Clinical trial NCT03397888: The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist
Official title: The Effect o f Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixiban, an Oral FXa Antagonist
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-01-12
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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


Eligibility criteria: 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.

Primary outcomes:
measure: PK - Plasma half-life (t1/2)
timeFrame: Day 1 through Day 6
measure: PK - Tmax
timeFrame: Day 1 through Day 6
measure: PK - Cmax
timeFrame: Day 1 through Day 6
measure: PK - AUC (0-last)
timeFrame: Day 1 through Day 6
measure: PK - (AUC(0-∞)).
timeFrame: Day 1 through Day 6
measure: PK - Volume of distribution
timeFrame: Day 1 through Day 6
measure: PK - Total clearance
timeFrame: Day 1 through Day 6
Secondary outcomes:
measure: Safety - Treatment Emergent AEs
timeFrame: Day -1 through up to Day 21
measure: Safety - Demographics
timeFrame: Day -30 through Day -2 (Screening)
measure: Safety - Vital Signs Temperature
timeFrame: Day -30 through up to Day 21
measure: Safety - Vital Signs Respiratory Rate
timeFrame: Day -30 through up to Day 21
measure: Safety - Vital Signs Heart Rate
timeFrame: Day -30 through up to Day 21
measure: Safety - Vital Signs Blood Pressure
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - PR
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - RR
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - WRS
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - QT
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - QTcF
timeFrame: Day -30 through up to Day 21
measure: Safety - 12 Lead ECG - QTcB
timeFrame: Day -30 through up to Day 21
measure: Safety - Physical Exam - Height
timeFrame: Day -30 through up to Day 21
measure: Safety - Physical Exam - Weight
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - hemoglobin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - hematocrit
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - white blood cell [WBC]
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Platelet Count
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Absolute Neutrophil Count
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Absolute Basophils
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Eosinophil's
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Lymphocytes
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Mean Corpuscular Hemoglobin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Concentration
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Mean Corpuscular Hemoglobin Volume
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Monocytes
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Neutrophils
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Red Blood Cell Count
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Red Cell Distribution Width
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Hematology - Reticulocyte
timeFrame: Day -30 through up to Day 21
measure: Safety- Lab - Coagulation - PT
timeFrame: Day -30 through up to Day 21
measure: Safety- Lab - Coagulation - INR
timeFrame: Day -30 through up to Day 21
measure: Safety- Lab - Coagulation - aPTT
timeFrame: Day -30 through up to Day 21
measure: Safety- Lab - Coagulation - Factor V Leiden
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Sodium
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Potassium
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Chloride
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Carbon Dioxide
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Glucose
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Blood Urea Nitrogen
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Creatinine
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - AST
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - ALT
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - GGT
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Total Protein
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Albumin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Alkaline Phosphatase
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Calcium
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Phosphorus
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Total Bilirubin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Fractionated Bilirubin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - Uric Acid
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Serum Chemistry - LDH
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urine toxicology Panel - Amphetamines
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urine toxicology Panel - Barbiturates
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urine toxicology Panel - Cannabinoids
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urine toxicology Panel - Cocaine
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urine toxicology Panel - Ethanol
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urine toxicology Panel - Opiates
timeFrame: Day -30 through Day -1
measure: Safety - Lab - Urinalysis - Specific Gravity
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - pH
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - Glucose
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - Protein
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - Hemoglobin
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - Leukocyte esterase
timeFrame: Day -30 through up to Day 21
measure: Safety - Lab - Urinalysis - Nitrate
timeFrame: Day -30 through up to Day 21
measure: Safety - Urine Occult Blood Testing
timeFrame: Day -30 through Day -2 (screening)
measure: Safety - Fecal Occult Blood Testing
timeFrame: Day -30 through Day -2 (screening)
measure: Safety - Lab - Blood Virology - HIV I
timeFrame: Day-30 through Day -2 (Screening)
measure: Safety - Lab - Blood Virology - HIV II
timeFrame: Day-30 through Day -2 (Screening)
measure: Safety - Lab - Blood Virology - Hepatitis B
timeFrame: Day-30 through Day -2 (Screening)
measure: Safety - Lab - Blood Virology - Hepatitis C
timeFrame: Day-30 through Day -2 (Screening)
measure: Safety - Lab - Serum Pregnancy
timeFrame: Day -30 through up to Day 21
measure: PD - Anti-Factor Xa Concentration
timeFrame: Day 1 through Day 6
measure: PD - Thrombin Concentrations
timeFrame: Day 1 through Day 6
Other outcomes:
Locations:
city: Hialeah
country: United States
facility: Clinical Pharmacology of Miami
state: Florida
Study officials:
References: