Overt Hepatic Encephalopathy
Conditions
Brief summary
Study to Assess the Efficacy and Safety of Rifaximin Soluble Solid Dispersion (SSD) Tablets Plus Lactulose for the Treatment of Overt Hepatic Encephalopathy (OHE).
Detailed description
The primary objective of this study is to assess the efficacy of rifaximin SSD plus lactulose versus placebo plus lactulose for the treatment of overt hepatic encephalopathy (OHE). The secondary objectives of this study are to assess the safety of rifaximin SSD in subjects with OHE and to assess the effects of treatment with rifaximin SSD on key secondary endpoints.
Interventions
DRUG40 mg Rifaximin SSD once daily
SSD once daily (QD)
DRUG40 mg Rifaximin SSD twice daily
SSD twice daily (BID)
DRUG80 mg Rifaximin SSD once daily
SSD once daily (QD)
DRUG80 mg Rifaximin SSD twice daily
SSD twice daily (BID)
DRUGPlacebo
Administered twice daily (BID)
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Blinding will be maintained in the QD SSD cohorts by administering placebo as the second daily dose.
Intervention model description
Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter Study
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female age 18 to 75 years of age (inclusive) at the time of screening. * Females of childbearing potential, defined as a female who is fertile following menarche, must have a negative serum pregnancy test at screening and agree to use an acceptable method of contraception throughout their participation in the study. Note: Female subjects who have been surgically sterilized (e.g., hysterectomy or bilateral tubal ligation) or who are postmenopausal (defined as total cessation of menses for \> 1 year) will not be considered female subjects of childbearing potential. * Subject is hospitalized with liver cirrhosis and/or OHE and has a confirmed diagnosis of OHE at Baseline. * Subject has a Grade 2 or Grade 3 HE episode according to the HE Grading Instrument (HEGI) following 8 to 12 hours of intravenous (IV) hydration and lactulose treatment.
Exclusion criteria
* Subject has an uncontrolled major psychiatric disorder including major depression or psychoses as determined by the investigator. * Subject has been diagnosed with an infection for which they are currently taking oral or parenteral antibiotics, which cannot be discontinued at time of enrollment. Note: Subjects currently taking Rifaximin are not excluded * Subject shows presence of intestinal obstruction or has inflammatory bowel disease. * Subject has uncontrolled Type 1 or Type 2 diabetes. Note: Subjects with controlled diabetes may be enrolled if they are on stable doses of oral hypoglycemic drugs for at least 3 months prior to screening, and demonstrate clinically acceptable blood glucose control at Baseline, as determined by the investigator. * Subject has an active malignancy (exceptions: non-melanoma skin cancers).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 14 days | A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 14 days | A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome). |
| Time to Hospital Discharge | 14 days | Time in days until discharge from the hospital |
Countries
United States
Participant flow
Recruitment details
Participants were randomized into 5 possible double-blind treatment arms during the Double-Blind Period. Upon completion of the Double-Blind Period, participants could continue in the 30 day Open-Label Extension Period in which all participants received rifaximin 550 mg.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 40 mg Rifaximin SSD Once Daily 40 mg Rifaximin immediate release (IR) rifaximin SSD once daily (QD) and lactulose
40 mg Rifaximin SSD once daily: SSD once daily (QD) and lactulose
lactulose: to be taken in the recommended adult size dosage. | 15 |
| Cohort 2 40 mg Rifaximin SSD Twice Daily 40 mg Rifaximin immediate release (IR) rifaximin SSD twice daily (BID) and lactulose
40 mg Rifaximin SSD twice daily: SSD twice daily (BID) and lactulose
lactulose: to be taken in the recommended adult size dosage. | 15 |
| Cohort 3 80 mg Rifaximin SSD Once Daily 80 mg Rifaximin sustained extended release (SER) rifaximin SSD once daily (QD) and lactulose
80 mg Rifaximin SSD once daily: SSD once daily (QD) and lactulose
lactulose: to be taken in the recommended adult size dosage. | 14 |
| Cohort 4 80 mg Rifaximin SSD Twice Daiy Cohort 4 80 mg Rifaximin SSD twice daily (BID) and lactulose
80 mg Rifaximin SSD twice daily: SSD twice daily (BID) and lactulose
lactulose: to be taken in the recommended adult size dosage. | 13 |
| Cohort 5 Placebo Twice Daily SSD placebo twice daily (BID) and lactulose
Placebo: Administered twice daily (BID) and lactulose
lactulose: to be taken in the recommended adult size dosage. | 14 |
| Total | 71 |
Baseline characteristics
| Characteristic | Cohort 1 40 mg Rifaximin SSD Once Daily | Total | Cohort 5 Placebo Twice Daily | Cohort 4 80 mg Rifaximin SSD Twice Daiy | Cohort 3 80 mg Rifaximin SSD Once Daily | Cohort 2 40 mg Rifaximin SSD Twice Daily |
|---|---|---|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 14.88 | 61.4 years STANDARD_DEVIATION 9.84 | 60.0 years STANDARD_DEVIATION 9.25 | 61.8 years STANDARD_DEVIATION 8.07 | 63.0 years STANDARD_DEVIATION 7.94 | 61.1 years STANDARD_DEVIATION 8.02 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 10 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 56 Participants | 9 Participants | 10 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Female | 7 Participants | 33 Participants | 2 Participants | 8 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 38 Participants | 12 Participants | 5 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 15 | 0 / 15 | 2 / 14 | 1 / 13 | 1 / 14 | 13 / 53 |
| other Total, other adverse events | 2 / 15 | 3 / 15 | 4 / 14 | 5 / 13 | 3 / 14 | 5 / 53 |
| serious Total, serious adverse events | 3 / 15 | 1 / 15 | 3 / 14 | 1 / 13 | 2 / 14 | 33 / 53 |
Outcome results
Primary
Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2
A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 40 mg Rifaximin SSD Once Daily | Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 36.1 hours |
| Cohort 2 40 mg Rifaximin SSD Twice Daily | Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 21.1 hours |
| Cohort 3 80 mg Rifaximin SSD Once Daily | Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 45.9 hours |
| Cohort 4 80 mg Rifaximin SSD Twice Daiy | Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 17.9 hours |
| Cohort 5 Placebo Twice Daily | Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | 62.7 hours |
Secondary
Time to Hospital Discharge
Time in days until discharge from the hospital
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 40 mg Rifaximin SSD Once Daily | Time to Hospital Discharge | 3.0 days |
| Cohort 2 40 mg Rifaximin SSD Twice Daily | Time to Hospital Discharge | 3.0 days |
| Cohort 3 80 mg Rifaximin SSD Once Daily | Time to Hospital Discharge | 3.0 days |
| Cohort 4 80 mg Rifaximin SSD Twice Daiy | Time to Hospital Discharge | 4.0 days |
| Cohort 5 Placebo Twice Daily | Time to Hospital Discharge | 4.5 days |
Secondary
Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement)
A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 40 mg Rifaximin SSD Once Daily | Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 2.5 days |
| Cohort 2 40 mg Rifaximin SSD Twice Daily | Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 2.0 days |
| Cohort 3 80 mg Rifaximin SSD Once Daily | Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 2.0 days |
| Cohort 4 80 mg Rifaximin SSD Twice Daiy | Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 2.0 days |
| Cohort 5 Placebo Twice Daily | Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | 3.0 days |