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

• Sponsor: Bausch Health Americas, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01842581
• Collaborator: (none)
• Enrollment: 222
• Locations: 43
• Arms: 2
• Actual Duration (Months): 23.3
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

• Study Type: Interventional
• 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: Jan 8, 2013
• Actual Primary Completion Date: Dec 17, 2014
• Actual Study Completion Date: Dec 17, 2014

Arms and Interventions

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 Names: 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 Names: Xifaxan® ; Drug: Lactulose; Laculose will be administered per the schedule specified in the respective arm.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting a First Breakthrough HE Episode [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 [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 [From randomization (Day 1) up to end of study (Day 186)]

Other Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Banner Research	Phoenix	Arizona	United States	85016
2	Southern California Liver Centers	Coronado	California	United States	92118
3	UCSF/Fresno - CRMC	Fresno	California	United States	93721
4	UCSD Clinical & Translational Research Institute	La Jolla	California	United States	92037
5	Salix Site	Long Beach	California	United States	90822
6	Inland Empire Liver Foundation	Rialto	California	United States	92377
7	Salix Site	Riverside	California	United States	92501
8	Salix Site	San Diego	California	United States	92103
9	Salix Site	San Francisco	California	United States	94115
10	University of Colorado Denver	Aurora	Colorado	United States	80045
11	South Denver GI	Englewood	Colorado	United States	80113
12	University of Florida Hepatology	Gainesville	Florida	United States	32610-0277
13	Tampa General Medical Group	Tampa	Florida	United States	33605
14	Gastroenterology Associates	Macon	Georgia	United States	31201
15	Salix Site	Chicago	Illinois	United States	60611
16	Indiana University	Indianapolis	Indiana	United States	46202
17	Central Iowa Hospital Corp	Des Moines	Iowa	United States	50309-1453
18	Salix Site	Jefferson	Louisiana	United States	70124
19	Delta Research Partners, LLC	Monroe	Louisiana	United States	71201
20	The Center for Liver and Biliary Disease	Baltimore	Maryland	United States	21202-2165
21	Brigham and Women's Hospital Division of Gastroenterology & Hepatology	Boston	Massachusetts	United States	02115
22	Mayo Clinic	Rochester	Minnesota	United States	55905
23	Kansas City Research Institute	Kansas City	Missouri	United States	64131
24	St. Louis University	Saint Louis	Missouri	United States	63104
25	Univ. of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3285
26	Concorde Medical Group PLLC	New York	New York	United States	10016
27	New York University Medical Center	New York	New York	United States	10016
28	Salix Site	New York	New York	United States	10016
29	Columbia University Medical Ctr. Center for Liver Disease & Transplantation	New York	New York	United States	10032
30	University of Rochester Strong Memorial Hospital	Rochester	New York	United States	14642
31	Asheville Gastroenterology Associates, PA	Asheville	North Carolina	United States	28801
32	UNC School of Medicine/Division of Gastroenterology and Hepatology	Chapel Hill	North Carolina	United States	27599-7584
33	Carolina Medical Center	Charlotte	North Carolina	United States	28204
34	Integris Nazh Zuhdi Transplant Institute	Oklahoma City	Oklahoma	United States	73112
35	Albert Einstien Medical Center	Philadelphia	Pennsylvania	United States	19141
36	Research Specialists of Texas	Houston	Texas	United States	77030
37	Amcare Research Inc	Houston	Texas	United States	77090
38	Salix Site	Odessa	Texas	United States	79761
39	Alamo Medical Research	San Antonio	Texas	United States	78215
40	Methodist Hospital	San Antonio	Texas	United States	78229
41	University of Utah Hospital	Salt Lake City	Utah	United States	84132
42	VCU/MCV Health Systems	Richmond	Virginia	United States	23298
43	University of Wisconsin Hospital & Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Bausch Health Americas, Inc.

