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

Hepatic Impairment Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03397888
• Other study ID #: 17-022
• Status: Completed
• Phase: Phase 1
• Start date: November 16, 2017
• Est. completion date: January 16, 2018

Study information

• Verified date: February 2023
• Source: Alexion Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: January 16, 2018
• Est. primary completion date: January 16, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. 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.

2. Body Mass Index between 18 and 35 kg*m-2 and weighs at least 50 kg.

3. 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.

4. 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.

5. The subject smokes <12 cigarettes per day or equivalent and agrees to no or reduced tobacco products while domiciled.

6. The subject is able to read and give written informed consent and signed the IRB approved consent form.

7. The subject has adequate venous access for blood sampling.

Exclusion Criteria:

1. 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.

2. 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.

3. The subject has a history of or risk factors for a hypercoagulable or thrombotic condition.

4. 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.

5. The subject has a calculated creatinine clearance of <60mL/min as determined by Cockcroft-Gault method.

6. Concomitant medication use:

1. For all subjects, illicit drugs, oral contraceptives, and hormone replacement therapy are excluded within 30 days prior to Day -1.

2. For all subjects, over the counter drugs, including dietary supplements and herbal products are excluded within 14 days prior to Day -1.

3. 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.

4. 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.

7. 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.

8. The subject has a history of blood donation of more than 500mL within 3 months prior to dosing.

9. 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.

10. The subject has positive screen for drugs of abuse at Day -1.

11. The subject does not agree to withhold from alcohol consumption from 48 hours prior to dosing through discharge.

12. The subject has a medical or surgical condition which may impair drug absorption.

13. The subject is pregnant or breastfeeding.

14. 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.

