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

Sponsor

Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02207257

Collaborator

Quintiles, Inc. (Industry)

Enrollment

Location

Arms

Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anticoagulation Reversal	Drug: PER977 Drug: Placebo Drug: Edoxaban	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

65 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

Single (Participant)

Primary Purpose:

Other

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 Start Date :

Mar 1, 2014

Actual Primary Completion Date :

Sep 1, 2015

Actual Study Completion Date :

Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 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).	Drug: PER977 Reversal of edoxaban-induced anticoagulation Drug: Placebo Reversal of edoxaban-induced anticoagulation Drug: Edoxaban
Experimental: Cohort 2 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).	Drug: PER977 Reversal of edoxaban-induced anticoagulation Drug: Placebo Reversal of edoxaban-induced anticoagulation Drug: Edoxaban
Experimental: Cohort 3 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).	Drug: PER977 Reversal of edoxaban-induced anticoagulation Drug: Placebo Reversal of edoxaban-induced anticoagulation Drug: Edoxaban
Experimental: Cohort 4 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).	Drug: PER977 Reversal of edoxaban-induced anticoagulation Drug: Placebo Reversal of edoxaban-induced anticoagulation Drug: Edoxaban
Experimental: Cohort 5 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.	Drug: PER977 Reversal of edoxaban-induced anticoagulation Drug: Placebo Reversal of edoxaban-induced anticoagulation Drug: Edoxaban

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Adults age 18 to 65 years, inclusive
Laboratory values are not clinically significant
No clinically significant findings on 12-lead electrocardiogram
Body mass index (BMI) 18 to ≤ 32 kg/m2, inclusive
Male subjects agree to use appropriate contraception .
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.
Subjects must sign informed consent

Exclusion Criteria:

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).
History of unexplained syncope
History of major bleeding, trauma, surgical procedure of any type, or vaginal delivery within six months prior to screening
History of peptic ulcer, gastrointestinal bleeding, including the mouth, within six months prior to screening
History of minor bleeding episodes such as epistaxis, rectal or hemorrhoidal bleeding or gingival bleeding within 1 month prior to screening
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
Females with a history of dysfunctional uterine bleeding, menorrhagia , metrorrhagia or polymenorrhea
Pregnant or breast-feeding
Males with a history of hormone therapy within 3 months prior to screening
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
Taking any type of chronic medication within the 4 weeks prior to study entry (use of hormonal contraceptives is acceptable)
Positive serologic test for HIV, HCV-Ab, or HBsAG
Donation of blood or blood products within 56 days prior to screening
Smokers or use of tobacco and/or nicotine containing products within 3 months prior to dosing as determined by the subject's verbal history
Participation in any study with an investigational compound or device within 30 days prior to signing informed consent
History of participation in any prior study of PER977 or edoxaban
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