Tolerability , PK/PD and Safety of Dabigatran Etexilate Oral Liquid Formulation in Children < 1 Year of Age

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to investigate the safety and tolerability of dabigatran etexilate solution in children aged less than 1 year, to demonstrate comparable PK/PD relationship to older children and adults and to confirm dabigatran etexilate dosing algorithm for children aged less than 1 year.

Detailed Description
-----------------
Purpose:

Official Title
-----------------
Open-label, Single Dose, Tolerability, Pharmacokinetic/Pharmacodynamics and Safety Study of Dabigatran Etexilate Given at the End of Standard Anticoagulant Therapy in Children Aged Less Than 1 Year Old

Conditions
-----------------
Venous Thromboembolism

Intervention / Treatment
-----------------
* Drug: dabigatran


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Neonates and infants with aged < 12 months at Visit 1 Objective diagnosis of VTE End of planned treatment course with anticoagulant therapy as per standard of care at the investigator site. Written informed consent provided by the patient's parent(s) (or legal guardian) according to local regulations at Visit 1. Exclusion criteria: Weight less than 3 kg at Visit 1 Conditions associated with an increased risk of bleeding renal dysfunction hepatic disease Anemia or thrombocytopenia at screening

Ages Eligible for Study
-----------------
Maximum Age: 12 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran<br>open label arm with dabigatran oral liquid formulation as single dose | Drug: dabigatran<br>* Experimental dose chosen based on age and weight<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Total Dabigatran, 2h and 12 h (+/-2h) Post Administration of Dabigatran Etexilate | Plasma concentrations of total dabigatran, 2h and 12 h (+/-2h) post administration of dabigatran etexilate. | 2 hours (h) and 12h after drug administration on day 1 | 
| Central Measurement: The Mean aPTT Coagulation Time at 2 h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean activated partial thromboplastin time (aPTT) coagulation time at 2 h and 12 h (±2 h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. | 2 h, and 12 h after dosing on day 1 | 
| Central Measurement: The Mean of ECT Coagulation Time at 2 h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean of Ecarin Clotting Time (ECT) coagulation time at 2 h and 12h (+/-2h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. | 2 h, and 12 h after dosing on day 1 | 
| Central Measurement: The Mean of Diluted Thrombin Time (dTT) Coagulation Time at 2 h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean of dTT (AntiFactor IIa activity) coagulation time at 2 h and 12h (+/-2h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. | 2 h, and 12 h after dosing on day 1 | 
| Central Measurement: The Mean aPTT Ratio at 2 h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean aPTT (activated partial thromboplastin time) ratio at 2 h and 12 h (±2 h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. aPTT ratio= aPTT (post dose)/aPTT (baseline). The mean of aPTT ratio is presented. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 
| Central Measurement: The Mean ECT Ratio at 2 h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean Ecarin Clotting Time (ECT) ratio at 2 h and 12h (+/-2h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. ECT ratio= ECT(Post dose)/ECT(baseline), The mean of ECT ratio is presented. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 
| Central Measurement: The Mean of dTT Ratio at 2h and 12h (+/-2h) Post Administration of Dabigatran Etexilate. | Central measurement: The mean of dTT (AntiFactor IIa activity) ratio at 2 h and 12 h (±2 h) post administration of dabigatran etexilate. Standard deviation is actually the Coefficient of Variation. dTT ratio= dTT(post dose)/dTT(baseline). The mean of dTT ratio is presented. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK-PD Relationship: Relationship Between Total Dabigatran Plasma Concentration and Coagulation Parameters APTT Values. | Linear regression models were used for modeling the relationship between total dabigatran plasma concentration and coagulation parameters APTT values. For our simple regression model, R-squared is equal to the square of Pearson's coefficient of correlation. The R-squared can be between 0 and 1. R-squared =1 means a perfect fit. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 
| PK-PD Relationship: Relationship Between Total Dabigatran Plasma Concentration and Coagulation Parameters ECT Values. | Linear regression models were used for modeling the relationship between total dabigatran plasma concentration and coagulation parameters ECT values. For our simple regression model, R-squared is equal to the square of Pearson's coefficient of correlation. The R-squared can be between 0 and 1. R-squared =1 means a perfect fit. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 
| PK-PD Relationship: Relationship Between Total Dabigatran Plasma Concentration and Coagulation Parameters dTT Values. | Linear regression models were used for modeling the relationship between total dabigatran plasma concentration and coagulation parameters dTT (AntiFactor IIa activity) values. For our simple regression model, R-squared is equal to the square of Pearson's coefficient of correlation. The R-squared can be between 0 and 1. R-squared =1 means a perfect fit. | baseline (0.5 h before intake of study medication), 2 h, and 12 h after dosing on day 1 | 
| Incidence of All Bleeding Events (Major, CRNM and Minor) During the Treatment Period. | Percentage of patients with Incidence of all bleeding events(major, clinically relevant non-major (CRNM) & minor) during the treatment period (including the residual effect period).Bleeding events were classified as follow: Major bleeding: 1) Fatal bleeding 2) Clinically overt bleeding associated with decrease in haemoglobin of at least 2 g/dL (20 g/L) in 24-h-period 3) Bleeding that was retroperitoneal, pulmonary, intracranial, or otherwise involved the central nervous system 4) Bleeding that required surgical intervention in an operating suite. CRNM bleeding: 1) Overt bleeding for which a blood product was administered & which was not directly attributable to the patient's underlying medical condition 2) Bleeding that required medical or surgical intervention to restore haemostasis, other than in an operating suite. Minor bleeding defined as any overt or macroscopic evidence of bleeding that did not fulfil the criteria for either major bleeding or CRNM bleeding. | Within two days after the administration of trial medication, up to 3 days | 
| Incidence of All AEs During the Treatment Period | Percentage of patients with all adverse events (AEs) during the treatment period (including REP). | Within two days after the administration of trial medication, up to 3 days | 
| Global Assessment of Acceptability and Tolerability of Study Medication | The investigator was to provide a global clinical assessment of tolerability and acceptability of study medication by the patient.This assessment was based on 5-point scale (good, satisfactory, not satisfactory, bad, not assessable). | Day 1 (immediately after dosing) |