Cirrhosis, Hepatic Encephalopathy
Conditions
Keywords
Liver Failure, Hepatic Insufficiency, Liver Diseases, Brain Diseases, Rifaximin, Cirrhosis
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.
Interventions
DRUGRifaximin
Rifaximin will be administered per the dose and schedule specified in the arms.
DRUGLactulose
Laculose will be administered per the schedule specified in the respective arm.
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Number of Participants Who Died Due to Any Reason | From randomization (Day 1) up to end of study (Day 186) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Rifaximin 550 mg BID Participants received rifaximin 550 mg tablet orally BID for 24 weeks. | 113 |
| 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. | 108 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 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 | Other than specified | 3 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Rifaximin 550 mg BID | Rifaximin 550 mg BID + Lactulose | Total |
|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 9.51 | 58.8 years STANDARD_DEVIATION 9.49 | 58.4 years STANDARD_DEVIATION 9.49 |
| Lactulose Usage Prior to First Dose No | 13 Participants | 8 Participants | 21 Participants |
| Lactulose Usage Prior to First Dose Yes | 100 Participants | 100 Participants | 200 Participants |
| Sex: Female, Male Female | 44 Participants | 38 Participants | 82 Participants |
| Sex: Female, Male Male | 69 Participants | 70 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 113 | 53 / 108 |
| serious Total, serious adverse events | 43 / 113 | 35 / 108 |
Outcome results
Primary
Number of Participants Reporting a First Breakthrough HE Episode
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
Population: ITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rifaximin 550 mg BID | Number of Participants Reporting a First Breakthrough HE Episode | 28 Participants |
| Rifaximin 550 mg BID + Lactulose | Number of Participants Reporting a First Breakthrough HE Episode | 15 Participants |
Comparison: 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.p-value: 0.035995% CI: [1.045, 3.672]Score statistics
Secondary
Number of Participants Who Died Due to Any Reason
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rifaximin 550 mg BID | Number of Participants Who Died Due to Any Reason | 2 Participants |
| Rifaximin 550 mg BID + Lactulose | Number of Participants Who Died Due to Any Reason | 2 Participants |
Secondary
Number of Participants Who Were Hospitalized Due to HE Episode
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
Population: ITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rifaximin 550 mg BID | Number of Participants Who Were Hospitalized Due to HE Episode | 23 Participants |
| Rifaximin 550 mg BID + Lactulose | Number of Participants Who Were Hospitalized Due to HE Episode | 14 Participants |
Comparison: 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.p-value: 0.098595% CI: [0.894, 3.382]Log Rank
Other Pre-specified
Change From Baseline in Critical Flicker Frequency (CFF) at 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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin 550 mg BID | Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 | Baseline | 35.14 hertz | Standard Deviation 7.767 |
| Rifaximin 550 mg BID | Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 | Change at Day 170 | 1.09 hertz | Standard Deviation 7.266 |
| Rifaximin 550 mg BID + Lactulose | Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 | Change at Day 170 | 2.10 hertz | Standard Deviation 6.699 |
| Rifaximin 550 mg BID + Lactulose | Change From Baseline in Critical Flicker Frequency (CFF) at Day 170 | Baseline | 34.64 hertz | Standard Deviation 7.29 |
Other Pre-specified
Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at 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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin 550 mg BID | Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 | Baseline | 4.13 units on a scale | Standard Deviation 1.11 |
| Rifaximin 550 mg BID | 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 0.86 |
| Rifaximin 550 mg BID + Lactulose | Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 | Baseline | 4.26 units on a scale | Standard Deviation 1.197 |
| Rifaximin 550 mg BID + Lactulose | Change From Baseline in Total Chronic Liver Disease Questionnaire (CLDQ) Score at Day 170 | Change at Day 170 | 0.08 units on a scale | Standard Deviation 1.055 |
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
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)
Population: Safety population was the same as the ITT population that included randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rifaximin 550 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 99 Participants |
| Rifaximin 550 mg BID + Lactulose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 81 Participants |