Clinical trial NCT02207257: Study of PER977 Administered to Subjects With Steady State Edoxaban Dosing and Re-anticoagulation With Edoxaban
Official title: Phase II Randomized, Sequential Group, Evaluation of Ascending Reversal Doses of PER977 Administered to Subjects With Steady State Edoxaban Dosing and Re-anticoagulation With Edoxaban Following PER977 Reversal
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anticoagulation Reversal
Keywords: PER977
anticoagulation reversal
pharmacokinetics
edoxaban
whole blood clotting time
D-dimer
prothrombin fragments 1 and 2
tissue factor pathway inhibitor
prothrombin time
Lead sponsor: AMAG Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2014-08-04
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Whole blood clotting time as a measure of edoxaban anticoagulation reversal by PER977
timeFrame: 5 days
Secondary outcomes:
measure: Pharmacokinetic profile of PER977
timeFrame: 5 days
measure: Pharmacokinetic profile of edoxaban
timeFrame: 5 days
measure: Safety coagulation measures
timeFrame: 5 days
measure: Safety and tolerability
timeFrame: 5 days
Other outcomes:
measure: Analytical measurement range (AMR), reproducibility, and precision of WBCT measurements
timeFrame: 5 days
Locations:
city: Overland Park
country: United States
facility: Quintiles
state: Kansas
Study officials:
affiliation: Quintiles, Inc.
name: Scott Rasmussen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sciascia S, Lopez-Pedrera C, Cecchi I, Pecoraro C, Roccatello D, Cuadrado MJ. Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome. Rheumatology (Oxford). 2016 Oct;55(10):1726-35. doi: 10.1093/rheumatology/kev445. Epub 2016 Feb 3.