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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Venous Thromboembolism, Deep Vein Thrombosis

Intervention / Treatment
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* Drug: Edoxaban low dose
* Drug: Edoxaban high dose


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Pharmacokinetics (PK), Pharmacodynamics (PDy), Anticoagulant, Safety