Venous Thromboembolism
Conditions
Brief summary
The main objectives of this large phase IIb/III paediatric study are to assess the efficacy and safety of dabigatran etexilate relative to standard of care and to document the appropriateness of the proposed dabigatran etexilate dosing algorithm for use in patients from birth to less than 18 years of age.
Interventions
DRUGdabigatran etexilate
Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation
DRUGstandard of care
Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 0 to less than 18 years of age at the time of informed consent / assent * Documented diagnosis of clinically stable VTE (e.g. DVT, PE, central line thrombosis, sinus vein thrombosis) per investigator judgment, initially treated (minimum of 5 to 7 days, but not longer than 21 days) with parenteral anticoagulation therapy, such as unfractionated heparin (UFH) or a low molecular weight heparin (LMWH). * Clinical indication for at least 3 month of treatment with anticoagulants for the VTE episode defined under the above inclusion criterion. * Written informed consent provided by the patient's parent or legal guardian and assent provided by the patient (if applicable) at the time of informed consent form (ICF) signature according to local regulations.
Exclusion criteria
* Conditions associated with an increased risk of bleeding * Renal dysfunction (eGFR \< 50 mL/min/1.73m\^2 using the Schwartz formula) or requirement for dialysis. eGFR retesting during the screening period is allowed (once). * Active infective endocarditis * Subjects with a heart valve prosthesis requiring anticoagulation. * Hepatic disease: Active liver disease, including known active hepatitis A, B or C or, Persistent alanine aminotransferase (ALT) or aspartate transaminase (AST) or alkaline phosphatase (AP) \> 3 × upper limit of normal (ULN) within 3 months of screening * Pregnant or breast feeding females. Females who have reached menarche and are not using a medically accepted contraceptive method per local guidelines. Acceptable methods of birth control must be used in a correct and consistent manner * Patients in stratum 3 (0 to \< 2 years) with gestational age at birth \< 37 weeks or with body weight lower than the 3rd percentile * Anemia (hemoglobin \< 80g/L) or thrombocytopenia (platelet count \< 80 x 109/L) at screening. Transfusions during the screening period are allowed, provided that a satisfactory hemoglobin or platelet level is attained prior to visit 2 * Patients who have taken prohibited or restricted medication within one week of the first dose of study medication other than medication for prior VTE treatment and P-glycoprotein inhibitors.. * Patients who have received an investigational drug in the past 30 days prior to screening * Patients who are allergic/sensitive to any component of the study medication including solvent * Patients or parents/legal guardians considered unreliable to participate in the trial per investigator judgment or any condition which would present a safety hazard to the patient based on investigator judgment * Patients or parents/legal guardians who are unwilling or unable to undergo or permit repeat of the baseline imaging tests required to confirm thrombus resolution at study day 84 (or eEOT, whichever comes first) or in whom repeating such imaging tests at these pre-specified time points may not be medically in the patient's best interest. Examples may include unwarranted radiation exposure as a result of a repeat CT scan at day 84 for a patient with an isolated case of pulmonary embolism evaluated at baseline solely by a CT scan. In such cases, the baseline radiological assessment (e.g. CT) may be supplemented with an acceptable non-radiological assessment at baseline (e.g. MRI) which could then be repeated at day 84 hence alleviating any potential unwarranted radiation exposure. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Primary Endpoint | From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days. | The primary endpoint was the combined endpoint of the proportions of patients with: * Complete thrombus resolution * Freedom from recurrent VTE * Freedom from mortality related to VTE. The events outlined in the above combined primary endpoint were assessed by radiologists or other such qualified clinicians using an appropriate method such as ultrasound, echocardiography, venography, or CT scan, based on the location of the thrombus and the test used to perform the baseline assessment. The primary efficacy endpoint contained 3 components. Each component was evaluated separately, and only if the criteria for all 3 components were satisfied, the primary endpoint was considered achieved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Steady State Plasma Concentrations of Total Dabigatran at Visit 3 | From the time of randomisation until visit 3 | Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate at visit 3 |
| Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment | From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days. | Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate after at least 3 days following any dabigatran etexilate dose adjustment |
