Clinical Trial Results:
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
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Summary
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EudraCT number |
2009-013618-29 |
Trial protocol |
FR AT NL ES LT SK LV IT BE Outside EU/EEA |
Global end of trial date |
18 Feb 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Sep 2016
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First version publication date |
02 Sep 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1160.89
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01083732 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination,
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination,
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 2430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000081-PIP01-07 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Mar 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Feb 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Feb 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objectives were:
• To provide paediatric PK/PD data
• To investigate the tolerability and safety of the dabigatran etexilate solution
in children aged 1 to <12 years who had completed planned treatment with either low molecular weight heparins or oral anticoagulation for a venous thrombotic event (VTE)
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Mar 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Lithuania: 2
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Country: Number of subjects enrolled |
Russian Federation: 3
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Country: Number of subjects enrolled |
Thailand: 4
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Worldwide total number of subjects |
18
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EEA total number of subjects |
5
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
6
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Children (2-11 years) |
12
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Out of 20 patients enrolled, 18 patients entered the trial. | ||||||||||||
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Pre-assignment
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Screening details |
All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be entered the trial if any one of the specific entry criteria were violated | ||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
This is an open label, non-randomised, uncontrolled, single arm study .
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dabigatran etexilate (single dose, age group 1 to <2 years) | ||||||||||||
Arm description |
The patients aged 1 to <2 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Dabigatran etexilate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
The patients were orally administered a single dose of liquid formulation of dabigatran etexilate. The dose was adjusted based on age and weight and was equivalent to the adult dose of 150 mg dabigatran etexilate.
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Arm title
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Dabigatran etexilate (single dose, age group 2 to <12 years) | ||||||||||||
Arm description |
The patients aged 2 to <12 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Dabigatran etexilate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
The patients were orally administered a single dose of liquid formulation of dabigatran etexilate. The dose was adjusted based on age and weight and was equivalent to the adult dose of 150 mg dabigatran etexilate.
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Arm title
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Dabigatran etexilate (multiple dose, age group 2 to <12 years) | ||||||||||||
Arm description |
The patients aged 2 to <12 years were orally administered a multiple dose (3 days, twice daily) of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Dabigatran etexilate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
The patients were orally administered multiple doses (3 days, twice daily) of dabigatran etexilate. The dose was adjusted based on age and weight. The first dose was chosen as 80% of the adult dose and the second up to the sixth dose were equivalent to the adult dose of 150 mg dabigatran etexilate.
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Baseline characteristics reporting groups
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Reporting group title |
Dabigatran etexilate (single dose, age group 1 to <2 years)
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Reporting group description |
The patients aged 1 to <2 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate (single dose, age group 2 to <12 years)
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Reporting group description |
The patients aged 2 to <12 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate (multiple dose, age group 2 to <12 years)
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Reporting group description |
The patients aged 2 to <12 years were orally administered a multiple dose (3 days, twice daily) of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dabigatran etexilate (single dose, age group 1 to <2 years)
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Reporting group description |
The patients aged 1 to <2 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||
Reporting group title |
Dabigatran etexilate (single dose, age group 2 to <12 years)
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Reporting group description |
The patients aged 2 to <12 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||
Reporting group title |
Dabigatran etexilate (multiple dose, age group 2 to <12 years)
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Reporting group description |
The patients aged 2 to <12 years were orally administered a multiple dose (3 days, twice daily) of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||
Subject analysis set title |
Dabigatran etexilate (single dose, age group 1 to <12 years)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The patients aged 1 to <12 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation)
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End point title |
Plasma concentration of total dabigatran (SUM BIBR 953 ZW) [1] | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Plasma concentration of total dabigatran (SUM BIBR 953 ZW).
Pharmacokinetic set (PKS): This patient set included all treated patients who provided at least one pharmacokinetic/ pharmacodynamic (PK/PD) observation and had no important protocol violations (PVs) with respect to the statistical analysis of PK or PD endpoints.
99999 denotes the "missing value" or "not applicable".
Missing values as time-points were not applicable for reporting results for respective dose groups.
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End point type |
Primary
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End point timeframe |
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.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
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| Notes [2] - PKS (evaluable cases) [3] - PKS (evaluable cases) [4] - PKS (evaluable cases) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Plasma concentration of free dabigatran (BIBR 953 ZW). [5] | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Plasma concentration of free dabigatran (SUM BIBR 953 ZW).
99999 denotes the "missing value" or "not applicable".
Missing values as time-points were not applicable for reporting results for respective dose groups.
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End point type |
Primary
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End point timeframe |
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
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
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| Notes [6] - PKS (evaluable cases) [7] - PKS (evaluable cases) [8] - PKS (evaluable cases) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Central measurement of ECT (ecarin clotting time) at predose and 2 and 10 h after intake of study medication. [9] [10] | |||||||||||||||||||||
End point description |
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 is actually the % coefficient of variation.
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End point type |
Primary
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End point timeframe |
at predose and 2 and 10 h after intake of study medication.
