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

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.

Study Overview

• Status: Completed
• Conditions: Bleeding
• Intervention / Treatment: Drug: 60mg edoxaban; Drug: 180mg edoxaban; Drug: 50 IU/kg Beriplex P/N; Drug: 25 IU/kg Beriplex P/N; Drug: 10 IU/kg Beriplex P/N

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Quintiles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 - 60mg edoxaban; Treatment A: single oral dose of 60 mg edoxaban (1 × 60 mg tablet)	Drug: 60mg edoxaban
Experimental: Part 1 - 180mg edoxaban; Treatment B: single oral dose of 180 mg edoxaban (3 × 60 mg tablet)	Drug: 180mg edoxaban
Experimental: Part 2 - 60mg edoxaban and 50 IU/kg Beriplex P/N; 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	Drug: 60mg edoxaban; Drug: 50 IU/kg Beriplex P/N
Experimental: Part 2 - 60mg edoxaban and 20 IU/kg Beriplex P/N; 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	Drug: 60mg edoxaban; Drug: 25 IU/kg Beriplex P/N
Experimental: Part 2 - 60mg edoxaban and 10 IU/kg Beriplex P/N; 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	Drug: 60mg edoxaban; Drug: 10 IU/kg Beriplex P/N

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Day 1
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	Day 1
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	Day 1
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	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Day 1
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	Day 1
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	Day 1
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	Day 1
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)	Day 1
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)	Day 1
coagulation factor concentrations	To evaluate the effects of Beriplex P/N following 60 mg edoxaban on coagulation factor concentrations	Day 1
cmax of edoxaban and its active metabolite, D21-2393	To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393	Day 1
tmax of edoxaban and its active metabolite, D21-2393	To evaluate single dose pharmacokinetics (PK) of edoxaban and its active metabolite, D21-2393	Day 1
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	Day 1

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: December 2, 2013
• First Submitted That Met QC Criteria: January 24, 2014
• First Posted (Estimate): January 28, 2014

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: punch biopsy
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban
• Other Study ID Numbers: DU176b-A-U158

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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 Supporting Information Type: STUDY_PROTOCOL; SAP; CSR