Atrial Fibrillation, Atrial Flutter
Conditions
Keywords
Betrixaban, MK-4448, nonvalvular atrial fibrillation
Brief summary
The primary purpose of this study is to optimize drug exposure in the target population.
Interventions
DRUGBetrixaban 30 mg
Betrixaban 30 mg once a day with food on Day 0 through Day 25 with concomitant amiodarone treatment.
DRUGAmiodarone
Patients on Amiodarone
DRUGBetrixaban 60 mg
Betrixaban 60 mg once a day with food on Day 0 through Day 25
DRUGBetrixaban 90 mg
Betrixaban 90 mg once a day with food on Day 0 through Day 25
Sponsors
Portola Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In the opinion of the investigator, participant requires long term anticoagulation for stroke prevention in atrial flutter (AF). * Men and women ≥18 years of age. * Participant has current non-valvular atrial fibrillation (NVAF) or AF or electrocardiogram (ECG) or Holter documentation within past 12 months. * Participant has an international normalized ratio (INR) ≤ 2.2 at allocation (Visit 2). * A participant who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the duration of the study. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, condom, vasectomy, and hormonal contraception. * Participant understands the study procedures and risks involved with the study, and voluntarily agree to participate by giving written informed consent.
Exclusion criteria
General * Participant is currently participating in another drug study or has received an investigational drug within 30 days prior to enrollment. * Participant is a woman who is pregnant, lactating or of child-bearing potential who refuses to use a medically acceptable form of contraception throughout the study. * Participant has a body weight less than 40 kg (88 lbs) or greater than 200 kg (440 lbs). * Participant routinely consumes more than 2 alcoholic drinks per day (average \>14 alcoholic drinks per week) or greater than 5 drinks within 2 hours on occasion. Prohibited Medical Conditions * Participant has any condition or situation which, in the opinion of the investigator, might pose a risk to the participant or interfere with participation in the study. * Conditions associated with an increased risk of bleeding Active bleeding. * Conditions other than AF that require chronic anticoagulation. * Severe aortic and mitral valvular disease requiring surgical intervention. * Previous known history of coagulopathy (e.g.: Factor V Leiden, Protein C Deficiency, Protein S Deficiency, Antiphospholipid Syndrome, etc.). * Active infective endocarditis. * Participant has history of familial long QT interval (the QT interval is the portion of an electrocardiogram (ECG) between the onset of the Q wave and the end of the T wave, representing the total time for ventricular depolarization and repolarization) syndrome or prolonged Bazett-corrected QT interval (QTcB) (males \> 470 msec; females \>480 msec) at baseline as measured on a 12-lead ECG. * Participant has serious pulmonary, hepatic, metabolic, gastrointestinal, central nervous system (CNS) or psychiatric disease, end-stage disease states, or any other disease that could interfere with the conduct or validity of the study or compromise participant safety. * Participant has a history of malignancy ≤ 5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer (melanoma, leukemia, lymphoma and myeloproliferative disorders of any duration are excluded). * Participant has a history of mental instability, drug/alcohol abuse within the past 5 years, or major psychiatric illness not adequately controlled and stable on pharmacotherapy. * Participant has reversible causes of atrial fibrillation (i.e.: cardiac surgery, pulmonary embolism, untreated hyperthyroidism). * Participant is to undergo pulmonary vein isolation or surgery for treatment of AF. * Participant had a severe, disabling stroke within the previous 6 months, any stroke within the previous 14 days, thromboembolism within previous 30 days or a transient ischemic attack (TIA) within 3 days prior to Visit 1. * Participant requires renal replacement therapies (hemo- or peritoneal dialysis). * Participant has any of a list of defined laboratory abnormalities. Prohibited Medications * Anti-platelet agents other than aspirin within 10 days prior to Visit 1 (excluding maintenance dose clopidogrel, prasugrel or ticlopidine) or fibrinolytic agents within 30 days prior to Visit 1. * Aspirin greater than 162 mg/day. * Daily non-steroidal anti-inflammatory drug (NSAID) use. * Dronedarone, verapamil or ketoconazole. * Vitamin K antagonists (VKA) or other anticoagulants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing | Days 14, 18, and 21 of the PK period | Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in low and high weight groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Steady-state C12 hr on Days 14, 18, and 21 After Weight and Amiodarone-based Dosing | Days 14, 18, and 21 of the PK period | Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in amiodarone, low and high weight groups |
Participant flow
Recruitment details
Between 9Sep10 & 22Apr11, 189 patients were enrolled by 68 study centers in 2 countries (USA, Canada). Patients were enrolled to 1 of 3 treatment groups (betrixaban once daily 30, 60 or 90 mg) based on weight or use of amiodarone at screening. The study had an initial pharmacokinetics (PK) phase of 4 weeks and a safety extension phase of 20 weeks.
Pre-assignment details
Patients weighing \< 80 kg received daily betrixaban 60 mg, patients weighing ≥ 80 kg received daily betrixaban 90 mg, and patients on amiodarone at screening, regardless of weight, received daily betrixaban 30 mg. 241 patients were screened for study participation. Of these patients, 189 were enrolled and received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Betrixaban 30 mg (+Amiodarone) Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone | 42 |
| Betrixaban 60 mg (<80 kg) Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks | 74 |
| Betrixaban 90 mg (≥80 kg) Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks | 73 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 | 3 |
| Overall Study | Lost to Follow-up | 3 | 0 | 1 |
| Overall Study | Non-compliance with Study Drug | 0 | 1 | 1 |
| Overall Study | Not Continuing Into Safety Extension | 3 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 3 | 0 |
| Overall Study | Protocol Violation | 4 | 6 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) | Total |
|---|---|---|---|---|
| Age, Continuous | 72.4 years STANDARD_DEVIATION 9.87 | 77.1 years STANDARD_DEVIATION 7.12 | 71.2 years STANDARD_DEVIATION 9.21 | 73.8 years STANDARD_DEVIATION 8.98 |
| Age, Customized <75 years | 23 Participants | 24 Participants | 46 Participants | 93 Participants |
| Age, Customized >=75 years | 19 Participants | 50 Participants | 27 Participants | 96 Participants |
| Sex: Female, Male Female | 19 Participants | 46 Participants | 16 Participants | 81 Participants |
| Sex: Female, Male Male | 23 Participants | 28 Participants | 57 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 42 | 34 / 74 | 35 / 73 |
| serious Total, serious adverse events | 6 / 42 | 13 / 74 | 6 / 73 |
Outcome results
Primary
Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing
Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in low and high weight groups
Time frame: Days 14, 18, and 21 of the PK period
Population: Per protocol analysis set, which includes all allocated patients who received at least one dose of study treatment and who were ≥ 90% compliant with study treatment, took study treatment within 24 hours prior to steadystate blood sampling, had at least two post steady-state blood samples collected, and not on amiodarone.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Betrixaban 60 mg (<80 kg) | Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing | 7.870 ng/mL |
| Betrixaban 90 mg (≥80 kg) | Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing | 10.517 ng/mL |
Comparison: Compared to Betrixaban 90 mg (≥80 kg)90% CI: [0.591, 0.948]
Secondary
Steady-state C12 hr on Days 14, 18, and 21 After Weight and Amiodarone-based Dosing
Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in amiodarone, low and high weight groups
Time frame: Days 14, 18, and 21 of the PK period
Population: Full Analysis Set population, which includes all patients who received at least one dose of study treatment within 24 hours prior to steady-state (SS) blood sampling, were ≥ 90% compliant with treatment, and had at least one post SS sample. The endpoint was to summarize the SS C12 hr concentration across treatments and time points as a single arm.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Betrixaban 30 mg (+Amiodarone) | Steady-state C12 hr on Days 14, 18, and 21 After Weight and Amiodarone-based Dosing | 9.498 ng/mL |