Phase 1 Pediatric Pharmacokinetics/Pharmacodynamics (PK/PD) Study

A Phase 1, Open-Label, Single-Dose, Non-Randomized Study to Evaluate Pharmacokinetics and Pharmacodynamics of Edoxaban in Pediatric Patients

This is the first evaluation of edoxaban in pediatric subjects. In this Phase 1 study, a single dose of edoxaban will be given to pediatric subjects who require anticoagulant therapy to see what the body does to the drug (pharmacokinetics) and what the drug does to the body (pharmacodynamics), and to compare if these effects are similar to those observed in adults.

Study Overview

• Status: Completed
• Conditions: Deep Vein Thrombosis; Venous Thromboembolism
• Intervention / Treatment: Drug: Edoxaban low dose; Drug: Edoxaban high dose

Detailed Description

Phase 1, open-label, multiple-center study in pediatric patients from 0 to < 18 years of age. Patients will receive a single dose of edoxaban to match either the 30 mg (low dose) or the 60 mg (high dose) exposure in adults. Exact doses will be selected during the study on the basis of PK modeling of emerging data. If unanticipated exposures are observed, the target doses may be modified to best match expected exposure response relationships observed in adults.

Enrollment in the study will start with the low dose, highest age group (adolescents) and will continue from low to high dose in each age group and from higher to lower age groups. Enrollment in the next dose/age cohort will begin after 50% of the subjects have completed the previous dose/age cohort.

Age cohorts and dose groups: (6 participants each in low and high dose groups, for a total of 12 participants per age cohort)

• 12 to < 18 years of age
• 6 to <12 years of age
• 2 to <6 years of age
• 6 months to <2 years of age
• 0 to <6 months of age

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ottawa, Canada, K1H8L1
    • Childrens Hospital of Eastern Ontario
  • Ontario
    • Hamilton, Ontario, Canada, L8N3Z5
      • McMaster Children's Hospital
• France
  • Montpellier, France, 34295
    • Hôpital Arnaud de Villeneuve
  • Pessac, France, 33604
    • CHU Bordeaux - Hopital Haut-Leveque
• India
  • Gujrat, India, 395002
    • Nirmal Hospital Pvt. Ltd
  • Kolkata, India, 700017
    • Institute of Child Health
  • Ludhiāna, India, 141008
    • Christian Medical College and Hospital
• Italy
  • Genova, Italy, 16148
    • Istituto Giannina Gaslini - UOSD Emostasi e Trombosi
  • Padova, Italy, 35127
    • A O Universita degli Studi di Padova ; Dipartimento di Salute della Donna e del Bambino-Universita di Padova
  • Rome, Italy, 165
    • Bambino Gesu Hospital
• Lebanon
  • Beirut, Lebanon, BP 165191
    • Hotel Dieu de France
  • Saida, Lebanon, 1600
    • Hammoud Hospital University Medical Center
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitario Vall d'Hebron
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofía
  • Madrid, Spain, 28040
    • Hospital Clínico San Carlos
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Vitoria Gasteiz, Spain, 01010
    • Hospital Universitario Araba
• Turkey
  • Izmir, Turkey, 35040
    • Ege University Medical Faculty - Department of Pediatric Hematology
• United Kingdom
  • Leeds, United Kingdom, LS1 3EB
    • Leeds General Infirmary
  • Leicester, United Kingdom, LE3 9QP
    • Glenfield Hospital
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • London, United Kingdom, SE1 7EH
    • Guy's and St Thomas Hospital NHS Trust
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles (UCLA)
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado Denver
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville ; Kosair Charities Pediatric Clincial Research Unit
  • North Carolina
    • Durham, North Carolina, United States, 22710
      • Duke University Medical Center (DUMC)
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center - Rainbow Babies and Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Hasbro Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital, Inc.
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Is a pediatric subject requiring anticoagulant therapy
• Will abstain from the use of nonsteroidal anti-inflammatory drugs (such as ibuprofen), and other antiplatelet and anticoagulant agents (except for aspirin) from 24 hours prior to edoxaban dose until after the last PK sample is collected
• Will follow food and concomitant medication restrictions

Exclusion Criteria:

• Any major or clinically relevant unexplained bleeding during prior anticoagulant therapy
• History of abnormal bleeding or coagulation within last 6 months prior to study drug administration
• Renal function with glomerular filtration rate (GFR) less than 50% of normal for age and size
• Malabsorption disorders (e.g., cystic fibrosis or short bowel syndrome)
• Hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk, alanine transaminase (ALT) > 5 times the upper limit of normal (ULN) or total bilirubin > 2 times the ULN with direct bilirubin > 20% of the total

