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

Sponsor

Daiichi Sankyo, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02303431

Collaborator

(none)

Enrollment

Locations

Arms

82.2

Actual Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Deep Vein Thrombosis Venous Thromboembolism	Drug: Edoxaban low dose Drug: Edoxaban high dose	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

66 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Nov 5, 2014

Actual Primary Completion Date :

Sep 11, 2021

Actual Study Completion Date :

Sep 11, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Pharmacokinetics (PK)- Apparent systemic clearance (CL/F) [within 36 hours postdose]
A sampling windows approach will be used: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 5 blood samplings)
PK- Apparent volume of distribution (V/F) [within 36 hours postdose]
A sampling windows approach will be used: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 5 blood samplings)
PK- Area under the concentration-time curve (AUC) for edoxaban and metabolites [within 36 hours postdose]
A sampling windows approach will be used: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 5 blood samplings); metabolites include D21-2393, D21-3231, D21-1402, and D21-2135
PK- Metabolite/parent ratios for AUC [within 36 hours postdose]
A sampling windows approach will be used: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 5 blood samplings); metabolites include D21-2393, D21-3231, D21-1402, and D21-2135

Secondary Outcome Measures

Pharmacodynamic (PDy)- Mean prothrombin time (PT) [Predose and within 36 hours postdose]
Predose and immediately after simultaneously scheduled PK blood samples, using a dosing windows approach: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 6 blood samplings)
PDy- Mean activated partial thromboplastin time (aPTT) [Predose and within 36 hours postdose]
Predose and immediately after simultaneously scheduled PK blood samples, using a dosing windows approach: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 6 blood samplings)
PDy- Mean anti-Factor Xa (FXa) [Predose and within 36 hours postdose]
Predose and immediately after simultaneously scheduled PK blood samples, using a dosing windows approach: 0.25 to 1, 1.5 to 3, 4 to 8, 9 to 14, and 24 to 36 hours postdose (total of 6 blood samplings)
Safety- Number of participants with clinically significant changes in safety assessments [Predose to Day 10]
Safety assessments: adverse events, physical examination findings, vital signs, clinical laboratory assessments, and urinalysis.

Other Outcome Measures

Mean palatability score for the liquid formulation on a 100 mm visual analog scale (VAS) [within 30 minutes after dosing]
Bitterness, sweetness, and overall taste or aroma will be assessed by participants receiving the liquid oral suspension or their guardians using visual analog scale (VAS) scores

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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