Anticoagulation Reversal
Conditions
Keywords
PER977, anticoagulation reversal, pharmacokinetics, edoxaban, whole blood clotting time, D-dimer, prothrombin fragments 1 and 2, tissue factor pathway inhibitor, prothrombin time
Brief summary
This study will evaluate the establishment of anticoagulation (re-anticoagulation) of subjects with edoxaban following reversal by PER977 and will identify a dose regimen of PER977 that reverses the effects of edoxaban for up to 21 hours.
Detailed description
This is a randomized, single-blind, sequential group, ascending PER977 reversal dose study in healthy volunteers. Subjects will be randomized in a 4:1 ratio to receive either PER977 or placebo. All subjects will receive a single dose of edoxaban 60 mg on Days 1-4. On Days 3 and 4, study drug will be administered 3 hours following edoxaban. Beginning with Cohort 2, study drug will be administered only to those subjects with a minimum increase in whole blood clotting time \>25% above baseline. Pharmacokinetic assessment of PER977 and tis metabolite, and edoxaban and its metabolite will be performed. Pharmacodynamic assessment of WBCT and Point of Care prothrombin time will be performed. Safety will be assessed throughout the study.
Interventions
DRUGPER977
Reversal of edoxaban-induced anticoagulation
DRUGPlacebo
Reversal of edoxaban-induced anticoagulation
DRUGEdoxaban
Sponsors
Quintiles, Inc.
Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Adults age 18 to 65 years, inclusive 2. Laboratory values are not clinically significant 3. No clinically significant findings on 12-lead electrocardiogram 4. Body mass index (BMI) 18 to ≤ 32 kg/m2, inclusive 5. Male subjects agree to use appropriate contraception . 6. Female subjects may be post-menopausal or, if of child-bearing potential, must have a negative serum pregnancy test prior to enrollment, and must agree to use two forms of acceptable contraception for the duration of the study and for a minimum of one complete menstrual cycle or 28 days following discharge from the study. 7. Subjects must sign informed consent
Exclusion criteria
1. History or current evidence of clinically significant disease, liver function tests greater than the upper limit of normal (presence of Gilbert's syndrome is acceptable), QTcF \> normal (440±10 msec for males or 460±10 msec for females). 2. History of unexplained syncope 3. History of major bleeding, trauma, surgical procedure of any type, or vaginal delivery within six months prior to screening 4. History of peptic ulcer, gastrointestinal bleeding, including the mouth, within six months prior to screening 5. History of minor bleeding episodes such as epistaxis, rectal or hemorrhoidal bleeding or gingival bleeding within 1 month prior to screening 6. Personal or family history of clotting disorder or abnormality, excessive bleeding, thrombovascular disease or any hematologic disorder involving platelets or clotting abnormalities or any condition requiring treatment with transfusions, or history of heparin-induced thrombocytopenia 7. Females with a history of dysfunctional uterine bleeding, menorrhagia , metrorrhagia or polymenorrhea 8. Pregnant or breast-feeding 9. Males with a history of hormone therapy within 3 months prior to screening 10. Administration of any blood product or anticoagulant within 3 months prior to study entry or any non steroidal anti-inflammatory drug or cyclooxygenase inhibitor within 2 weeks prior to screening 11. Taking any type of chronic medication within the 4 weeks prior to study entry (use of hormonal contraceptives is acceptable) 12. Positive serologic test for HIV, HCV-Ab, or HBsAG 13. Donation of blood or blood products within 56 days prior to screening 14. Smokers or use of tobacco and/or nicotine containing products within 3 months prior to dosing as determined by the subject's verbal history 15. Participation in any study with an investigational compound or device within 30 days prior to signing informed consent 16. History of participation in any prior study of PER977 or edoxaban 17. Active drug or alcohol dependence within the prior 12 months or any condition that, in the opinion of the Investigator, would interfere with adherence to study protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole blood clotting time as a measure of edoxaban anticoagulation reversal by PER977 | 5 days | To evaluate the safety, tolerability and effect on whole blood clotting time of escalating intravenous doses of PER977 (25, 50, 100, 300 mg, and 600 mg) administered after 60 mg edoxaban as a rescue medication in healthy volunteers and repeated for a second day to investigate any effects of PER977 on the re-anticoagulation with edoxaban and second reversal with PER977. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic profile of PER977 | 5 days | To assess the maximal concentration, half-life and plasma and urinary clearance of PER977 and its metabolite following intravenous administration |
| Pharmacokinetic profile of edoxaban | 5 days | To evaluate the maximal concentration, half-life, and clearance of edoxaban and its metabolite when administered with PER977 |
| Safety coagulation measures | 5 days | To evaluate changes in point of care prothrombin time, d-dimer, prothrombin factors 1 and 2, tissue factor pathway inhibitor, and possibly other biomarkers following escalating intravenous doses of PER977 administered after edoxaban in healthy volunteers |
| Safety and tolerability | 5 days | To determine if adverse events occurred in healthy volunteers who received PER977 after edoxaban |
Other
| Measure | Time frame | Description |
|---|---|---|
| Analytical measurement range (AMR), reproducibility, and precision of WBCT measurements | 5 days | To determine to normal range, variability, and reproducibility of WBCT in blood collected from healthy volunteers |
Countries
United States
Outcome results
None listed