Investigators

• Study Director: Lindsey Mathew, Bausch Health Americas, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bausch Health Americas, Inc.
• ClinicalTrials.gov Identifier: NCT01842581
• Other Study ID Numbers: RFHE4044
• First Posted: Apr 29, 2013
• Last Update Posted: Sep 9, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by Bausch Health Americas, Inc.: Liver Failure; Hepatic Insufficiency; Liver Diseases; Brain Diseases; Rifaximin; Cirrhosis
• Additional relevant MeSH terms: Hepatic Encephalopathy; Brain Diseases; Fibrosis; Rifaximin; Lactulose

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 milligrams (mg) tablet orally twice daily (BID) for 24 weeks.	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.
Period Title: Overall Study
STARTED	113	109
Received at Least 1 Dose of Study Drug	113	108
COMPLETED	69	79
NOT COMPLETED	44	30

Baseline Characteristics

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose	Total
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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 of all reporting groups
Overall Participants	113	108	221
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (9.51)	58.8 (9.49)	58.4 (9.49)
Sex: Female, Male (Count of Participants)
Female	44 38.9%	38 35.2%	82 37.1%
Male	69 61.1%	70 64.8%	139 62.9%
Lactulose Usage Prior to First Dose (Count of Participants)
Yes	100 88.5%	100 92.6%	200 90.5%
No	13 11.5%	8 7.4%	21 9.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting a First Breakthrough HE Episode
Description	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.
Time Frame	From randomization (Day 1) up to Day 170

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Count of Participants [Participants]	28 24.8%	15 13.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rifaximin 550 mg BID, Rifaximin 550 mg BID + Lactulose
	Comments	Hazard ratio estimate (hazard of breakthrough HE for rifaximin compared to rifaximin + lactulose) obtained from Cox proportional hazards model with effect for treatment, stratified by analysis region.
	Type of Statistical Test	Non-Inferiority
	Comments	Threshold for significance=upper bound of the 2-sided 95% confidence interval (CI) for hazard ratio less than (<) 1.56.
Statistical Test of Hypothesis	p-Value	0.0359
	Comments
	Method	Score statistics
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.959
	Confidence Interval	(2-Sided) 95%; 1.045 to 3.672
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Who Were Hospitalized Due to HE Episode
Description	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.
Time Frame	From randomization (Day 1) up to Day 170

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Count of Participants [Participants]	23 20.4%	14 13%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rifaximin 550 mg BID, Rifaximin 550 mg BID + Lactulose
	Comments	Analysis was performed using log-rank test stratified by analysis region. Hazard ratio estimate (hazard of breakthrough HE for rifaximin compared to rifaximin + lactulose) obtained from Cox proportional hazards model with effect for treatment, stratified by analysis region.
	Type of Statistical Test	Superiority
	Comments	2-sided test at a significance level of 0.05.
Statistical Test of Hypothesis	p-Value	0.0985
	Comments	Threshold for significance at 0.05 level.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.739
	Confidence Interval	(2-Sided) 95%; 0.894 to 3.382
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants Who Died Due to Any Reason
Time Frame	From randomization (Day 1) up to end of study (Day 186)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Count of Participants [Participants]	2 1.8%	2 1.9%

4. Other Pre-specified Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	From randomization (Day 1) up to end of study (Day 186)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Count of Participants [Participants]	99 87.6%	81 75%

5. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Baseline	4.13 (1.110)	4.26 (1.197)
Change at Day 170	0.29 (0.860)	0.08 (1.055)

6. Other Pre-specified Outcome

Title	Change From Baseline in Critical Flicker Frequency (CFF) at Day 170
Description	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.
Time Frame	Baseline, Day 170

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rifaximin 550 mg BID	Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.	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.
Measure Participants	113	108
Baseline	35.14 (7.767)	34.64 (7.290)
Change at Day 170	1.09 (7.266)	2.10 (6.699)

