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

NCT02047565 | Completed Phase 1

• 1 other identifier: DU176b-A-U158
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

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.

Conditions

Bleeding

Keywords

punch biopsy

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (10)

• Prothrombin Time

  Day 1

• International Normalized Ratio

  Day 1

• Activated Partial Thromboplastin Time

  Day 1

• Thrombin Generation Assay

  Day 1

• procoagulant markers D dimer

  Day 1

Study Arms (5)

Part 1 - 60mg edoxaban

EXPERIMENTAL

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

Drug: 60mg edoxaban

Part 1 - 180mg edoxaban

EXPERIMENTAL

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

Drug: 180mg edoxaban

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Interventions

60mg edoxaban DRUG

Part 1 - 60mg edoxaban; Part 2 - 60mg edoxaban and 10 IU/kg Beriplex P/N; Part 2 - 60mg edoxaban and 20 IU/kg Beriplex P/N; Part 2 - 60mg edoxaban and 50 IU/kg Beriplex P/N

180mg edoxaban DRUG

Part 1 - 180mg edoxaban

50 IU/kg Beriplex P/N DRUG

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

25 IU/kg Beriplex P/N DRUG

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

10 IU/kg Beriplex P/N DRUG

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

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (1)

Quintiles

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• 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.

  PMID: 25403645 DERIVED

MeSH Terms

Conditions

Hemorrhage

Interventions

edoxaban; factor IX, factor VII, factor X, prothrombin drug combination

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2013
• First Posted: January 28, 2014
• Study Start: October 1, 2013
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: February 12, 2019

Record last verified: 2015-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

US (1)