	5.3% 6/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	1.9% 2/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal distension	2.7% 3/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	6.5% 7/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	7.1% 8/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	7.4% 8/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Ascites	6.2% 7/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	9.3% 10/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	15.9% 18/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	8.3% 9/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	4.4% 5/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	12.0% 13/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Flatulence	0.88% 1/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	5.6% 6/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	14.2% 16/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	10.2% 11/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	5.3% 6/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	5.6% 6/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
General disorders Asthenia	5.3% 6/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	1.9% 2/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
General disorders Fatigue	14.2% 16/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	8.3% 9/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
General disorders Oedema peripheral	16.8% 19/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	13.9% 15/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Hepatobiliary disorders Jaundice	3.5% 4/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	5.6% 6/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	10.6% 12/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	4.6% 5/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Decreased appetite	7.1% 8/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	4.6% 5/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	8.0% 9/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	10.2% 11/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Nervous system disorders Headache	6.2% 7/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	4.6% 5/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Anxiety	5.3% 6/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	9.3% 10/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Depression	2.7% 3/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	5.6% 6/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Insomnia	11.5% 13/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	13.9% 15/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	5.3% 6/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	4.6% 5/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.2% 7/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	9.3% 10/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Pruritus generalised	9.7% 11/113 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.	5.6% 6/108 • From randomization (Day 1) up to end of study (Day 186) Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.