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

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ClinicalTrials.gov Identifier: NCT02207257
Recruitment Status : Completed
First Posted : August 4, 2014
Last Update Posted : November 17, 2017
Sponsor:
Collaborator:
Quintiles, Inc.
Information provided by (Responsible Party):
Perosphere, Inc.

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 Type : Interventional  (Clinical Trial)
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 : March 2014
Actual Primary Completion Date : September 2015
Actual Study Completion Date : November 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Edoxaban

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



Primary Outcome Measures :
  1. Whole blood clotting time as a measure of edoxaban anticoagulation reversal by PER977 [ Time Frame: 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 :
  1. Pharmacokinetic profile of PER977 [ Time Frame: 5 days ]
    To assess the maximal concentration, half-life and plasma and urinary clearance of PER977 and its metabolite following intravenous administration

  2. Pharmacokinetic profile of edoxaban [ Time Frame: 5 days ]
    To evaluate the maximal concentration, half-life, and clearance of edoxaban and its metabolite when administered with PER977

  3. Safety coagulation measures [ Time Frame: 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

  4. Safety and tolerability [ Time Frame: 5 days ]
    To determine if adverse events occurred in healthy volunteers who received PER977 after edoxaban


Other Outcome Measures:
  1. Analytical measurement range (AMR), reproducibility, and precision of WBCT measurements [ Time Frame: 5 days ]
    To determine to normal range, variability, and reproducibility of WBCT in blood collected from healthy volunteers



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02207257


Locations
United States, Kansas
Quintiles
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Perosphere, Inc.
Quintiles, Inc.
Investigators
Principal Investigator: Scott Rasmussen, MD Quintiles, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Perosphere, Inc.
ClinicalTrials.gov Identifier: NCT02207257     History of Changes
Other Study ID Numbers: PER977-02-001
First Posted: August 4, 2014    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017

Keywords provided by Perosphere, Inc.:
PER977
anticoagulation reversal
pharmacokinetics
edoxaban
whole blood clotting time
D-dimer
prothrombin fragments 1 and 2
tissue factor pathway inhibitor
prothrombin time

Additional relevant MeSH terms:
Edoxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants