Hepatic Encephalopathy
Conditions
Brief summary
This study will look at the safety of a drug used in participants who have had hepatic encephalopathy (HE) in the past.
Detailed description
Eligible participants had a history of HE, a Conn score of 0 to 2 at enrollment, and either had successfully participated in a previous HE study with rifaximin (that is, RFHE3001 \[NCT00298038\]), or were new participants enrolled with ≥1 verifiable episode of HE (equivalent to a Conn score of ≥2) associated with cirrhosis or portal hypertension within 12 months of screening. Successful participation in a previous rifaximin study was defined as having received ≥80% and ≤120% of the expected tablets, having been reasonably compliant with study procedures, and having not been discontinued from the previous study due to study drug-related Adverse Events. Participants who experienced HE or associated symptoms during or after the RFHE3001 study were considered eligible for entry into this open-label study if the participant and Investigator did not perceive study medication as a possible cause of the HE episode or associated symptoms. Participants who did not participate in a previous HE study with rifaximin were eligible if this open-label study was the only rifaximin HE study available at an individual site.
Interventions
DRUGRifaximin
Oral
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must sign an Informed Consent Form * In remission from past HE * Appropriate birth control measures * More than or equal to 18 years of age * Must be potential for benefit from treatment * Recent HE episodes * Capable and willing to comply with all study procedures * Participant has support network
Exclusion criteria
* Significant medical conditions or Investigator decision not to include the participant * Allergies to the study drug or similar drugs * Laboratory abnormalities * Recent participation in another clinical trial * Problems experienced in a previous HE trial * Pregnant or at risk of pregnancy * Recent alcohol consumption * Active or latent bacterial or viral Infections * Bowel issues * Recent Active Cancer * On a prohibited medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event | Baseline up to Month 36 | A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Baseline up to Month 36 | 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. |
| Number Of Participants With A Significant Mean Change From Baseline In Vital Signs | Baseline up to Month 36 | 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. |
| Change From Baseline In Conn Score At Last Assessment | Baseline up to Month 36 | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
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).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 252 |
| 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. | 70 |
| Total | 322 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 2 |
| Overall Study | Death | 45 | 14 |
| Overall Study | Liver Transplant | 23 | 8 |
| Overall Study | Lost to Follow-up | 15 | 3 |
| Overall Study | Moved to Another State | 1 | 0 |
| Overall Study | Noncompliance | 9 | 0 |
| Overall Study | Personal Reason | 0 | 1 |
| Overall Study | Principal Investigator Decision | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Recurrent Hepatic Encephalopathy Episode | 1 | 2 |
| Overall Study | Transferred to Nursing Home | 1 | 0 |
| Overall Study | Withdrawal by Subject | 23 | 5 |
Baseline characteristics
| Characteristic | New Rifaximin | Continuing Rifaximin | Total |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 8.9 | 56.7 years STANDARD_DEVIATION 9.36 | 57.4 years STANDARD_DEVIATION 57 |
| Sex: Female, Male Female | 94 Participants | 32 Participants | 126 Participants |
| Sex: Female, Male Male | 158 Participants | 38 Participants | 196 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 212 / 252 | 52 / 70 |
| serious Total, serious adverse events | 158 / 252 | 49 / 70 |
Outcome results
Primary
Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event
A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline up to Month 36
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| New Rifaximin | Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event | Non-Serious Adverse Event | 78 Participants |
| New Rifaximin | Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event | Serious Adverse Event | 158 Participants |
| Continuing Rifaximin | Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event | Non-Serious Adverse Event | 15 Participants |
| Continuing Rifaximin | Number Of Participants Reporting A Non-serious Adverse Event Or A Serious Adverse Event | Serious Adverse Event | 49 Participants |
Secondary
Change From Baseline In Conn Score At Last Assessment
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.
Time frame: Baseline up to Month 36
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| New Rifaximin | Change From Baseline In Conn Score At Last Assessment | Baseline | 0.4 score on a scale | Standard Deviation 0.58 |
| New Rifaximin | Change From Baseline In Conn Score At Last Assessment | Change from Baseline | -0.1 score on a scale | Standard Deviation 0.77 |
| Continuing Rifaximin | Change From Baseline In Conn Score At Last Assessment | Baseline | 0.2 score on a scale | Standard Deviation 0.4 |
| Continuing Rifaximin | Change From Baseline In Conn Score At Last Assessment | Change from Baseline | 0.1 score on a scale | Standard Deviation 0.41 |
Secondary
Number Of Participants With A Significant Mean Change From Baseline In Vital Signs
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.
Time frame: Baseline up to Month 36
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| New Rifaximin | Number Of Participants With A Significant Mean Change From Baseline In Vital Signs | 0 Participants |
| Continuing Rifaximin | Number Of Participants With A Significant Mean Change From Baseline In Vital Signs | 0 Participants |
Secondary
Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants
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.
Time frame: Baseline up to Month 36
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Hemoglobin | 15 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Hematocrit | 12 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Platelets | 18 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Prothrombin Time | 16 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | International Normalized Ratio | 24 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | White Blood Cells | 15 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Lymphocytes | 24 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Glucose, random, serum | 8 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Potassium | 17 Participants |
| New Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Direct Bilirubin | 14 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Glucose, random, serum | 8 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Hemoglobin | 12 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | White Blood Cells | 2 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Hematocrit | 4 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Direct Bilirubin | 5 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Platelets | 6 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Lymphocytes | 10 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Prothrombin Time | 7 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | Potassium | 7 Participants |
| Continuing Rifaximin | Number Of Participants With Postbaseline Potentially Clinically Significant Laboratory (Hematology and Blood Chemistry) Abnormal Results In ≥5% of Participants | International Normalized Ratio | 8 Participants |