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases

Intervention

Drug:
• Betrixaban
80 mg capsule

Locations

Country	Name	City	State
United States	Clinical Pharmacology of Miami	Hialeah	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Portola Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PK - Plasma half-life (t1/2)	Plasma half-life (t1/2), distribution half-life and terminal half-life.	Day 1 through Day 6
Primary	PK - Tmax	Time to maximum observed plasma concentration (Tmax).	Day 1 through Day 6
Primary	PK - Cmax	Maximum observed plasma concentration (Cmax)	Day 1 through Day 6
Primary	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
Primary	PK - (AUC(0-8)).	Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0-8)).	Day 1 through Day 6
Primary	PK - Volume of distribution	Apparent volume of distribution (Vd/F).	Day 1 through Day 6
Primary	PK - Total clearance	Apparent total clearance (CL/F).	Day 1 through Day 6
Secondary	Safety - Treatment Emergent AEs	Safety evaluation will study the adverse event (AE) profile	Day -1 through up to Day 21
Secondary	Safety - Demographics	Safety will be evaluated by assessment of Demographics	Day -30 through Day -2 (Screening)
Secondary	Safety - Vital Signs Temperature	Safety will be evaluated by assessment of Temperature - Celsius	Day -30 through up to Day 21
Secondary	Safety - Vital Signs Respiratory Rate	Safety will be evaluated by assessment of Respiratory Rate - Breaths per Minute	Day -30 through up to Day 21
Secondary	Safety - Vital Signs Heart Rate	Safety will be evaluated by assessment of Heart Rate - Beats per Minute	Day -30 through up to Day 21
Secondary	Safety - Vital Signs Blood Pressure	Safety will be evaluated by assessment of Blood Pressure - mmHg	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - PR	Safety will be evaluated by assessment of 12 ECG - PR (ms)	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - RR	Safety will be evaluated by assessment of 12 ECG - RR (ms)	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - WRS	Safety will be evaluated by assessment of 12 ECG - WRS (ms)	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - QT	Safety will be evaluated by assessment of 12 ECG - QT (ms)	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - QTcF	Safety will be evaluated by assessment of 12 ECG - QTcF (ms)	Day -30 through up to Day 21
Secondary	Safety - 12 Lead ECG - QTcB	Safety will be evaluated by assessment of 12 ECG - QTcB (ms)	Day -30 through up to Day 21
Secondary	Safety - Physical Exam - Height	Safety will be evaluated by assessment Physical Exam - Height (centimeters)	Day -30 through up to Day 21
Secondary	Safety - Physical Exam - Weight	Safety will be evaluated by assessment Physical Exam - Weight (kilogram)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - hemoglobin	Safety will be evaluated by analyzing Hematology - hemoglobin (g/dL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - hematocrit	Safety will be evaluated by analyzing Hematology - hematocrit (%)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - white blood cell [WBC]	Safety will be evaluated by analyzing Hematology - WBC (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Platelet Count	Safety will be evaluated by analyzing Platelet Count (Plt/mL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Absolute Neutrophil Count	Safety will be evaluated by analyzing Absolute Neutrophil Count (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Absolute Basophils	Safety will be evaluated by analyzing Absolute Basophils (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Eosinophil's	Safety will be evaluated by analyzing Eosinophil's (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Lymphocytes	Safety will be evaluated by analyzing Lymphocytes (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Mean Corpuscular Hemoglobin	Safety will be evaluated by analyzing Mean Corpuscular Hemoglobin (PG)	Day -30 through up to Day 21
Secondary	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
Secondary	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
Secondary	Safety - Lab - Hematology - Monocytes	Safety will be evaluated by analyzing Monocytes (K/UL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Neutrophils	Safety will be evaluated by analyzing Neutrophils (K/UL)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Hematology - Red Cell Distribution Width	Safety will be evaluated by analyzing Red Cell Distribution Width (%)	Day -30 through up to Day 21
Secondary	Safety - Lab - Hematology - Reticulocyte	Safety will be evaluated by analyzing Reticulocyte (K/UL)	Day -30 through up to Day 21
Secondary	Safety- Lab - Coagulation - PT	Safety will be evaluated by analyzing Coagulation - PT (seconds)	Day -30 through up to Day 21
Secondary	Safety- Lab - Coagulation - INR	Safety will be evaluated by analyzing Coagulation - INR (no unit)	Day -30 through up to Day 21
Secondary	Safety- Lab - Coagulation - aPTT	Safety will be evaluated by analyzing Coagulation - aPTT (seconds)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - Sodium	Safety will be evaluated by analyzing Serum Chemistry - Sodium (mEq/L)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - Potassium	Safety will be evaluated by analyzing Serum Chemistry - Potassium (mEq/L)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - Chloride	Safety will be evaluated by analyzing Serum Chemistry - Chloride (mEq/L)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - Glucose	Safety will be evaluated by analyzing Serum Chemistry - Glucose (mg/dL)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - Creatinine	Safety will be evaluated by analyzing Serum Chemistry - Creatinine (mg/dL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - AST	Safety will be evaluated by analyzing Serum Chemistry - AST (U/L)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - ALT	Safety will be evaluated by analyzing Serum Chemistry - ALT (U/L)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - GGT	Safety will be evaluated by analyzing Serum Chemistry - GGT (U/L)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - Albumin	Safety will be evaluated by analyzing Serum Chemistry - Albumin(g/dL)	Day -30 through up to Day 21
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - Calcium	Safety will be evaluated by analyzing Serum Chemistry - Calcium (mg/dL)	Day -30 through up to Day 21
Secondary	Safety - Lab - Serum Chemistry - Phosphorus	Safety will be evaluated by analyzing Serum Chemistry - Phosphorus (mg/dL)	Day -30 through up to Day 21
Secondary	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
Secondary	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
Secondary	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
Secondary	Safety - Lab - Serum Chemistry - LDH	Safety will be evaluated by analyzing Serum Chemistry LDH (U/L)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urine toxicology Panel - Amphetamines	Safety will be evaluated by analyzing Urine toxicology Panel - Amphetamines (NG/ML)	Day -30 through Day -1
Secondary	Safety - Lab - Urine toxicology Panel - Barbiturates	Safety will be evaluated by analyzing Urine toxicology Panel - Barbiturates (NG/ML)	Day -30 through Day -1
Secondary	Safety - Lab - Urine toxicology Panel - Cannabinoids	Safety will be evaluated by analyzing Urine toxicology Panel - Cannabinoids (NG/ML)	Day -30 through Day -1
Secondary	Safety - Lab - Urine toxicology Panel - Cocaine	Safety will be evaluated by analyzing Urine toxicology Panel - Cocaine (NG/ML)	Day -30 through Day -1
Secondary	Safety - Lab - Urine toxicology Panel - Ethanol	Safety will be evaluated by analyzing Urine toxicology Panel - Ethanol (MG/DL)	Day -30 through Day -1
Secondary	Safety - Lab - Urine toxicology Panel - Opiates	Safety will be evaluated by analyzing Urine toxicology Panel - Opiates (NG/ML)	Day -30 through Day -1
Secondary	Safety - Lab - Urinalysis - Specific Gravity	Safety will be evaluated by analyzing Urinalysis - Specific Gravity (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - pH	Safety will be evaluated by analyzing Urinalysis - pH (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - Glucose	Safety will be evaluated by analyzing Urinalysis - Glucose (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - Protein	Safety will be evaluated by analyzing Urinalysis - Protein (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - Hemoglobin	Safety will be evaluated by analyzing Urinalysis - Hemoglobin (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - Leukocyte esterase	Safety will be evaluated by analyzing Urinalysis - Leukocyte esterase (no unit)	Day -30 through up to Day 21
Secondary	Safety - Lab - Urinalysis - Nitrate	Safety will be evaluated by analyzing Urinalysis - Nitrate (no unit)	Day -30 through up to Day 21
Secondary	Safety - Urine Occult Blood Testing	Safety will be evaluated by assessment of Urine Occult Blood Testing (positive/negative)	Day -30 through Day -2 (screening)
Secondary	Safety - Fecal Occult Blood Testing	Safety will be evaluated by assessment of Fecal Occult Blood Testing (positive/negative)	Day -30 through Day -2 (screening)
Secondary	Safety - Lab - Blood Virology - HIV I	Safety will be evaluated by analyzing Blood Virology - HIV I (positive/negative)	Day-30 through Day -2 (Screening)
Secondary	Safety - Lab - Blood Virology - HIV II	Safety will be evaluated by analyzing Blood Virology - HIV II (positive/negative)	Day-30 through Day -2 (Screening)
Secondary	Safety - Lab - Blood Virology - Hepatitis B	Safety will be evaluated by analyzing Blood Virology - Hepatitis B (positive/negative)	Day-30 through Day -2 (Screening)
Secondary	Safety - Lab - Blood Virology - Hepatitis C	Safety will be evaluated by analyzing Blood Virology - Hepatitis C (positive/negative)	Day-30 through Day -2 (Screening)
Secondary	Safety - Lab - Serum Pregnancy	Safety will be evaluated by analyzing Serum Pregnancy	Day -30 through up to Day 21
Secondary	PD - Anti-Factor Xa Concentration	Anti-fXa will be analyzed for changes/percent changes from baseline over time.	Day 1 through Day 6
Secondary	PD - Thrombin Concentrations	Thrombin will be analyzed for changes/percent changes from baseline over time.	Day 1 through Day 6