Safety and Tolerability of Dabigatran Etexilate Solution in Children 1 to < 12 Years of Age

Study Overview
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Brief Summary
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To investigate the safety and tolerability of dabigatran etexilate solution in children and to obtain preliminary pharmacokinetic/pharmacodynamic data

Detailed Description
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Purpose:

Official Title
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Single Dose Open-label PK/PD, Safety and Tolerability Study of Dabigatran Etexilate Mesilate Given at the End of Standard Anticoagulant Therapy in Successive Groups of Children Aged 2 Years to Less Than 12 Years Followed by 1 Year to Less Than 2 Years

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: males or females 1 to less than 12 years of age objective diagnosis of primary VTE completion of planned treatment course with LMWH or OAC for primary VTE written informed consent by parent (legal guardian) and patient assent (if applicable) Exclusion criteria: weight less than 9 kg conditions associated with increased risk of bleeding patients who have any condition that would not allow safe participation in study Note: Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 11 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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran etexilate<br>treatment with dabigatran oral solution as a single dose | Drug: dabigatran etexilate<br>* Experimental dose chosen based on age and weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of Total Dabigatran (SUM BIBR 953 ZW) | Plasma concentration of total dabigatran (SUM BIBR 953 ZW) | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate and at 2 h, 50 h, and 72 h after multiple dose administration of dabigatran etexilate | 
| Plasma Concentration of Free Dabigatran (BIBR 953 ZW). | Plasma concentration of free dabigatran (BIBR 953 ZW) | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate and at 2 h, 50 h, and 72 h after multiple dose administration of dabigatran etexilate | 
| Plasma Concentration of Unchanged Dabigatran Etexilate (BIBR 1048 BS) | Plasma concentration of unchanged dabigatran etexilate (BIBR 1048 BS). Some values are NA because Values were below the limit of quantification. Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the Geometric Mean (gMean) and Geometric Coefficient of Variation (gCV) is not calculated according to internal rules. | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate and at 2 h, 50 h, and 72 h after multiple dose administration of dabigatran etexilate | 
| Plasma Concentration of Metabolite BIBR 951 BS | Plasma concentration of metabolite BIBR 951 BS | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate and at 2 h, 50 h, and 72 h after multiple dose administration of dabigatran etexilate | 
| Plasma Concentration of Metabolite BIBR 1087 SE | Plasma concentration of metabolite BIBR 1087 SE | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate and at 2 h, 50 h, and 72 h after multiple dose administration of dabigatran etexilate | 
| Central Measurement of Activated Partial Thromboplastin Time (aPTT) at Predose and 2 and 10 h After Intake of Study Medication. | Central measurement of aPTT (activated partial thromboplastin time) at predose and 2 and 10 h after intake of study medication. For multiple dose patients only local measurements were planned. The Standard Deviation presented below is actually the % coefficient of variation. | at predose and 2 and 10 h after intake of study medication. | 
| Central Measurement of Ecarin Clotting Time (ECT) at Predose and 2 and 10 h After Intake of Study Medication. | Central measurement of ECT (ecarin clotting time) at predose and 2 and 10 h after intake of study medication. ECT was not planned to be measured in the multiple dose group. The Standard Deviation presented below are actually the % coefficient of variation | at predose and 2 and 10 h after intake of study medication. | 
| Central Measurement of Diluted Thrombin Time (dTT) at Predose and 2 and 10 h After Intake of Study Medication. | Central measurement of dTT (diluted thrombin time) at predose and 2 and 10 h after intake of study medication. The Standard Deviation presented below are actually the % coefficient of variation | at predose and 2 and 10 h after intake of study medication. | 
| Cmax (Maximum Measured Concentration of Total Dabigatran in Plasma) | Cmax (maximum measured concentration of total dabigatran in plasma). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of Cmax (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| Tmax (Time From Dosing to Maximum Measured Concentration of Total Dabigatran in Plasma) | tmax (time from dosing to maximum measured concentration of total dabigatran in plasma). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of tmax (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| AUC0-tz (Area Under the Concentration Time Curve of the Total Dabigatran in Plasma Over the Time Interval 0 up to the Last Quantifiable Data Point) | AUC0-tz (area under the concentration time curve of the total dabigatran in plasma over the time interval 0 up to the last quantifiable data point). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of AUC0-tz (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| Cmax (Maximum Measured Concentration of Free Dabigatran in Plasma) | Cmax (maximum measured concentration of free dabigatran in plasma). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of Cmax (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| Tmax (Time From Dosing to Maximum Measured Concentration of Free Dabigatran in Plasma) | tmax (time from dosing to maximum measured concentration of free dabigatran in plasma). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of tmax (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| AUC0-tz (Area Under the Concentration Time Curve of the Free Dabigatran in Plasma Over the Time Interval 0 up to the Last Quantifiable Data Point) | AUC0-tz (area under the concentration time curve of the free dabigatran in plasma over the time interval 0 up to the last quantifiable data point). Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of AUC0-tz (no profile, only one measurement after selected doses, refer to primary outcome no. 1 and 2). | At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate | 
| Percentage of Patients With Incidence of Any Bleeding Events (Major, Clinically Relevant Non-major (CRNM) and Minor) During the Treatment Period. | Major: Fatal bleeding, Clinically overt bleeding associated with decrease in haemoglobin of at least 2 g/dL in 24-h-period,bleeding that was retroperitoneal,pulmonary,intracranial,or otherwise involved the central nervous system,bleeding that required surgical intervention in an operating suite. CRNM: Overt bleeding for which a blood product was administered & which was not directly attributable to the patient's underlying medical condition,bleeding that required medical or surgical intervention to restore haemostasis,other than in an operating suite. Minor: Any overt or macroscopic evidence of bleeding that did not fulfil the criteria for either major bleeding or CRNM bleeding. For multiple dosing,all events with an onset date after the date of first dose until the end of trial treatment including 3 days after the last treatment and for single dosing,all events with an onset during the 48-h-period after study medication intake were assigned to the on-treatment period. | Up to 6 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Any Adverse Events During the Treatment Period | Percentage of patients with any adverse events during the treatment period. For patients with multiple dosing, all AEs with an onset date after the date of first dose until the end of trial treatment including 3 days after the last treatment were assigned to the on-treatment period. For patients with single dosing, all AEs with an onset during the 48-h-period after study medication intake were assigned to the on-treatment period. | Up to 6 days | 
| Global Assessment of Tolerability of Study Medication- Taste Assessment | The investigator was to provide a global clinical assessment of tolerability including patient taste assessment.This assessment was based on 6-point scale (Very good, good, satisfactory, bad, very bad, missing). The taste assessment was only provided when the patient was old enough to evaluate the taste. | Day 1 (immediately after dosing) | 
| Percentage of Patients With Changes in Laboratory and Clinical Parameters Such as Liver Enzymes and Physical Examination | Percentage of patients with changes in laboratory and clinical parameters such as liver enzymes and physical examination. Clinically Relevant Abnormalities for Laboratory Parameters were reported. | During the treatment period, Up to 6 days | 
| Global Assessment of Tolerability of Study Medication | The investigator was to provide a global clinical assessment of tolerability 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) |