Clinical Trial Results:
Open-label safety and tolerability study of dabigatran etexilate given for 3 days at the end of standard anticoagulant therapy in children aged 12 years to less than 18 years
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Summary
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EudraCT number |
2008-006866-27 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
16 Feb 2012
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jun 2016
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First version publication date |
16 Jul 2015
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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 |
1160.88
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00844415 | ||
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 Pharma GmbH & Co. KG
, +1 8002430127 , clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure
, Boehringer Ingelheim Pharma GmbH & Co. KG
, +1 8002430127 , 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 |
15 Mar 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Feb 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Feb 2012
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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 |
To investigate tolerability and safety of dabigatran etexilate capsules in adolescents. To explore preliminary pharmacokinetic and pharmacodynamic parameters in
adolescents.
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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 |
02 Mar 2009
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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 |
Canada: 9
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Worldwide total number of subjects |
9
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EEA total number of subjects |
0
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
9
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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 |
Adolescent (12 to <18years) patients who successfully completed planned treatment with either low molecular weight heparins or oral anticoagulation for primary venous thrombotic event (VTE). | ||||||||||||||||||
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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 subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not assigned to trial treatment if any one of the specific entry criteria were violated. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (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 |
Open-label study, only one investigational product used
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Arms
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Arm title
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All patients | ||||||||||||||||||
Arm description |
Dabigatran was administered twice daily for three consecutive days (total 6 doses). All patients received an initial oral dose of 1.71mg/kg of dabigatran (80 percent of the adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on thrombin time (TT) and clinical assessment, the dose was adjusted to the target dose of 2.14 mg/kg of dabigatran (100 percent of the adult dose adjusted for the patient’s weight). Three patients received 75 mg dabigatran (first dose) followed by 100 mg twice daily (BID). Three patients took dabigatran 100 mg (first dose) followed by 125 mg BID. Two patients received a dose of 125 mg dabigatran followed by 150 mg BID. One patient received only a single dose of dabigatran (75 mg). | ||||||||||||||||||
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 |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Dose 1: 50 mg capsule BID (100 mg daily)
Dose 2: 75 mg capsule BID (150 mg daily)
Dose 3: 2 X 50 mg capsules BID (200 mg daily)
Dose 4: 50 mg capsule & 75 mg capsule BID (250 mg daily)
Dose 5: 2 X 75 mg capsules BID (300 mg daily)
Maximum dose 150 mg BID
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Since the dose was adjusted by body weight, patients could receive different doses of dabigatran. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Since the dose was adjusted by body weight, patients could receive different doses of dabigatran. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Since the dose was adjusted by body weight, patients could receive different doses of dabigatran. [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Since the dose was adjusted by body weight, patients could receive different doses of dabigatran. |
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Baseline characteristics reporting groups
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Reporting group title |
All patients
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Reporting group description |
Dabigatran was administered twice daily for three consecutive days (total 6 doses). All patients received an initial oral dose of 1.71mg/kg of dabigatran (80 percent of the adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on thrombin time (TT) and clinical assessment, the dose was adjusted to the target dose of 2.14 mg/kg of dabigatran (100 percent of the adult dose adjusted for the patient’s weight). Three patients received 75 mg dabigatran (first dose) followed by 100 mg twice daily (BID). Three patients took dabigatran 100 mg (first dose) followed by 125 mg BID. Two patients received a dose of 125 mg dabigatran followed by 150 mg BID. One patient received only a single dose of dabigatran (75 mg). | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All patients
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Reporting group description |
Dabigatran was administered twice daily for three consecutive days (total 6 doses). All patients received an initial oral dose of 1.71mg/kg of dabigatran (80 percent of the adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on thrombin time (TT) and clinical assessment, the dose was adjusted to the target dose of 2.14 mg/kg of dabigatran (100 percent of the adult dose adjusted for the patient’s weight). Three patients received 75 mg dabigatran (first dose) followed by 100 mg twice daily (BID). Three patients took dabigatran 100 mg (first dose) followed by 125 mg BID. Two patients received a dose of 125 mg dabigatran followed by 150 mg BID. One patient received only a single dose of dabigatran (75 mg). | ||
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End point title |
Number of patients with bleeding events (major and minor) [1] | ||||||
End point description |
Patients were carefully assessed for signs and symptoms of bleeding. Bleeding was to be classified as major or minor. Major bleeding had to satisfy one or more of the following criteria: Overt bleeding associated with a decrease in haemoglobin of at least 2 g/dL in 24 hours, Overt bleeding requiring a transfusion of red blood cells, Overt bleeding which was retroperitoneal, intracranial, intraocular, or intraarticular, any overt bleeding deemed by the attending physician to require discontinuation of study medication. Minor bleeds were clinical bleeds that did not fulfill the criteria for major bleeds.
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End point type |
Primary
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End point timeframe |
From Screening until 30 days after first drug administration (end of trial visit)
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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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [2] - Treated Set (TS), all patients dispensed study medication that have taken at least one dose |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of patients with adverse events [3] | ||||||||||||||
End point description |
Patients with treatment drug related adverse events (DRAEs) and serious adverse events (SAEs) are reported separately for on-treatment and post-treatment period. Events were considered „on-treatment“ if occurring within 72 hours after last drug administration.