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: ECT was not planned to be measured in the multiple dose group |
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| Notes [11] - PKS (evaluable cases) [12] - PKS (evaluable cases) |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Cmax (maximum measured concentration of total dabigatran in plasma) [13] [14] | ||||||||||||
End point description |
Cmax (maximum measured concentration of total dabigatran in plasma).
Cmax can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of Cmax.
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of Cmax. |
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| Notes [15] - PKS [16] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
tmax (time from dosing to maximum measured concentration of total dabigatran in plasma) [17] [18] | ||||||||||||
End point description |
tmax (time from dosing to maximum measured concentration of total dabigatran in plasma)
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate.
Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of this parameter.
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| Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of tmax. |
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| Notes [19] - PKS [20] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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) [21] [22] | ||||||||||||
End point description |
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 this parameter.
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate
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| Notes [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of AUC0-tz. |
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| Notes [23] - PKS [24] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Cmax (maximum measured concentration of free dabigatran in plasma) [25] [26] | ||||||||||||
End point description |
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 this parameter.
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate
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| Notes [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of Cmax. |
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| Notes [27] - PKS [28] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
tmax (time from dosing to maximum measured concentration of free dabigatran in plasma) [29] [30] | ||||||||||||
End point description |
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 this parameter.
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate
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| Notes [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of tmax. |
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| Notes [31] - PKS [32] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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) [33] [34] | ||||||||||||
End point description |
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 this parameter.
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End point type |
Primary
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End point timeframe |
At 1 hour (h), 2 h, 4 h, 6 h, and 10 h after single administration of dabigatran etexilate
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| Notes [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoint can only be calculated for single dose patients. For multiple dose patients the time points do not allow calculation of AUC0-tz. |
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| Notes [35] - PKS [36] - PKS |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of patients with incidence of any bleeding events (major, clinically relevant non-major (CRNM) and minor) during the treatment period. [37] | ||||||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Up to 6 days
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| Notes [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
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| Notes [38] - TS [39] - TS [40] - TS |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of patients with any adverse events during the treatment period [41] | ||||||||||||||||
End point description |
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.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 6 days
|
||||||||||||||||
| Notes [41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
|||||||||||||||||
|
|||||||||||||||||
| Notes [42] - TS [43] - TS [44] - TS |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
||||||||||||||||||||||
End point title |
Central measurement of aPTT (activated partial thromboplastin time) at predose and 2 and 10 h after intake of study medication [45] [46] | |||||||||||||||||||||
End point description |
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
|
|||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||
End point timeframe |
at predose and 2 and 10 h after intake of study medication
|
|||||||||||||||||||||
| Notes [45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: For mulitple dose patients central measurement of aPTT had not been planned. |
||||||||||||||||||||||
|
||||||||||||||||||||||
| Notes [47] - PKS (evaluable cases) [48] - PKS (evaluable cases) |
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
End point title |
Plasma concentration of unchanged dabigatran etexilate (BIBR 1048 BS) [49] [50] | |||||||||||||||||||||||||||||||||
End point description |
Plasma concentration of unchanged dabigatran etexilate (BIBR 1048 BS).
99999 denotes the "missing value";
For single dose group at 4h and 10h and multiple dose group at 2h, 50h and 72h values are missing as 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 gMean and gCV is not calculated according to internal rules.
For single dose group at 6h, all patients except one patient had values below the limit of quantification.
Other values missing in the table are due to the time-points not applicable for the respective dose groups.
|
|||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
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
|
|||||||||||||||||||||||||||||||||
| Notes [49] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| Notes [51] - PKS (evaluable cases) [52] - PKS (evaluable cases) |
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
End point title |
Plasma concentration of metabolite BIBR 951 BS [53] [54] | |||||||||||||||||||||||||||||||||
End point description |
Plasma concentration of metabolite BIBR 951 BS.
99999 denotes the "missing value";
For single dose group at 6h and 10h and multiple dose group at 2h, 50h and 72h values are missing as 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 gMean and gCV is not calculated according to internal rules.
Other values missing in the table are due to the time-points not applicable for the respective dose groups.
|
|||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
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
|
|||||||||||||||||||||||||||||||||
| Notes [53] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| Notes [55] - PKS (evaluable cases) [56] - PKS (evaluable cases) |
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
End point title |
Plasma concentration of metabolite BIBR 1087 SE [57] [58] | |||||||||||||||||||||||||||||||||
End point description |
Plasma concentration of metabolite BIBR 1087 SE.
99999 denotes the "missing value";
For single dose group at 6h and 10h and multiple dose group at 2h, 50h and 72h values are missing as 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 gMean and gCV is not calculated according to internal rules.
For single dose group at 4h, all patients except one patient had values below the limit of quantification.
