The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist

Study Overview
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Brief Summary
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Single center, prospective open label PK and PD study of betrixaban in subjects with mild and moderate hepatic impairment vs healthy volunteers.

Official Title
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The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Betrixaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohorts 1 & 2: Man or a woman 18 to 70 with stable chronic hepatic impairment disease due to cirrhosis confirmed by biopsy, ultrasound, CT or MRI (Cohort 1 - Mild impairment, Child-Pugh Category A; Cohort 2 - Moderate Impairment, Child-Pugh Category B). Cohort 3: essentially healthy man or woman without liver disease whose sex, age and weight match patients in Cohorts 1 & 2 in order to result in similar average demographics. Body Mass Index between 18 and 35 kg*m-2 and weighs at least 50 kg. Contraception. Men must agree to acceptable methods of contraception. Women of child-bearing potential must agree to two acceptable forms of contraception. Post-menopausal women must have had no regular menstrual bleeding for at least one year prior to initial dosing and confirmed by an elevated plasma Follicle-stimulating hormone level test at screening for women not in receipt of hormone replacement therapy (HRT). Women who report surgical sterilization must have had the procedure at least six months prior to dosing, supported by clinical documentation. The subject has clinical unremarkable medical history, physical examination, ECG, laboratory values and vital signs, as determined by the investigator. Subjects in Cohorts 1 & 2 may have: abnormal liver function tests, INR up to 2.2, PT up to 6 seconds over control, aPPT up to 45 seconds and platelets down to 45,000/uL. The subject smokes <12 cigarettes per day or equivalent and agrees to no or reduced tobacco products while domiciled. The subject is able to read and give written informed consent and signed the IRB approved consent form. The subject has adequate venous access for blood sampling. Exclusion Criteria: The subject has a history, symptoms of, or risk factors for bleeding or a stool specimen within 6 months of dosing positive for occult blood. The subject has an absolute/relative contraindication to anticoagulation due to: history of intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery or major surgery within 6 months of dosing. The subject has a history of or risk factors for a hypercoagulable or thrombotic condition. The subject has a history of any clinically significant cardiac, endocrinologic, hematologic, hepatic (except for Cohorts 1 & 2), immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or other major disease other than the underlying disease in Cohorts 1 & 2. The subject has a calculated creatinine clearance of <60mL/min as determined by Cockcroft-Gault method. Concomitant medication use: For all subjects, illicit drugs, oral contraceptives, and hormone replacement therapy are excluded within 30 days prior to Day -1. For all subjects, over the counter drugs, including dietary supplements and herbal products are excluded within 14 days prior to Day -1. Subjects enrolled in Cohort 3 will be excluded if the subject has taken any prescription drugs in the 30 days prior to dosing. Furthermore, the subject will be excluded if he/she does not agree to refrain from concomitant drugs throughout the study unless medically necessary as determined by the Investigator. Subjects enrolled in Cohort 1 and 2 may continue taking stable preexisting medications throughout the study with the exception of strong P-gp inhibitors. Strong P-gp inhibitors include but are not limited to: amiodarone, azithromycin, clarithromycin, erythromycin, ketoconazole, and verapamil. Prescribed stable acetaminophen use up to 2,000 mg per day is allowable. Any acetaminophen use with alcohol within 48 hours of dosing is prohibited. Furthermore, the subject will be excluded if he/she does not agree to refrain from additional concomitant drugs throughout the study unless medically necessary as determined by the Investigator. The subject has a history of severe trauma or bone fracture within 6 months prior to dosing; or planned surgery within 1 month after dosing. The subject has a history of blood donation of more than 500mL within 3 months prior to dosing. The subject has received an investigational drug product within 30 days or 5 half-lives of the investigational compound, whichever is greater, from Day -1. The subject has positive screen for drugs of abuse at Day -1. The subject does not agree to withhold from alcohol consumption from 48 hours prior to dosing through discharge. The subject has a medical or surgical condition which may impair drug absorption. The subject is pregnant or breastfeeding. The subject has any condition which could interfere with or for which the treatment might interfere with the conduct of the study, or would, in the opinion of the Investigator, increase the risk of the subject's participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Mild Impairment, Child-Pugh Category A | Drug: Betrixaban<br>* 80 mg capsule<br>|
| Experimental: Cohort 2<br>Moderate Impairment, Child-Pugh Category B | Drug: Betrixaban<br>* 80 mg capsule<br>|
| Experimental: Cohort 3<br>Essentially Healthy man or woman without liver disease matched to Cohorts 1 & 2 for age, sex and weight. | Drug: Betrixaban<br>* 80 mg capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK - Plasma half-life (t1/2) | Plasma half-life (t1/2), distribution half-life and terminal half-life. | Day 1 through Day 6 | 
