Study of PER977 Administered to Subjects With Steady State Edoxaban Dosing and Re-anticoagulation With Edoxaban

Perosphere Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Anticoagulation Reversal

Treatments: Drug: Placebo; Drug: PER977; Drug: Edoxaban

Study type: Interventional

Funder types: Industry

Identifiers

NCT02207257

PER977-02-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 65 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Single Blind

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65 participants in 5 patient groups

Cohort 1

Experimental group

Description:

Subjects will receive 60 mg edoxaban in the morning on Days 1-2. On Day 3 and 4, they will receive a single dose of 60 mg edoxaban, followed 3 hours later by a single dose of 25 mg PER977 or placebo (n=10).

Treatment:

Drug: Edoxaban

Drug: Placebo

Drug: PER977

Cohort 2

Experimental group

Description:

Subjects will receive 60 mg edoxaban in the morning on Days 1-2. On Day 3 and 4, they will receive a single dose of 60 mg edoxaban, followed 3 hours later by a single dose of 50 mg PER977 or placebo (n=10).

Treatment:

Drug: Edoxaban

Drug: Placebo

Drug: PER977

Cohort 3

Experimental group

Description:

Subjects will receive 60 mg edoxaban in the morning on Days 1-2. On Day 3 and 4, they will receive a single dose of 60 mg edoxaban, followed 3 hours later by a single dose of 100 mg PER977 or placebo (n=10).

Treatment:

Drug: Edoxaban

Drug: Placebo

Drug: PER977

Cohort 4

Experimental group

Description:

Subjects will receive 60 mg edoxaban in the morning on Days 1-2. On Day 3 and 4, they will receive a single dose of 60 mg edoxaban, followed 3 hours later by a single dose of 300 mg PER977 or placebo (n=10). Study amendments expanded the cohort to include an additional 7 subjects (randomized 1:6 PER977:placebo) and up to an additional 4 placebo and 8 active subjects (ongoing).

Treatment:

Drug: Edoxaban

Drug: Placebo

Drug: PER977

Cohort 5

Experimental group

Description:

Subjects will receive 60 mg edoxaban in the morning on Days 1-2. On Day 3 and 4, they will receive a single dose of 60 mg edoxaban, followed 3 hours later by a single dose of 600 mg PER977 or placebo (n=10). A protocol amendment expanded the cohort to include an additional 2 placebo and up to an additional 4 active subject.

Treatment:

Drug: Edoxaban

Drug: Placebo

Drug: PER977