Liver Cirrhosis, Portal Hypertension
Conditions
Brief summary
This placebo-controlled study will assess the safety and efficacy of a 90-day course of treatment with ifetroban for portal hypertension in cirrhotic patients
Interventions
DRUGIfetroban
thromboxane prostanoid receptor antagonist delivered as infusion and oral capsule
DRUGPlacebo
matched placebo delivered as infusion and oral capsule
Sponsors
Cumberland Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* liver cirrhosis * baseline hepatic venous pressure gradient (HVPG) \>= 8 mmHg and \<= 18 mmHg * stable liver function enzymes
Exclusion criteria
* portal or splenic vein thrombosis * Transjugular intrahepatic portosystemic shunt (TIPS) or portocaval shunt * variceal bleed in last 2 months * hemodialysis * Child-Pugh Score \>= 12 * Model for End-stage Liver Disease- Sodium score (MELD-Na) \>= 20 * Acute kidney injury, Chronic kidney disease and/or Serum Creatinine \>= 2.0 mg/dL * current alcohol consumption \> 2 drinks per day * Platelet count (PLT) \< 60 x 10\^3/microliter (uL) * A change in statin therapy in the last 3 months * Current Hepatitis Virus B or C (HBV or HCV) therapy; or planned initiation of therapy during the treatment period * Myocardial infarction within 30 days * History of bleeding diathesis or current (within previous 14 days) or planned use of anticoagulant or antiplatelet drugs including aspirin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety (Incidence and Severity of Adverse Events) | Through 97 days (90 days treatment and 7 days follow-up) | Incidence is measured as the total number of adverse events reported during the treatment and follow-up period for each treatment group. |
| Safety (Severity of Adverse Events) | Through 90 days treatment and 7 days follow-up | The severity of each event is reported by the investigator according to the following protocol/CTCAE definitions: Grade 1-Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2-Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living; Grade 3-Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4-Life-threatening consequences; urgent intervention indicated; Grade 5-Death related to adverse event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alanine Aminotransferase (ALT) | Baseline and 90 days | ALT values through Day 90 will be compared to baseline |
| Change in Hepatic Venous Pressure Gradient (HVPG) | Baseline and 90 days | The HVPG will be measured through Day 90 and will be compared to baseline |
| Variceal Bleeds (Occurrence of Variceal Bleeds) | Through Day 97 | The number of variceal bleeds during the treatment and follow-up periods will be evaluated |
| Aspartate Aminotransferase/Platelet Ratio (APRI) | Baseline and 90 days | The Aspartate Aminotransferase/Platelet Ratio through Day 90 will be compared to baseline |
| Change in Aspartate Aminotransferase (AST) | Baseline and 90 days | AST values through Day 90 will be compared to baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ifetroban 90 day course of oral ifetroban following intravenous loading dose
Ifetroban: thromboxane prostanoid receptor antagonist delivered as infusion and oral capsule | 20 |
| Placebo 90 day course of placebo following intravenous dose of D5W
Placebo: matched placebo delivered as infusion and oral capsule | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Ifetroban | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.8 years STANDARD_DEVIATION 8.1 | 58.2 years STANDARD_DEVIATION 9.1 | 55.2 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 9 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Primary Cirrhosis Etiology Alcoholic | 4 Participants | 4 Participants | 8 Participants |
| Primary Cirrhosis Etiology Auto-immune | 3 Participants | 0 Participants | 3 Participants |
| Primary Cirrhosis Etiology Cryptogenic | 2 Participants | 0 Participants | 2 Participants |
| Primary Cirrhosis Etiology Hepatitis B and C | 1 Participants | 0 Participants | 1 Participants |
| Primary Cirrhosis Etiology Hepatitis B only | 0 Participants | 0 Participants | 0 Participants |
| Primary Cirrhosis Etiology Hepatitis C only | 2 Participants | 3 Participants | 5 Participants |
| Primary Cirrhosis Etiology Non-alcoholic Steatohepatitis | 8 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Female | 15 Participants | 8 Participants | 23 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 10 |
| other Total, other adverse events | 10 / 20 | 1 / 10 |
| serious Total, serious adverse events | 2 / 20 | 1 / 10 |
Outcome results
Primary
Safety (Incidence and Severity of Adverse Events)
Incidence is measured as the total number of adverse events reported during the treatment and follow-up period for each treatment group.
