Trial Outcomes & Findings for Safety and Tolerability Study of Rifaximin in Participants With a History of Hepatic Encephalopathy (NCT NCT00686920)

Last Updated: 2019-08-14

Results Overview

A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

322 participants

Primary outcome timeframe

Baseline up to Month 36

Results posted on

2019-08-14

Participant Flow

A total of 152 (47%) participants with hepatic encephalopathy (HE) rolled over from the double-blind study RFHE3001 (NCT00298038); 70 rifaximin participants (designated to the "Continued Rifaximin" arm in Study RFHE3002) and 82 placebo participants (designated to the "New Rifaximin" arm along with the new 170 \[53%\] participants in Study RFHE3002).

Participant milestones

Participant milestones
Measure	New Rifaximin Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Overall Study STARTED	252	70
Overall Study Received At Least 1 Dose Of Study Drug	252	70
Overall Study COMPLETED	120	34
Overall Study NOT COMPLETED	132	36

Reasons for withdrawal

Reasons for withdrawal
Measure	New Rifaximin Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Overall Study Death	45	14
Overall Study Liver Transplant	23	8
Overall Study Recurrent Hepatic Encephalopathy Episode	1	2
Overall Study Withdrawal by Subject	23	5
Overall Study Protocol Violation	2	1
Overall Study Adverse Event	10	2
Overall Study Personal Reason	0	1
Overall Study Lost to Follow-up	15	3
Overall Study Moved to Another State	1	0
Overall Study Transferred to Nursing Home	1	0
Overall Study Noncompliance	9	0
Overall Study Principal Investigator Decision	2	0

Baseline Characteristics

Safety and Tolerability Study of Rifaximin in Participants With a History of Hepatic Encephalopathy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	New Rifaximin n=252 Participants Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 Participants Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Total n=322 Participants Total of all reporting groups
Age, Continuous	57.6 years STANDARD_DEVIATION 8.90 • n=5 Participants	56.7 years STANDARD_DEVIATION 9.36 • n=7 Participants	57.4 years STANDARD_DEVIATION 57.0 • n=5 Participants
Sex: Female, Male Female	94 Participants n=5 Participants	32 Participants n=7 Participants	126 Participants n=5 Participants
Sex: Female, Male Male	158 Participants n=5 Participants	38 Participants n=7 Participants	196 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to Month 36

Population: All participants who received at least 1 dose of study drug.

A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	New Rifaximin n=252 Participants Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 Participants Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event Non-Serious Adverse Event	78 Participants	15 Participants
Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event Serious Adverse Event	158 Participants	49 Participants

SECONDARY outcome

Timeframe: Baseline up to Month 36

Population: All participants who received at least 1 dose of study drug.

Hematology and blood chemistry with potentially significant values included: Hemoglobin \<9, \>18, or ≥3 (grams/deciliter \[g/dL\]) decrease from previous visit or ≥4 g/dL decrease from baseline; Hematocrit \<0.27%, \>0.54%, or ≥0.10% decrease from previous visit or ≥0.15% decrease from baseline; Platelets \<50 or \>400\*10\^9/(liter \[L\]); Prothrombin time 9 seconds above baseline or upper limit of normal range; International normalized ratio \>1.7; White blood cells \<2.0 or \>12.0\*10\^9/L; Lymphocytes \<13.5% or \>70%; Glucose, random, serum \<2.2 or \>16.5 millimole (mmol)/L; Potassium ≤3.0 or ≥5.5 mmol/L; Direct bilirubin increases 3-fold from baseline or \>85.5 micromole (umol)/L. Baseline value was defined as the last available value (including the applicable values from the participants who rolled over from Study RFHE3001) prior to the first dose of study drug. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	New Rifaximin n=252 Participants Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 Participants Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Hemoglobin	15 Participants	12 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Hematocrit	12 Participants	4 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Platelets	18 Participants	6 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Prothrombin Time	16 Participants	7 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants International Normalized Ratio	24 Participants	8 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants White Blood Cells	15 Participants	2 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Lymphocytes	24 Participants	10 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Glucose, random, serum	8 Participants	8 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Potassium	17 Participants	7 Participants
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants Direct Bilirubin	14 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline up to Month 36

Population: All participants who received at least 1 dose of study drug.

Vital signs were measured and included sitting blood pressure, heart rate, oral temperature, and weight. These were collected at each scheduled study visit. Participants were placed supine for 5 minutes prior to each assessment of vital signs. Baseline value was defined as last available value (including the applicable values from the participants who rolled over from Study RFHE3001) prior to the first dose of study drug. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Outcome measures

Outcome measures
Measure	New Rifaximin n=252 Participants Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 Participants Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Number Of Participants With A Significant Mean Change From Baseline In Vital Signs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Month 36

Population: All participants who received at least 1 dose of study drug.