| PK - Tmax | Time to maximum observed plasma concentration (Tmax). | Day 1 through Day 6 | 
| PK - Cmax | Maximum observed plasma concentration (Cmax) | Day 1 through Day 6 | 
| PK - AUC (0-last) | Area under the plasma concentration-time curve from 0 to last measurable concentration (AUC (0-last)). | Day 1 through Day 6 | 
| PK - (AUC(0-∞)). | Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)). | Day 1 through Day 6 | 
| PK - Volume of distribution | Apparent volume of distribution (Vd/F). | Day 1 through Day 6 | 
| PK - Total clearance | Apparent total clearance (CL/F). | Day 1 through Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Treatment Emergent AEs | Safety evaluation will study the adverse event (AE) profile | Day -1 through up to Day 21 | 
| Safety - Demographics | Safety will be evaluated by assessment of Demographics | Day -30 through Day -2 (Screening) | 
| Safety - Vital Signs Temperature | Safety will be evaluated by assessment of Temperature - Celsius | Day -30 through up to Day 21 | 
| Safety - Vital Signs Respiratory Rate | Safety will be evaluated by assessment of Respiratory Rate - Breaths per Minute | Day -30 through up to Day 21 | 
| Safety - Vital Signs Heart Rate | Safety will be evaluated by assessment of Heart Rate - Beats per Minute | Day -30 through up to Day 21 | 
| Safety - Vital Signs Blood Pressure | Safety will be evaluated by assessment of Blood Pressure - mmHg | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - PR | Safety will be evaluated by assessment of 12 ECG - PR (ms) | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - RR | Safety will be evaluated by assessment of 12 ECG - RR (ms) | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - WRS | Safety will be evaluated by assessment of 12 ECG - WRS (ms) | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - QT | Safety will be evaluated by assessment of 12 ECG - QT (ms) | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - QTcF | Safety will be evaluated by assessment of 12 ECG - QTcF (ms) | Day -30 through up to Day 21 | 
| Safety - 12 Lead ECG - QTcB | Safety will be evaluated by assessment of 12 ECG - QTcB (ms) | Day -30 through up to Day 21 | 
| Safety - Physical Exam - Height | Safety will be evaluated by assessment Physical Exam - Height (centimeters) | Day -30 through up to Day 21 | 
| Safety - Physical Exam - Weight | Safety will be evaluated by assessment Physical Exam - Weight (kilogram) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - hemoglobin | Safety will be evaluated by analyzing Hematology - hemoglobin (g/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - hematocrit | Safety will be evaluated by analyzing Hematology - hematocrit (%) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - white blood cell [WBC] | Safety will be evaluated by analyzing Hematology - WBC (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Platelet Count | Safety will be evaluated by analyzing Platelet Count (Plt/mL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Absolute Neutrophil Count | Safety will be evaluated by analyzing Absolute Neutrophil Count (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Absolute Basophils | Safety will be evaluated by analyzing Absolute Basophils (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Eosinophil's | Safety will be evaluated by analyzing Eosinophil's (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Lymphocytes | Safety will be evaluated by analyzing Lymphocytes (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Mean Corpuscular Hemoglobin | Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin (PG) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Concentration | Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Concentration (g/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Volume | Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin Volume (FL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Monocytes | Safety will be evaluated by analyzing Monocytes (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Neutrophils | Safety will be evaluated by analyzing Neutrophils (K/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Red Blood Cell Count | Safety will be evaluated by analyzing Red Blood Cell Count (MIL/UL) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Red Cell Distribution Width | Safety will be evaluated by analyzing Red Cell Distribution Width (%) | Day -30 through up to Day 21 | 
| Safety - Lab - Hematology - Reticulocyte | Safety will be evaluated by analyzing Reticulocyte (K/UL) | Day -30 through up to Day 21 | 
| Safety- Lab - Coagulation - PT | Safety will be evaluated by analyzing Coagulation - PT (seconds) | Day -30 through up to Day 21 | 
| Safety- Lab - Coagulation - INR | Safety will be evaluated by analyzing Coagulation - INR (no unit) | Day -30 through up to Day 21 | 
| Safety- Lab - Coagulation - aPTT | Safety will be evaluated by analyzing Coagulation - aPTT (seconds) | Day -30 through up to Day 21 | 