Adverse Events

Time Frame	From randomization (Day 1) up to end of study (Day 186)
Adverse Event Reporting Description	Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Rifaximin 550 mg BID		Rifaximin 550 mg BID + Lactulose
Arm/Group Description	Participants received rifaximin 550 mg tablet orally BID for 24 weeks.		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.
All Cause Mortality
	Rifaximin 550 mg BID		Rifaximin 550 mg BID + Lactulose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rifaximin 550 mg BID		Rifaximin 550 mg BID + Lactulose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/113 (38.1%)		35/108 (32.4%)
Blood and lymphatic system disorders
Anaemia	5/113 (4.4%)		1/108 (0.9%)
Coagulopathy	0/113 (0%)		1/108 (0.9%)
Thrombocytopenia	1/113 (0.9%)		0/108 (0%)
Cardiac disorders
Acute myocardial infarction	0/113 (0%)		1/108 (0.9%)
Atrial fibrillation	0/113 (0%)		1/108 (0.9%)
Cardiac failure congestive	1/113 (0.9%)		1/108 (0.9%)
Supraventricular tachycardia	0/113 (0%)		2/108 (1.9%)
Gastrointestinal disorders
Abdominal pain	1/113 (0.9%)		1/108 (0.9%)
Ascites	2/113 (1.8%)		7/108 (6.5%)
Diarrhoea	1/113 (0.9%)		0/108 (0%)
Gastrointestinal haemorrhage	1/113 (0.9%)		2/108 (1.9%)
Haematemesis	1/113 (0.9%)		0/108 (0%)
Haematochezia	1/113 (0.9%)		0/108 (0%)
Nausea	2/113 (1.8%)		0/108 (0%)
Upper gastrointestinal haemorrhage	1/113 (0.9%)		1/108 (0.9%)
Vomiting	1/113 (0.9%)		0/108 (0%)
General disorders
Asthenia	1/113 (0.9%)		0/108 (0%)
Chest pain	1/113 (0.9%)		0/108 (0%)
Non-cardiac chest pain	1/113 (0.9%)		0/108 (0%)
Systemic inflammatory response syndrome	1/113 (0.9%)		0/108 (0%)
Hepatobiliary disorders
Chronic hepatic failure	1/113 (0.9%)		0/108 (0%)
Hepatic cirrhosis	0/113 (0%)		1/108 (0.9%)
Hepatic failure	1/113 (0.9%)		0/108 (0%)
Hepatitis	1/113 (0.9%)		0/108 (0%)
Hepatorenal syndrome	1/113 (0.9%)		0/108 (0%)
Infections and infestations
Bronchitis	2/113 (1.8%)		0/108 (0%)
Cellulitis	3/113 (2.7%)		1/108 (0.9%)
Diverticulitis	0/113 (0%)		1/108 (0.9%)
Gastroenteritis	0/113 (0%)		1/108 (0.9%)
Herpes zoster	1/113 (0.9%)		0/108 (0%)
Necrotising fasciitis	0/113 (0%)		1/108 (0.9%)
Peritonitis bacterial	2/113 (1.8%)		2/108 (1.9%)
Pneumococcal bacteraemia	1/113 (0.9%)		0/108 (0%)
Pneumonia	1/113 (0.9%)		2/108 (1.9%)
Sepsis	1/113 (0.9%)		1/108 (0.9%)
Septic shock	1/113 (0.9%)		1/108 (0.9%)
Staphylococcal bacteraemia	0/113 (0%)		1/108 (0.9%)
Urinary tract infection	1/113 (0.9%)		4/108 (3.7%)
Injury, poisoning and procedural complications
Craniocerebral injury	1/113 (0.9%)		0/108 (0%)
Incisional hernia	0/113 (0%)		1/108 (0.9%)
Multiple drug overdose	0/113 (0%)		1/108 (0.9%)
Subdural haematoma	1/113 (0.9%)		0/108 (0%)
Metabolism and nutrition disorders
Dehydration	1/113 (0.9%)		0/108 (0%)
Fluid overload	1/113 (0.9%)		2/108 (1.9%)
Hyperglycaemia	1/113 (0.9%)		1/108 (0.9%)
Hyperkalaemia	2/113 (1.8%)		0/108 (0%)
Hyponatraemia	0/113 (0%)		1/108 (0.9%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	0/113 (0%)		1/108 (0.9%)
Muscular weakness	0/113 (0%)		1/108 (0.9%)
Synovitis	0/113 (0%)		1/108 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/113 (0%)		1/108 (0.9%)
