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 Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Bleeding

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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punch biopsy