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A Two-part Study in Edoxaban-treated Healthy Subjects to Establish a Punch Biopsy Bleeding Model and to Evaluate the Effect of a 4-factor Prothrombin Complex Concentrate on Anticoagulation

Primary Purpose

Bleeding

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
60mg edoxaban
180mg edoxaban
50 IU/kg Beriplex P/N
25 IU/kg Beriplex P/N
10 IU/kg Beriplex P/N
Sponsored by
Daiichi Sankyo, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Bleeding focused on measuring punch biopsy

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy subjects between 18 and 45 years of age, with a body mass index between 18 and 30 kg/m2, and weighing ≤ 110 kg.

Exclusion Criteria:

  • Women of childbearing potential without proper contraceptive measures and women who are pregnant or breastfeeding. Women of childbearing potential who participate in the study must agree to use proper contraceptive measures from screening through 13 weeks after the last dose of study drug.
  • Subjects with history of unexplained syncope. Subjects who have prior clearance of vasovagal events may be included.
  • Subjects who have used any drugs or substances known to be strong inhibitors or strong inducers of cytochrome P450 (CYP) 3A4/5 enzymes or P-glycoprotein within 28 days prior to the first dosing.
  • Subjects who have used any other nonprescription drugs (including herbal supplemental), except acetaminophen (up to 3 g/day) within 14 days prior to check-in.
  • Subjects with history of major bleeding, major trauma, or major surgical procedure of any type within 6 months of dosing.
  • Subjects with history of peptic ulcer, gastrointestinal bleeding (including hematemesis, melena, and rectal bleeding), or bleeding from hemorrhoids.
  • Subjects with history of minor bleeding episodes such as epistaxis, rectal bleeding (spots of blood on toilet paper), and gingival bleeding within 3 months before the first dose.
  • Subjects who have any family history, suspected or documented, of coagulopathy.
  • Subjects who have participated in a previous edoxaban study within 6 months prior to the first dose.
  • Subjects who used anticoagulants (eg, warfarin, low molecular weight heparin), antiplatelet agents (eg, clopidogrel), non-steroidal anti-inflammatory drugs, and/or acetylsalicylic acid 30 days prior to punch biopsy or who expect to use these during the study.
  • Subjects with hemoglobin levels below 12 g/dL (men) or 11 g/dL (women) at screening.
  • Subjects with creatinine clearance ≤ 80 mL/min (based on the Cockcroft-Gault equation).
  • Subjects who are considered inappropriate for the punch biopsy procedure based on inability to visualize surface blood vessels, and history or likelihood of forming keloid scars.
  • Subjects with known heparin-induced thrombocytopenia.
  • Subjects who have a platelet count, PT, or INR outside of the normal range at baseline.
  • Subjects with history or current evidence of clinically significant cardiac, hepatic, renal, pulmonary, endocrine, neurologic, infectious, gastrointestinal, hematologic, or oncologic disease as determined by screening history, physical examination, laboratory test results, or 12-lead electrocardiogram (ECG).

In addition, for Part 2:

  • Subjects who are deficient in Factor V Leiden mutation.
  • Subjects who are deficient in protein S, protein C, antithrombin, or factor II, or have prothrombin 20210A mutation.
  • Subjects with known anaphylactic or severe systemic reactions to Beriplex P/N or any components in Beriplex P/N including heparin; FII, FVII, FIX, and FX; proteins C and S; antithrombin III; and human albumin.
  • Subjects with current or history of disseminated intravascular coagulation.

Sites / Locations

  • Quintiles

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part 1 - 60mg edoxaban

Part 1 - 180mg edoxaban

Part 2 - 60mg edoxaban and 50 IU/kg Beriplex P/N

Part 2 - 60mg edoxaban and 20 IU/kg Beriplex P/N

Part 2 - 60mg edoxaban and 10 IU/kg Beriplex P/N

Arm Description

Treatment A: single oral dose of 60 mg edoxaban (1 × 60 mg tablet)

Treatment B: single oral dose of 180 mg edoxaban (3 × 60 mg tablet)

Dose cohort 1: 60 mg edoxaban + 50 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period

Dose cohort 2: 60 mg edoxaban + 25 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period

Dose cohort 3: 60 mg edoxaban + 10 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period

Outcomes

Primary Outcome Measures

Bleeding duration 60mg edoxaban
To assess the variability and effect size of bleeding duration (BD) following punch biopsy in healthy subjects administered 60 mg edoxaban
Bleeding volume 60mg edoxaban
To assess the variability and effect size of bleeding volume (BV) following punch biopsy in healthy subjects administered 60 mg edoxaban
Bleeding duration 180mg edoxaban
To assess the variability and effect size of bleeding duration (BD) following punch biopsy in healthy subjects administered 180 mg edoxaban
Bleeding volume 180mg edoxaban
To assess the variability and effect size of bleeding volume (BV) following punch biopsy in healthy subjects administered 180 mg edoxaban

Secondary Outcome Measures

Prothrombin Time
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
International Normalized Ratio
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Activated Partial Thromboplastin Time
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Thrombin Generation Assay
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
procoagulant markers D dimer
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on the procoagulant markers D dimer and prothrombin fragment F1 + 2 (F1 + 2)
prothrombin fragment F1 + 2
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on the procoagulant markers D dimer and prothrombin fragment F1 + 2 (F1 + 2)
coagulation factor concentrations
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on coagulation factor concentrations
cmax of edoxaban and its active metabolite, D21-2393
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393
tmax of edoxaban and its active metabolite, D21-2393
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393
AUC 0-24 of edoxaban and its active metabolite, D21-2393
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393

Full Information

First Posted
December 2, 2013
Last Updated
February 8, 2019
Sponsor
Daiichi Sankyo, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02047565
Brief Title
A Two-part Study in Edoxaban-treated Healthy Subjects to Establish a Punch Biopsy Bleeding Model and to Evaluate the Effect of a 4-factor Prothrombin Complex Concentrate on Anticoagulation
Official Title
A Two-part Study in Edoxaban-treated Healthy Subjects to Establish a Punch Biopsy Bleeding Model and to Evaluate the Effect of a 4-factor Prothrombin Complex Concentrate on Anticoagulation
Study Type
Interventional

2. Study Status

Record Verification Date
January 2015
Overall Recruitment Status
Completed
Study Start Date
October 2013 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Daiichi Sankyo, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This Phase 1 study consists of 2 parts. Part 1 will be an open-label, randomized, 2 treatment, 2-way crossover study. Part 2 will be a double-blind (Sponsor unblinded), randomized, placebo controlled, sequential descending prothrombin complex concentrate dose, 2 sequence, 2 period crossover study. In both parts of the study, the assessor of BD and BV will remain blinded. In Part 2 of the study, both the subject and the clinic staff involved in study conduct will be blinded (with the exception of the pharmacist or nurse who prepares the blinded individual treatments from open-label supplies). The study programmer and statistician will also be blinded to treatment assignment. The Sponsor will remain unblinded for both parts of the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bleeding
Keywords
punch biopsy

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
110 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1 - 60mg edoxaban
Arm Type
Experimental
Arm Description
Treatment A: single oral dose of 60 mg edoxaban (1 × 60 mg tablet)
Arm Title
Part 1 - 180mg edoxaban
Arm Type
Experimental
Arm Description
Treatment B: single oral dose of 180 mg edoxaban (3 × 60 mg tablet)
Arm Title
Part 2 - 60mg edoxaban and 50 IU/kg Beriplex P/N
Arm Type
Experimental
Arm Description
Dose cohort 1: 60 mg edoxaban + 50 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period
Arm Title
Part 2 - 60mg edoxaban and 20 IU/kg Beriplex P/N
Arm Type
Experimental
Arm Description
Dose cohort 2: 60 mg edoxaban + 25 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period
Arm Title
Part 2 - 60mg edoxaban and 10 IU/kg Beriplex P/N
Arm Type
Experimental
Arm Description
Dose cohort 3: 60 mg edoxaban + 10 IU/kg Beriplex P/N in 1 period and placebo (0.9% Sodium Chloride Injection, USP), in the other period
Intervention Type
Drug
Intervention Name(s)
60mg edoxaban
Intervention Type
Drug
Intervention Name(s)
180mg edoxaban
Intervention Type
Drug
Intervention Name(s)
50 IU/kg Beriplex P/N
Intervention Type
Drug
Intervention Name(s)
25 IU/kg Beriplex P/N
Intervention Type
Drug
Intervention Name(s)
10 IU/kg Beriplex P/N
Primary Outcome Measure Information:
Title
Bleeding duration 60mg edoxaban
Description
To assess the variability and effect size of bleeding duration (BD) following punch biopsy in healthy subjects administered 60 mg edoxaban
Time Frame
Day 1
Title
Bleeding volume 60mg edoxaban
Description
To assess the variability and effect size of bleeding volume (BV) following punch biopsy in healthy subjects administered 60 mg edoxaban
Time Frame
Day 1
Title
Bleeding duration 180mg edoxaban
Description
To assess the variability and effect size of bleeding duration (BD) following punch biopsy in healthy subjects administered 180 mg edoxaban
Time Frame
Day 1
Title
Bleeding volume 180mg edoxaban
Description
To assess the variability and effect size of bleeding volume (BV) following punch biopsy in healthy subjects administered 180 mg edoxaban
Time Frame
Day 1
Secondary Outcome Measure Information:
Title
Prothrombin Time
Description
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Time Frame
Day 1
Title
International Normalized Ratio
Description
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Time Frame
Day 1
Title
Activated Partial Thromboplastin Time
Description
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Time Frame
Day 1
Title
Thrombin Generation Assay
Description
To evaluate the reversal of the effect of 60 mg edoxaban on Prothrombin Time (PT), International Normalized Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and Thrombin Generation Assay (TGA) parameters by Beriplex P/N
Time Frame
Day 1
Title
procoagulant markers D dimer
Description
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on the procoagulant markers D dimer and prothrombin fragment F1 + 2 (F1 + 2)
Time Frame
Day 1
Title
prothrombin fragment F1 + 2
Description
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on the procoagulant markers D dimer and prothrombin fragment F1 + 2 (F1 + 2)
Time Frame
Day 1
Title
coagulation factor concentrations
Description
To evaluate the effects of Beriplex P/N following 60 mg edoxaban on coagulation factor concentrations
Time Frame
Day 1
Title
cmax of edoxaban and its active metabolite, D21-2393
Description
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393
Time Frame
Day 1
Title
tmax of edoxaban and its active metabolite, D21-2393
Description
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393
Time Frame
Day 1
Title
AUC 0-24 of edoxaban and its active metabolite, D21-2393
Description
To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393
Time Frame
Day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy subjects between 18 and 45 years of age, with a body mass index between 18 and 30 kg/m2, and weighing ≤ 110 kg. Exclusion Criteria: Women of childbearing potential without proper contraceptive measures and women who are pregnant or breastfeeding. Women of childbearing potential who participate in the study must agree to use proper contraceptive measures from screening through 13 weeks after the last dose of study drug. Subjects with history of unexplained syncope. Subjects who have prior clearance of vasovagal events may be included. Subjects who have used any drugs or substances known to be strong inhibitors or strong inducers of cytochrome P450 (CYP) 3A4/5 enzymes or P-glycoprotein within 28 days prior to the first dosing. Subjects who have used any other nonprescription drugs (including herbal supplemental), except acetaminophen (up to 3 g/day) within 14 days prior to check-in. Subjects with history of major bleeding, major trauma, or major surgical procedure of any type within 6 months of dosing. Subjects with history of peptic ulcer, gastrointestinal bleeding (including hematemesis, melena, and rectal bleeding), or bleeding from hemorrhoids. Subjects with history of minor bleeding episodes such as epistaxis, rectal bleeding (spots of blood on toilet paper), and gingival bleeding within 3 months before the first dose. Subjects who have any family history, suspected or documented, of coagulopathy. Subjects who have participated in a previous edoxaban study within 6 months prior to the first dose. Subjects who used anticoagulants (eg, warfarin, low molecular weight heparin), antiplatelet agents (eg, clopidogrel), non-steroidal anti-inflammatory drugs, and/or acetylsalicylic acid 30 days prior to punch biopsy or who expect to use these during the study. Subjects with hemoglobin levels below 12 g/dL (men) or 11 g/dL (women) at screening. Subjects with creatinine clearance ≤ 80 mL/min (based on the Cockcroft-Gault equation). Subjects who are considered inappropriate for the punch biopsy procedure based on inability to visualize surface blood vessels, and history or likelihood of forming keloid scars. Subjects with known heparin-induced thrombocytopenia. Subjects who have a platelet count, PT, or INR outside of the normal range at baseline. Subjects with history or current evidence of clinically significant cardiac, hepatic, renal, pulmonary, endocrine, neurologic, infectious, gastrointestinal, hematologic, or oncologic disease as determined by screening history, physical examination, laboratory test results, or 12-lead electrocardiogram (ECG). In addition, for Part 2: Subjects who are deficient in Factor V Leiden mutation. Subjects who are deficient in protein S, protein C, antithrombin, or factor II, or have prothrombin 20210A mutation. Subjects with known anaphylactic or severe systemic reactions to Beriplex P/N or any components in Beriplex P/N including heparin; FII, FVII, FIX, and FX; proteins C and S; antithrombin III; and human albumin. Subjects with current or history of disseminated intravascular coagulation.
Facility Information:
Facility Name
Quintiles
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66211
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
IPD Sharing Time Frame
Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
IPD Sharing Access Criteria
Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
IPD Sharing URL
https://vivli.org/ourmember/daiichi-sankyo/
Citations:
PubMed Identifier
25403645
Citation
Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, Lomeli B, Feussner A, Feng W, He L, Grosso MA, Lanz HJ, Antman EM. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015 Jan 6;131(1):82-90. doi: 10.1161/CIRCULATIONAHA.114.013445. Epub 2014 Nov 17. Erratum In: Circulation. 2015 Jan 6;131(1):e10.
Results Reference
derived

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A Two-part Study in Edoxaban-treated Healthy Subjects to Establish a Punch Biopsy Bleeding Model and to Evaluate the Effect of a 4-factor Prothrombin Complex Concentrate on Anticoagulation

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