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End point type |
Primary
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End point timeframe |
From Screening until 30 days after first drug administration (end of trial visit)
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| Notes [3] - 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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [4] - Treated Set (TS), all patients dispensed study medication that have taken at least one dose |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Plasma concentration of free dabigatran [5] | ||||||||||||
End point description |
Plasma concentration of free dabigatran measured at 72 hours after first dose
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End point type |
Primary
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End point timeframe |
3 days
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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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [6] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Plasma concentration of total dabigatran [7] | ||||||||||||
End point description |
Plasma concentration of total dabigatran measured at 72 hours after first dose
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End point type |
Primary
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End point timeframe |
Day 3
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| Notes [7] - 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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [8] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Thrombin time (TT) centrally measured [9] | ||||||||||||
End point description |
Measurement of TT was performed centrally by Hemoclot Thrombin Inhibitor clotting assay.
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End point type |
Primary
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End point timeframe |
Day 3
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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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [10] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
TT locally measured [11] | ||||||||||||
End point description |
Measurement of TT was performed locally by Hemoclot Thrombin Inhibitor clotting assay.
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End point type |
Primary
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End point timeframe |
Day 3
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| Notes [11] - 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: According to the exploratory nature of this study only descriptive statistical methods were applied to all endpoints. |
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| Notes [12] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Activated Partial Thromboplastin Time (aPTT) centrally measured at 72 hours after first dose | ||||||||||||
End point description |
Measurement of aPTT was performed centrally using validated assays.
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End point type |
Secondary
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End point timeframe |
Day 3
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| Notes [13] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
aPTT locally measured | ||||||||||||
End point description |
Measurement of aPTT was performed locally using validated assays.
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End point type |
Secondary
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End point timeframe |
Day 3
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| Notes [14] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Ecarin Clotting Time (ECT) centrally measured | ||||||||||||
End point description |
Measurement of ECT was performed centrally using validated assays. Descriptive statistics are only performed for the centrally measured ECT.
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End point type |
Secondary
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End point timeframe |
Day 3
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| Notes [15] - Treated Set, all patients taking >= one dose. Statistics reported only for groups with > 2 patients |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Patients with clinically relevant changes in any laboratory parameter, Electrocardiogram (ECG) or vital signs | ||||||
End point description |
Changes in any laboratory parameter, ECG or vital signs were judged clinically relevant by the investigator.
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End point type |
Secondary
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End point timeframe |
Baseline and 3 days
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| Notes [16] - Treated Set (TS), all patients dispensed study medication that have taken at least one dose |
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| No statistical analyses for this end point | |||||||
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End point title |
Occurences of clinical outcome | ||||||||||||||||||
End point description |
Occurrences of clinical outcomes including recurrent venous thrombolic event (VTE), post thrombotic syndrome (PTS), pulmonary emboli (PEs), and total and VTE related mortality objectively assessed for example by ultrasound, venography or computed chromatography (CT) scan (based on the thrombus location). Number of patients with particular clinical outcome are reported.
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End point type |
Secondary
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End point timeframe |
3 days
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| Notes [17] - Treated Set (TS), all patients dispensed study medication that have taken at least one dose |
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 3 days
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Assessment type |
Systematic | ||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||
Dictionary version |
14.1
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Reporting groups
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Reporting group title |
All patients
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Reporting group description |
Dabigatran was administered twice daily for three consecutive days (total 6 doses). All patients received an initial oral dose of 1.71mg/kg of dabigatran (80 percent of the adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on thrombin time (TT) and clinical assessment, the dose was adjusted to the target dose of 2.14 mg/kg of dabigatran (100 percent of the adult dose adjusted for the patient’s weight). Three patients received 75 mg dabigatran (first dose) followed by 100 mg twice daily (BID). Three patients took dabigatran 100 mg (first dose) followed by 125 mg BID. Two patients received a dose of 125 mg dabigatran followed by 150 mg BID. One patient received only a single dose of dabigatran (75 mg). | ||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Mar 2009 |
Amendment 1 (06 March 2009) was implemented immediately as this amendment added verapamil to the
list of restricted medications when new information became available concerning a potential
interaction with dabigatran. There was also an administrative change to allow for analysis of
screening/baseline TT and ECT. |
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29 Sep 2009 |
Amendment 2 (29 Sep 2009) was implemented to:
1.) Request parental consent / child assent for any left over plasma from local analyses and
for an additional sample to be taken to be preserved for future research in coagulation
studies performed by one of the Coordinating Investigators, Lesley Mitchell at the
University of Alberta. This change to the protocol required Health Canada approval and
REB approval prior to implementation.
2.) Provide clarification of some protocol requirements and to make administrative changes.
These administrative changes to the protocol could be implemented without approval
from Health Canada or institutional REBs. |
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19 Feb 2010 |
Amendment 3 (19Feb10), was implemented immediately when the
results of two interaction study results became available. Total dabigatran concentrations
were increased up to 2.5-fold by ketaconazole, a P-glycoprotein inhibitor. Rifampicin, a
strong P-glycoprotein inducer, showed reductions in dabigatran concentrations by about 67%.
A few minor administrative changes were also implemented. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