Other values missing in the table are due to the time-points not applicable for the respective dosegroups.
|
|||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
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
|
|||||||||||||||||||||||||||||||||
| Notes [57] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| Notes [59] - PKS (evaluable cases) [60] - PKS (evaluable cases) |
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Global assessment of tolerability of study medication- Taste assessment [61] | ||||||||||||||||||||||||||||||||||||||||
End point description |
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.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1 (immediately after dosing)
|
||||||||||||||||||||||||||||||||||||||||
| Notes [61] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
|||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| Notes [62] - TS [63] - TS [64] - TS |
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Central measurement of dTT (diluted thrombin time) at predose and 2 and 10 h after intake of study medication [65] | ||||||||||||||||||||||||||||
End point description |
Central measurement of dTT (diluted thrombin time) at predose and 2 and 10 h after intake of study medication. 99999 denotes the "missing value"; Missing values as time-points were not applicable for the respective dose groups. The Standard Deviation presented below is actually the % coefficient of variation.
|
||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||
End point timeframe |
at predose and 2 and 10 h after intake of study medication
|
||||||||||||||||||||||||||||
| Notes [65] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| Notes [66] - PKS (evaluable cases) [67] - PKS (evaluable cases) [68] - PKS (evaluable cases) |
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of patients with changes in laboratory and clinical parameters such as liver enzymes and physical examination | ||||||||||||||||
End point description |
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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
During the treatment period, Up to 6 days
|
||||||||||||||||
|
|||||||||||||||||
| Notes [69] - TS [70] - TS [71] - TS |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Global assessment of tolerability of study medication | ||||||||||||||||||||||||||||||||||||
End point description |
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).
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1 (immediately after dosing)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| Notes [72] - TS [73] - TS [74] - TS |
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All adverse events (AEs) during the treatment period, up to 6 days.
|
||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
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 and 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.
|
||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
|
||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate (single dose, age group 1 to <2 years)
|
||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The patients aged 1 to <2 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate (multiple dose, age group 2 to <12 years)
|
||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The patients aged 2 to <12 years were orally administered a multiple dose (3 days, twice daily) of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dabigatran etexilate (single dose, age group 2 to <12 years)
|
||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The patients aged 2 to <12 years were orally administered a single dose of dabigatran etexilate (Dabigatran etexilate oral liquid formulation (6.25 mg/mL) after reconstitution from dabigatran etexilate granules (167.5 mg) and solvent for oral liquid formulation) | ||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
18 Feb 2010 |
Several P-glycoprotein inhibitors (amiodarone, cyclosporine, itraconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, tacrolimus) and P-glycoprotein inducers (rifampicin, St.John’s Wort, carbamazepin, phenytoin) were added as restricted concomitant medication. Other changes were of administrative nature. |
||
14 Jul 2010 |
-The individual doses of the multiple dosing scheme were changed. No patients were treated in this trial before implementation of Global Amendment 2. Originally, the dosing was to increase from 50% of the target dose (Day 1) to 80% (Day 2) to 100% (Day 3). Based on data from other trial 1160.88 (NCT00844415), concerns were raised that patients may not have reached the full therapeutic dose by Day 3 when they received the 100% dose. Therefore, Global Amendment 2 changed the multiple dosing to 80% of the target dose for Dose 1 on Day 1, followed by 100% for all subsequent 5 doses
- The exclusion criterion 3J was revised to correct the definition of uncontrolled hypertension
- The planned target dose was corrected to 1.38 mg/kg
- Other changes related to clarifications of wording |
||
11 Nov 2010 |
In exclusion criterion 4, severe renal dysfunction was no longer defined as serum creatinine ≥200 μM but as eGFR <80 mL/min/1.73m2 using the Schwartz formula; this reflects the more common definition in children. Other changes were of administrative nature or related to clarifications of wording. |
||
28 Mar 2011 |
This amendment introduced the following changes:
- The endpoint ‘global assessment of tolerability to study medication (including taste assessment)’was changed to a secondary endpoint. The taste assessment was now to be done by the patient (if old enough). If patients withdrew early, the taste was also to be assessed
- Wording was changed to reflect that the DMC first evaluated the older age group before recruitment of the younger age group started
- Exclusion criterion 2 (‘previous history of cerebral venous thromboembolism’) was removed: children with a history of cerebral VTE would be at a low risk of bleeding once the clot had resolved. The greatest risk would be at the onset of the cerebral VTE and the start of standard therapy
- Wording was changed for removal of individual patients. Patients with a minor bleeding event were no longer automatically removed from the study, but could continue in the study as per investigator judgement
- Asparaginase was added as a restricted concomitant medication
- Other changes were of administrative nature or related to clarifications of wording. |
||
27 Mar 2012 |
This amendment introduced the following changes:
- The dosing changed from multiple (3 days twice daily) to a single dose, as approved by the Paediatric Committee of the European Medicines Agency
- The list of restricted medications was modified: ASA and ASA-containing over-the counter medications and oral corticosteroids were removed as restricted medication as their use in this single dose study had no impact on the PK of dabigatran, on coagulation tests measuring PD effects or on safety
- Procedures for analysing/reporting drug-induced liver injury (DILI) event were added
- Other changes were of administrative nature or related to clarifications of wording |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