| Frequency of Dose Adjustment During the Treatment Phase | From first administration of trial medication until last administration of trial medication +6 days (residual effect period). | Frequency of dose adjustments (i.e. number of patients with dose adjustment), temporary and permanent discontinuation from therapy, and number of patients with laboratory monitoring requirements for dose |
| Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another | From first administration of trial medication until last administration of trial medication +6 days (residual effect period). | Frequency of patients switching the type of anti-coagulation therapy including Dabigatran etexilate (DE) to standard of care (SoC) treatment and switching from one standard of care treatment to another. For DE arm, only the switch from DE to SoC was counted, while for the SoC arm, all switches among SoC treatments were counted. |
| Freedom From Thrombus Progression at End of Therapy Compared With Baseline | From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days. | Freedom from thrombus progression at end of therapy compared with baseline, based on adjudication-confirmed data. |
| Freedom From Major Bleeding Events (MBEs) | From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days. | Freedom from major bleeding events (MBEs), defined as either fatal bleeding, clinically overt bleeding associated with a decrease in haemoglobin of at least 20 g/L in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial or otherwise involves the central nervous system, or bleeding that requires intervention in an operating suite. |
| All-cause Mortality | From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days. | Patients being alive at the end of observational period will be censored for all-cause mortality at the date of patients' last date known to be alive, or the date of data cut-off whichever comes first. |
| All Components of the Primary Efficacy Endpoint | From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days. | Patients with VTE-related death occurring between randomisation to Day 84 + 7 days were considered as not meeting the endpoint. The presence of recurrent VTE(s) was examined throughout the trial, and only the date of first occurrence was used for analysis. Assessment of index VTE status (best overall response) was scheduled on Day 84 ± 7 days (Visit 8) for patients who were alive without an early consent withdraw. In the case a Patient discontinued trial medication prematurely due to any reason the index VTE assessment took place at the early end of treatment visit. |
| Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules) | Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination. | Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire capsules: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire capsules: How acceptable was the DE treatment for the child? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Patients questionnaire capsules: Was taking the study capsules easy or difficult? The score is 1 (Very easy), 2 (easy), 3 (neither easy nor difficult), 4 (difficult) and 5 (very difficult). Scores refers to the end of treatment. |
| Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets) | Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination. | Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire pellets: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire pellets: Do you think that spitting occurs? The score is 1 (Never), 2 (sometimes) and 3 (often). Scores refers to the end of treatment. |
| Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF) | Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination. | Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire flavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Investigator questionnaire unflavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire flavoured OLF.: Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often). Parents questionnaire unflavoured OLF:Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often). Scores refers to the end of treatment. |
| All Bleeding Events | From first administration of trial medication until last adminstration of trial medication +6 days (residual effect period). Up to 97 days. | The number of participants with bleeding events includes major bleeding events (MBEs), clinically relevant non-major (CRNM) bleeding, minor bleeding events, any bleeding events, and the numbers of the combined endpoint of major and CRNM bleeding events was presented, based on adjudication-confirmed data. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Lithuania, Mexico, Norway, Russia, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
A multi-centre, open-label, randomised, parallel-group, active-controlled, non-inferiority trial of dabigatran etexilate (DE) versus standard of care (SoC) in children from birth to less than 18 years of age.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Etexilate Oral administration of dabigatran etexilate (DE) twice daily. Patients aged ≥8 years: age- and weight-adjusted DE dosing via capsules using 50 milligram (mg), 75 mg, 110 mg, and 150 mg capsules. Patients aged \<8 years or for patients who cannot take capsules even if older than 8 (but \<12 years of age): age- and weight-adjusted dosing via DE pellets. Patients aged \<12 months: age- and weight-adjusted dosing via DE oral liquid formulation (OLF). | 177 |
| Standard of Care Investigators decided on SoC treatment at time of randomisation: either low molecular weight heparin (LMWH) or vitamin K antagonists (VKA) or fondaparinux. | 90 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Non-compliance with the CTP | 2 | 1 |
| Overall Study | Not treated | 1 | 0 |
| Overall Study | Other reasons | 3 | 2 |
Baseline characteristics
| Characteristic | Total | Dabigatran Etexilate | Standard of Care |
|---|---|---|---|
| Age, Continuous | 11.1 Years STANDARD_DEVIATION 6.1 | 11.1 Years STANDARD_DEVIATION 6.1 | 11.0 Years STANDARD_DEVIATION 6.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 255 Participants | 169 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 10 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 245 Participants | 163 Participants | 82 Participants |
| Sex: Female, Male Female | 134 Participants | 96 Participants | 38 Participants |
| Sex: Female, Male Male | 133 Participants | 81 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 176 | 2 / 90 |
| other Total, other adverse events | 59 / 176 | 16 / 90 |
| serious Total, serious adverse events | 25 / 176 | 18 / 90 |
Outcome results
Primary
Composite Primary Endpoint
The primary endpoint was the combined endpoint of the proportions of patients with: * Complete thrombus resolution * Freedom from recurrent VTE * Freedom from mortality related to VTE. The events outlined in the above combined primary endpoint were assessed by radiologists or other such qualified clinicians using an appropriate method such as ultrasound, echocardiography, venography, or CT scan, based on the location of the thrombus and the test used to perform the baseline assessment. The primary efficacy endpoint contained 3 components. Each component was evaluated separately, and only if the criteria for all 3 components were satisfied, the primary endpoint was considered achieved.
Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Population: The randomised set (RS) included all randomised patients in the treatment groups to which they were randomised, regardless whether they took trial medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabigatran Etexilate | Composite Primary Endpoint | Complete thrombus resolution | 81 Participants |
| Dabigatran Etexilate | Composite Primary Endpoint | Freedom from recurrent VTE | 170 Participants |
| Dabigatran Etexilate | Composite Primary Endpoint | Freedom from mortality related to VTE | 177 Participants |
| Dabigatran Etexilate | Composite Primary Endpoint | Composite endpoint met | 81 Participants |
| Standard of Care | Composite Primary Endpoint | Composite endpoint met | 38 Participants |
| Standard of Care | Composite Primary Endpoint | Complete thrombus resolution | 38 Participants |
| Standard of Care | Composite Primary Endpoint | Freedom from mortality related to VTE | 89 Participants |
| Standard of Care | Composite Primary Endpoint | Freedom from recurrent VTE | 83 Participants |
Comparison: The primary analysis of the primary efficacy endpoint used the randomised set, following the intention-to-treat principle, based on adjudication-confirmed data. Age group was used as stratification factor using a Mantel-Haenszel type weighted average of differences.p-value: =0.000190% CI: [-0.141, 0.066]Cochran-Mantel-Haenszel
Secondary
All Bleeding Events
The number of participants with bleeding events includes major bleeding events (MBEs), clinically relevant non-major (CRNM) bleeding, minor bleeding events, any bleeding events, and the numbers of the combined endpoint of major and CRNM bleeding events was presented, based on adjudication-confirmed data.
Time frame: From first administration of trial medication until last adminstration of trial medication +6 days (residual effect period). Up to 97 days.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabigatran Etexilate | All Bleeding Events | Major bleeding | 4 Participants |
| Dabigatran Etexilate | All Bleeding Events | Minor bleeding | 33 Participants |
| Dabigatran Etexilate | All Bleeding Events | CRNM bleeding | 2 Participants |
| Dabigatran Etexilate | All Bleeding Events | Major and CRNM bleeding | 6 Participants |
| Dabigatran Etexilate | All Bleeding Events | Any bleeding | 38 Participants |
| Standard of Care | All Bleeding Events | Major and CRNM bleeding | 3 Participants |
| Standard of Care | All Bleeding Events | Any bleeding | 22 Participants |
| Standard of Care | All Bleeding Events | Major bleeding | 2 Participants |
| Standard of Care | All Bleeding Events | CRNM bleeding | 1 Participants |
| Standard of Care | All Bleeding Events | Minor bleeding | 21 Participants |
Comparison: Any bleeding events was analysed as time-to-event endpoint using a stratified Cox proportional hazard model with treatment as a covariate in the model and age group as the stratification factor. A pooling of age groups was performed as no events were observed in certain age group.90% CI: [0.736, 1.78]
Secondary
All-cause Mortality
Patients being alive at the end of observational period will be censored for all-cause mortality at the date of patients' last date known to be alive, or the date of data cut-off whichever comes first.
Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate | All-cause Mortality | 0 Participants |
| Standard of Care | All-cause Mortality | 1 Participants |
Comparison: All-cause mortality was analyzed as time-to-event endpoint using a stratified Cox proportional hazard model with treatment as a covariate in the model.p-value: 0.997690% CI: [0, 999999999]Cox proportional hazard model
Secondary
All Components of the Primary Efficacy Endpoint
Patients with VTE-related death occurring between randomisation to Day 84 + 7 days were considered as not meeting the endpoint. The presence of recurrent VTE(s) was examined throughout the trial, and only the date of first occurrence was used for analysis. Assessment of index VTE status (best overall response) was scheduled on Day 84 ± 7 days (Visit 8) for patients who were alive without an early consent withdraw. In the case a Patient discontinued trial medication prematurely due to any reason the index VTE assessment took place at the early end of treatment visit.
Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Population: The randomised set (RS) included all randomised patients in the treatment groups to which they were randomised, regardless whether they took trial medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabigatran Etexilate | All Components of the Primary Efficacy Endpoint | Complete thrombus resolution by Day 84 | 81 Participants |
| Dabigatran Etexilate | All Components of the Primary Efficacy Endpoint | Recurrent VTE by Day 84 | 7 Participants |
| Dabigatran Etexilate | All Components of the Primary Efficacy Endpoint | VTE-related death by Day 84 | 0 Participants |
| Standard of Care | All Components of the Primary Efficacy Endpoint | Recurrent VTE by Day 84 | 7 Participants |
| Standard of Care | All Components of the Primary Efficacy Endpoint | Complete thrombus resolution by Day 84 | 38 Participants |
| Standard of Care | All Components of the Primary Efficacy Endpoint | VTE-related death by Day 84 | 1 Participants |
Secondary
Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules)
Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire capsules: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire capsules: How acceptable was the DE treatment for the child? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Patients questionnaire capsules: Was taking the study capsules easy or difficult? The score is 1 (Very easy), 2 (easy), 3 (neither easy nor difficult), 4 (difficult) and 5 (very difficult). Scores refers to the end of treatment.
Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules) | Investigator questionnaire capsules | 1.0 Score | Standard Deviation 0.2 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules) | Parents questionnaire capsules | 1.0 Score | Standard Deviation 0 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules) | Patient questionnaire capsules | 1.6 Score | Standard Deviation 0.9 |
Secondary
Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF)
Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire flavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Investigator questionnaire unflavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire flavoured OLF.: Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often). Parents questionnaire unflavoured OLF:Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often). Scores refers to the end of treatment.
Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF) | Investigator questionnaire flavoured OLF | 1.6 Score | Standard Deviation 0.8 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF) | Investigator questionnaire unflavoured OLF | 1.2 Score | Standard Deviation 0.4 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF) | Parents questionnaire flavoured OLF | 1.4 Score | Standard Deviation 0.5 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF) | Parents questionnaire unflavoured OLF | 1.8 Score | Standard Deviation 0.4 |
Secondary
Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets)
Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff. Investigator questionnaire pellets: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad). Parents questionnaire pellets: Do you think that spitting occurs? The score is 1 (Never), 2 (sometimes) and 3 (often). Scores refers to the end of treatment.