Time frame: Through 97 days (90 days treatment and 7 days follow-up)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ifetroban | Safety (Incidence and Severity of Adverse Events) | 23 Number of adverse events |
| Placebo | Safety (Incidence and Severity of Adverse Events) | 2 Number of adverse events |
Primary
Safety (Severity of Adverse Events)
The severity of each event is reported by the investigator according to the following protocol/CTCAE definitions: Grade 1-Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2-Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living; Grade 3-Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4-Life-threatening consequences; urgent intervention indicated; Grade 5-Death related to adverse event.
Time frame: Through 90 days treatment and 7 days follow-up
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Ifetroban | Safety (Severity of Adverse Events) | Grade 2 (moderate) | 8 Adverse Events |
| Ifetroban | Safety (Severity of Adverse Events) | Grade 4 (life-threatening) | 0 Adverse Events |
| Ifetroban | Safety (Severity of Adverse Events) | Greade 3 (severe) | 4 Adverse Events |
| Ifetroban | Safety (Severity of Adverse Events) | Grade 5 (death) | 0 Adverse Events |
| Ifetroban | Safety (Severity of Adverse Events) | Grade 1 (mild) | 11 Adverse Events |
| Placebo | Safety (Severity of Adverse Events) | Grade 5 (death) | 0 Adverse Events |
| Placebo | Safety (Severity of Adverse Events) | Grade 1 (mild) | 1 Adverse Events |
| Placebo | Safety (Severity of Adverse Events) | Grade 2 (moderate) | 0 Adverse Events |
| Placebo | Safety (Severity of Adverse Events) | Greade 3 (severe) | 1 Adverse Events |
| Placebo | Safety (Severity of Adverse Events) | Grade 4 (life-threatening) | 0 Adverse Events |
Secondary
Alanine Aminotransferase (ALT)
ALT values through Day 90 will be compared to baseline
Time frame: Baseline and 90 days
Population: The analysis was performed on all subjects that had data available for the Baseline to Day 90 comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Alanine Aminotransferase (ALT) | -4.8 U/L | Standard Deviation 7.4 |
| Placebo | Alanine Aminotransferase (ALT) | 2.2 U/L | Standard Deviation 9.1 |
Secondary
Aspartate Aminotransferase/Platelet Ratio (APRI)
The Aspartate Aminotransferase/Platelet Ratio through Day 90 will be compared to baseline
Time frame: Baseline and 90 days
Population: The analysis was performed on all subjects that had data available for the Baseline to Day 90 comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Aspartate Aminotransferase/Platelet Ratio (APRI) | 0.84 ratio | Standard Deviation 0.52 |
| Placebo | Aspartate Aminotransferase/Platelet Ratio (APRI) | 0.98 ratio | Standard Deviation 0.61 |
Secondary
Change in Aspartate Aminotransferase (AST)
AST values through Day 90 will be compared to baseline
Time frame: Baseline and 90 days
Population: The analysis was performed on all subjects that had data available for the Baseline to Day 90 comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Change in Aspartate Aminotransferase (AST) | -1.2 U/L | Standard Deviation 9.1 |
| Placebo | Change in Aspartate Aminotransferase (AST) | 4.2 U/L | Standard Deviation 12.9 |
Secondary
Change in Hepatic Venous Pressure Gradient (HVPG)
The HVPG will be measured through Day 90 and will be compared to baseline
Time frame: Baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Change in Hepatic Venous Pressure Gradient (HVPG) | 1.6 mmHg | Standard Deviation 3.7 |
| Placebo | Change in Hepatic Venous Pressure Gradient (HVPG) | -0.1 mmHg | Standard Deviation 2.7 |
Secondary
Variceal Bleeds (Occurrence of Variceal Bleeds)
The number of variceal bleeds during the treatment and follow-up periods will be evaluated
Time frame: Through Day 97
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ifetroban | Variceal Bleeds (Occurrence of Variceal Bleeds) | 0 events of variceal bleeding |
| Placebo | Variceal Bleeds (Occurrence of Variceal Bleeds) | 1 events of variceal bleeding |