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1a; 12 to < 18 years of age: edoxaban low dose group	Drug: Edoxaban low dose; Edoxaban low dose
Experimental: Cohort 1b; 12 to < 18 years of age: edoxaban high dose group	Drug: Edoxaban high dose; Edoxaban high dose
Experimental: Cohort 2a; 6 to < 12 years of age: edoxaban low dose group	Drug: Edoxaban low dose; Edoxaban low dose
Experimental: Cohort 2b; 6 to < 12 years of age: edoxaban high dose group	Drug: Edoxaban high dose; Edoxaban high dose
Experimental: Cohort 3a; 2 to < 6 years of age: edoxaban low dose group	Drug: Edoxaban low dose; Edoxaban low dose
Experimental: Cohort 3b; 2 to < 6 years of age: edoxaban high dose group	Drug: Edoxaban high dose; Edoxaban high dose
Experimental: Cohort 4a; 6 months to <2 years of age: edoxaban low dose group	Drug: Edoxaban low dose; Edoxaban low dose
Experimental: Cohort 4b; 6 months to <2 years of age: edoxaban high dose group	Drug: Edoxaban high dose; Edoxaban high dose
Experimental: Cohort 5a; 0 to 6 months of age: edoxaban low dose group	Drug: Edoxaban low dose; Edoxaban low dose
Experimental: Cohort 5b; 0 to 6 months: edoxaban high dose group	Drug: Edoxaban high dose; Edoxaban high dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Parameter of Apparent Systemic Clearance (CL/F)	A model-based pooled population pharmacokinetic (PK) method was used to estimate systemic clearance (CL/F). As prespecified in the protocol, arms were pooled due to sparse PK samples being collected. the median PK estimate is reported in all participants at a total of 5 blood samplings.	0.25 to 1 hours, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
Pharmacokinetic Parameter of Apparent Volume of Distribution (V/F)	A model-based pooled population pharmacokinetic (PK) method was used to estimate apparent volume of distribution (V/F). As prespecified in the protocol, arms were pooled due to sparse PK samples being collected. the median PK estimate is reported in all participants at a total of 5 blood samplings.	0.25 to 1 hours, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic Parameter Mean Prothrombin Time (PT)	Descriptive statistics were used to assess Mean Prothrombin Time (PT) by cohort at a total of 6 blood samplings.	Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
Pharmacodynamic Parameter Mean Activated Partial Thromboplastin Time (aPTT)	Descriptive statistics were used to assess Mean Activated Partial Thromboplastin Time by cohort for a total of 6 blood samplings.	Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
Pharmacodynamic Parameter Mean Anti-Factor Xa (FXa)	Descriptive statistics were used to assess Mean Anti-Factor Xa (FXa) by cohort for a total of 6 blood samplings.	Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Palatability Score for the Liquid Formulation on a 100 mm Visual Analog Scale (VAS)	Overall palatability, bitterness, sweetness, and overall taste or aroma were assessed by participants (or guardians) receiving the liquid oral suspension where each subscale used a 100 mm visual analog scale (VAS), where a 0 score corresponded to a sad face and indicated a low palatability, bitter (sharp, pungent taste or smell), not sweet, and no aroma score (eg, patients not pleased; worse outcome in terms of palatability) and a 100 score corresponded to a happy face and indicated a high palatability, not bitter, very sweet, very tasty, and high aroma score (eg, patients were pleased; best outcome in terms of palatability). Patients who were old enough scored the VAS themselves. For younger children, the parents provided this information, if possible. For the youngest children, there was free text input available to provide information on whether the patient spat it out or may not have liked the flavor, etc.	Baseline up to 30 minutes post-dose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Investigators: Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2014
• Primary Completion (Actual): September 16, 2021
• Study Completion (Actual): September 16, 2021

Study Registration Dates

• First Submitted: October 10, 2014
• First Submitted That Met QC Criteria: November 28, 2014
• First Posted (Estimated): December 1, 2014

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Safety; Pediatric; Anticoagulant; Pharmacokinetics (PK); Pharmacodynamics (PDy)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban
• Other Study ID Numbers: DU176b-A-U157; 2015-005732-18 (EudraCT Number)

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