The assessment for change in mental status during the study was measured by the Conn score (also known as the West Haven score). The following scale was used in the Conn scoring system: Grade 0=No personality or behavioral abnormality detected. Grade 1=Trivial lack of awareness, euphoria, or anxiety; shortened attention span; or impairment of addition or subtraction. Grade 2=Lethargy; disorientation for time; obvious personality change; and inappropriate behavior. Grade 3=Somnolence to semi-stupor, responsive to stimuli; confused; gross disorientation; and bizarre behavior. Grade 4=Coma, unable to test mental state. Participants entered the study with a Conn score of 0 to 2. Baseline value was defined as last available value (including the applicable values from the participants who rolled over from Study RFHE3001) prior to the first dose of study drug.

Outcome measures

Outcome measures
Measure	New Rifaximin n=252 Participants Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 Participants Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Change From Baseline In Conn Score At Last Assessment Baseline	0.4 score on a scale Standard Deviation 0.58	0.2 score on a scale Standard Deviation 0.40
Change From Baseline In Conn Score At Last Assessment Change from Baseline	-0.1 score on a scale Standard Deviation 0.77	0.1 score on a scale Standard Deviation 0.41

Adverse Events

New Rifaximin

Serious events: 158 serious events

Other events: 212 other events

Deaths: 0 deaths

Continuing Rifaximin

Serious events: 49 serious events

Other events: 52 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	New Rifaximin n=252 participants at risk Participants new to receiving rifaximin were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.	Continuing Rifaximin n=70 participants at risk Participants who received rifaximin in the previous rifaximin HE study were administered a single rifaximin 550 milligram (mg) tablet 2 times per day (approximately every 12 hours) for at least 24 months, until regulatory approval of rifaximin for reduction in risk of overt HE recurrence, or until the sponsor closed the study.
Blood and lymphatic system disorders Anaemia	11.1% 28/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	10.0% 7/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	3.6% 9/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	20.6% 52/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	21.4% 15/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Ascites	15.1% 38/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	8.6% 6/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	13.5% 34/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	11.4% 8/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	11.9% 30/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	11.4% 8/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	11.5% 29/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	12.9% 9/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	13.1% 33/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain upper	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Varices oesophageal	5.2% 13/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	10.0% 7/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Gastrointestinal disorders Haemorrhoids	3.6% 9/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
General disorders Oedema peripheral	19.0% 48/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	18.6% 13/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
General disorders Fatigue	12.3% 31/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	10.0% 7/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
General disorders Pyrexia	5.6% 14/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	8.6% 6/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
General disorders Oedema	6.7% 17/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	2.9% 2/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
General disorders Asthenia	5.6% 14/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	4.3% 3/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Hepatobiliary disorders Cholelithiasis	3.6% 9/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	19.8% 50/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	21.4% 15/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Infections and infestations Upper respiratory tract infection	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Infections and infestations Cellulitis	6.3% 16/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	1.4% 1/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Infections and infestations Pneumonia	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	2.9% 2/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Infections and infestations Peritonitis bacterial	2.4% 6/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Procedural pain	6.3% 16/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	4.3% 3/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Contusion	3.2% 8/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypokalaemia	14.7% 37/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	11.4% 8/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperkalaemia	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	8.6% 6/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypomagnesaemia	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Dehydration	5.2% 13/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	8.6% 6/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyponatraemia	5.2% 13/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	4.3% 3/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Diabetes mellitus	4.0% 10/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	4.0% 10/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	11.9% 30/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	11.4% 8/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	9.1% 23/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 10/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	8.6% 6/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	3.2% 8/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Nervous system disorders Dizziness	9.9% 25/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	10.0% 7/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Nervous system disorders Headache	8.7% 22/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Psychiatric disorders Depression	11.9% 30/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	12.9% 9/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Psychiatric disorders Insomnia	11.9% 30/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Psychiatric disorders Anxiety	6.0% 15/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	11.4% 8/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Renal and urinary disorders Renal failure acute	5.2% 13/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	1.4% 1/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.3% 31/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	10.0% 7/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	7.1% 18/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	7.1% 5/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.6% 14/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	2.9% 2/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	7.9% 20/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	4.3% 3/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash	7.5% 19/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Vascular disorders Hypotension	6.7% 17/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.
Vascular disorders Hypertension	6.3% 16/252 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.	5.7% 4/70 • Baseline up to Month 36 All participants who received at least 1 dose of study drug.