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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Anticoagulation Reversal

Intervention / Treatment
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* Drug: PER977
* Drug: Placebo
* Drug: Edoxaban


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Placebo<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Edoxaban<br> <br> |
| Experimental: Cohort 2<br>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<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Placebo<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Edoxaban<br> <br> |
| Experimental: Cohort 3<br>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<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Placebo<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Edoxaban<br> <br> |
| Experimental: Cohort 4<br>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<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Placebo<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Edoxaban<br> <br> |
| Experimental: Cohort 5<br>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<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Placebo<br>* Reversal of edoxaban-induced anticoagulation<br>Drug: Edoxaban<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole blood clotting time as a measure of edoxaban anticoagulation reversal by PER977 | 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. | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of PER977 | To assess the maximal concentration, half-life and plasma and urinary clearance of PER977 and its metabolite following intravenous administration | 5 days | 
| Pharmacokinetic profile of edoxaban | To evaluate the maximal concentration, half-life, and clearance of edoxaban and its metabolite when administered with PER977 | 5 days | 
| Safety coagulation measures | 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 | 5 days | 
| Safety and tolerability | To determine if adverse events occurred in healthy volunteers who received PER977 after edoxaban | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PER977, anticoagulation reversal, pharmacokinetics, edoxaban, whole blood clotting time, D-dimer, prothrombin fragments 1 and 2, tissue factor pathway inhibitor, prothrombin time