| Safety- Lab - Coagulation - Factor V Leiden | Safety will be evaluated by analyzing Coagulation - Factor V Leiden (positive/negative) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Sodium | Safety will be evaluated by analyzing Serum Chemistry - Sodium (mEq/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Potassium | Safety will be evaluated by analyzing Serum Chemistry - Potassium (mEq/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Chloride | Safety will be evaluated by analyzing Serum Chemistry - Chloride (mEq/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Carbon Dioxide | Safety will be evaluated by analyzing Serum Chemistry - Carbon Dioxide (mEq/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Glucose | Safety will be evaluated by analyzing Serum Chemistry - Glucose (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Blood Urea Nitrogen | Safety will be evaluated by analyzing Serum Chemistry - Blood Urea Nitrogen (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Creatinine | Safety will be evaluated by analyzing Serum Chemistry - Creatinine (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - AST | Safety will be evaluated by analyzing Serum Chemistry - AST (U/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - ALT | Safety will be evaluated by analyzing Serum Chemistry - ALT (U/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - GGT | Safety will be evaluated by analyzing Serum Chemistry - GGT (U/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Total Protein | Safety will be evaluated by analyzing Serum Chemistry - Total Protein (g/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Albumin | Safety will be evaluated by analyzing Serum Chemistry - Albumin(g/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Alkaline Phosphatase | Safety will be evaluated by analyzing Serum Chemistry - Alkaline Phosphatase (U/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Calcium | Safety will be evaluated by analyzing Serum Chemistry - Calcium (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Phosphorus | Safety will be evaluated by analyzing Serum Chemistry - Phosphorus (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Total Bilirubin | Safety will be evaluated by analyzing Serum Chemistry - Total Bilirubin (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Fractionated Bilirubin | Safety will be evaluated by analyzing Serum Chemistry - Fractionated Bilirubin(mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - Uric Acid | Safety will be evaluated by analyzing Serum Chemistry - Uric Acid (mg/dL) | Day -30 through up to Day 21 | 
| Safety - Lab - Serum Chemistry - LDH | Safety will be evaluated by analyzing Serum Chemistry LDH (U/L) | Day -30 through up to Day 21 | 
| Safety - Lab - Urine toxicology Panel - Amphetamines | Safety will be evaluated by analyzing Urine toxicology Panel - Amphetamines (NG/ML) | Day -30 through Day -1 | 
| Safety - Lab - Urine toxicology Panel - Barbiturates | Safety will be evaluated by analyzing Urine toxicology Panel - Barbiturates (NG/ML) | Day -30 through Day -1 | 
| Safety - Lab - Urine toxicology Panel - Cannabinoids | Safety will be evaluated by analyzing Urine toxicology Panel - Cannabinoids (NG/ML) | Day -30 through Day -1 | 
| Safety - Lab - Urine toxicology Panel - Cocaine | Safety will be evaluated by analyzing Urine toxicology Panel - Cocaine (NG/ML) | Day -30 through Day -1 | 
| Safety - Lab - Urine toxicology Panel - Ethanol | Safety will be evaluated by analyzing Urine toxicology Panel - Ethanol (MG/DL) | Day -30 through Day -1 | 
| Safety - Lab - Urine toxicology Panel - Opiates | Safety will be evaluated by analyzing Urine toxicology Panel - Opiates (NG/ML) | Day -30 through Day -1 | 
| Safety - Lab - Urinalysis - Specific Gravity | Safety will be evaluated by analyzing Urinalysis - Specific Gravity (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - pH | Safety will be evaluated by analyzing Urinalysis - pH (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - Glucose | Safety will be evaluated by analyzing Urinalysis - Glucose (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - Protein | Safety will be evaluated by analyzing Urinalysis - Protein (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - Hemoglobin | Safety will be evaluated by analyzing Urinalysis - Hemoglobin (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - Leukocyte esterase | Safety will be evaluated by analyzing Urinalysis - Leukocyte esterase (no unit) | Day -30 through up to Day 21 | 
| Safety - Lab - Urinalysis - Nitrate | Safety will be evaluated by analyzing Urinalysis - Nitrate (no unit) | Day -30 through up to Day 21 | 
| Safety - Urine Occult Blood Testing | Safety will be evaluated by assessment of Urine Occult Blood Testing (positive/negative) | Day -30 through Day -2 (screening) | 
| Safety - Fecal Occult Blood Testing | Safety will be evaluated by assessment of Fecal Occult Blood Testing (positive/negative) | Day -30 through Day -2 (screening) | 
| Safety - Lab - Blood Virology - HIV I | Safety will be evaluated by analyzing Blood Virology - HIV I (positive/negative) | Day-30 through Day -2 (Screening) | 
| Safety - Lab - Blood Virology - HIV II | Safety will be evaluated by analyzing Blood Virology - HIV II (positive/negative) | Day-30 through Day -2 (Screening) | 
| Safety - Lab - Blood Virology - Hepatitis B | Safety will be evaluated by analyzing Blood Virology - Hepatitis B (positive/negative) | Day-30 through Day -2 (Screening) | 
| Safety - Lab - Blood Virology - Hepatitis C | Safety will be evaluated by analyzing Blood Virology - Hepatitis C (positive/negative) | Day-30 through Day -2 (Screening) | 
| Safety - Lab - Serum Pregnancy | Safety will be evaluated by analyzing Serum Pregnancy | Day -30 through up to Day 21 | 
| PD - Anti-Factor Xa Concentration | Anti-fXa will be analyzed for changes/percent changes from baseline over time. | Day 1 through Day 6 | 
| PD - Thrombin Concentrations | Thrombin will be analyzed for changes/percent changes from baseline over time. | Day 1 through Day 6 |