Time frame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets) | Parents questionnaire pellets | 1.2 Score | Standard Deviation 0.5 |
| Dabigatran Etexilate | Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets) | Investigator questionnaire pellets | 1.2 Score | Standard Deviation 0.6 |
Secondary
Freedom From Major Bleeding Events (MBEs)
Freedom from major bleeding events (MBEs), defined as either fatal bleeding, clinically overt bleeding associated with a decrease in haemoglobin of at least 20 g/L in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial or otherwise involves the central nervous system, or bleeding that requires intervention in an operating suite.
Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate | Freedom From Major Bleeding Events (MBEs) | 0.977 Proportion of participants |
| Standard of Care | Freedom From Major Bleeding Events (MBEs) | 0.977 Proportion of participants |
Comparison: Time-to event endpoint using Kaplan-Meier estimates based on adjudication-confirmed data. Due to the low event rate of major bleeding, age group stratification was not considered.90% CI: [-0.032, 0.032]Kaplan-Meier estimate
Secondary
Freedom From Thrombus Progression at End of Therapy Compared With Baseline
Freedom from thrombus progression at end of therapy compared with baseline, based on adjudication-confirmed data.
Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Population: The randomised set (RS) included all randomised patients in the treatment groups to which they were randomised, regardless whether they took trial medication
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dabigatran Etexilate | Freedom From Thrombus Progression at End of Therapy Compared With Baseline | 148 Participants |
| Standard of Care | Freedom From Thrombus Progression at End of Therapy Compared With Baseline | 73 Participants |
Secondary
Frequency of Dose Adjustment During the Treatment Phase
Frequency of dose adjustments (i.e. number of patients with dose adjustment), temporary and permanent discontinuation from therapy, and number of patients with laboratory monitoring requirements for dose
Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dabigatran Etexilate | Frequency of Dose Adjustment During the Treatment Phase | With dose adjustment | 63 Participants |
| Dabigatran Etexilate | Frequency of Dose Adjustment During the Treatment Phase | With temporary interruption | 25 Participants |
| Dabigatran Etexilate | Frequency of Dose Adjustment During the Treatment Phase | Laboratory monitoring required | 175 Participants |
| Standard of Care | Frequency of Dose Adjustment During the Treatment Phase | With dose adjustment | 56 Participants |
| Standard of Care | Frequency of Dose Adjustment During the Treatment Phase | With temporary interruption | 6 Participants |
| Standard of Care | Frequency of Dose Adjustment During the Treatment Phase | Laboratory monitoring required | 82 Participants |
Secondary
Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another
Frequency of patients switching the type of anti-coagulation therapy including Dabigatran etexilate (DE) to standard of care (SoC) treatment and switching from one standard of care treatment to another. For DE arm, only the switch from DE to SoC was counted, while for the SoC arm, all switches among SoC treatments were counted.
Time frame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
Population: The treated set (TS) includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial medication
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dabigatran Etexilate | Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another | 22 Participants |
| Standard of Care | Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another | 2 Participants |
Secondary
Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment
Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate after at least 3 days following any dabigatran etexilate dose adjustment
Time frame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Population: The pharmacokinetic set (PKS) included all patients treated with DE who had at least~1 evaluable PK measurement and had no protocol deviations relevant to the evaluation of PK endpoints. Only scheduled visits were considered
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate | Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment | 81.7 nanogram per milliliter | Geometric Coefficient of Variation 54.7 |
Secondary
Steady State Plasma Concentrations of Total Dabigatran at Visit 3
Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate at visit 3
Time frame: From the time of randomisation until visit 3
Population: The pharmacokinetic set (PKS) included all patients treated with DE who had at least 1 evaluable PK measurement and had no protocol deviations relevant to the evaluation of PK endpoints. Only scheduled visits were considered
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate | Steady State Plasma Concentrations of Total Dabigatran at Visit 3 | 79.8 nanogram per milliliter | Geometric Coefficient of Variation 68.6 |