Nervous system disorders
Alcoholic seizure	1/113 (0.9%)		0/108 (0%)
Altered state of consciousness	0/113 (0%)		1/108 (0.9%)
Cerebrovascular accident	1/113 (0.9%)		0/108 (0%)
Convulsion	0/113 (0%)		1/108 (0.9%)
Dizziness	0/113 (0%)		1/108 (0.9%)
Headache	1/113 (0.9%)		0/108 (0%)
Hepatic encephalopathy	21/113 (18.6%)		10/108 (9.3%)
Presyncope	0/113 (0%)		1/108 (0.9%)
Spinal claudication	0/113 (0%)		1/108 (0.9%)
Subarachnoid haemorrhage	1/113 (0.9%)		0/108 (0%)
Toxic encephalopathy	1/113 (0.9%)		0/108 (0%)
Psychiatric disorders
Anxiety disorder	1/113 (0.9%)		0/108 (0%)
Suicidal ideation	1/113 (0.9%)		0/108 (0%)
Renal and urinary disorders
Calculus ureteric	1/113 (0.9%)		0/108 (0%)
Oliguria	1/113 (0.9%)		0/108 (0%)
Renal failure	1/113 (0.9%)		0/108 (0%)
Renal failure acute	6/113 (5.3%)		3/108 (2.8%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/113 (0.9%)		0/108 (0%)
Dyspnoea	1/113 (0.9%)		0/108 (0%)
Hepatic hydrothorax	0/113 (0%)		1/108 (0.9%)
Hypoxia	0/113 (0%)		1/108 (0.9%)
Pleural effusion	1/113 (0.9%)		2/108 (1.9%)
Pneumothorax	0/113 (0%)		1/108 (0.9%)
Pulmonary hypertension	0/113 (0%)		1/108 (0.9%)
Respiratory failure	0/113 (0%)		2/108 (1.9%)
Surgical and medical procedures
Liver transplant	2/113 (1.8%)		0/108 (0%)
Vascular disorders
Hypovolaemic shock	1/113 (0.9%)		0/108 (0%)
Other (Not Including Serious) Adverse Events
	Rifaximin 550 mg BID		Rifaximin 550 mg BID + Lactulose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/113 (60.2%)		53/108 (49.1%)
Blood and lymphatic system disorders
Anaemia	6/113 (5.3%)		2/108 (1.9%)
Gastrointestinal disorders
Abdominal distension	3/113 (2.7%)		7/108 (6.5%)
Abdominal pain	8/113 (7.1%)		8/108 (7.4%)
Ascites	7/113 (6.2%)		10/108 (9.3%)
Constipation	18/113 (15.9%)		9/108 (8.3%)
Diarrhoea	5/113 (4.4%)		13/108 (12%)
Flatulence	1/113 (0.9%)		6/108 (5.6%)
Nausea	16/113 (14.2%)		11/108 (10.2%)
Vomiting	6/113 (5.3%)		6/108 (5.6%)
General disorders
Asthenia	6/113 (5.3%)		2/108 (1.9%)
Fatigue	16/113 (14.2%)		9/108 (8.3%)
Oedema peripheral	19/113 (16.8%)		15/108 (13.9%)
Hepatobiliary disorders
Jaundice	4/113 (3.5%)		6/108 (5.6%)
Infections and infestations
Urinary tract infection	12/113 (10.6%)		5/108 (4.6%)
Metabolism and nutrition disorders
Decreased appetite	8/113 (7.1%)		5/108 (4.6%)
Musculoskeletal and connective tissue disorders
Muscle spasms	9/113 (8%)		11/108 (10.2%)
Nervous system disorders
Headache	7/113 (6.2%)		5/108 (4.6%)
Psychiatric disorders
Anxiety	6/113 (5.3%)		10/108 (9.3%)
Depression	3/113 (2.7%)		6/108 (5.6%)
Insomnia	13/113 (11.5%)		15/108 (13.9%)
Respiratory, thoracic and mediastinal disorders
Cough	6/113 (5.3%)		5/108 (4.6%)
Dyspnoea	7/113 (6.2%)		10/108 (9.3%)
Skin and subcutaneous tissue disorders
Pruritus generalised	11/113 (9.7%)		6/108 (5.6%)

Limitations/Caveats

The rifaximin monotherapy arm included a subset of rifaximin/lactulose dependent participants for whom lactulose was withdrawn upon randomization (88.5% of participants in that group), which led to earlier HE breakthrough in this subset.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Please contact Sponsor directly for additional information.