Thrombosis
Conditions
Brief summary
To investigate the safety and pharmacokinetics of apixaban in children with congenital or acquired heart disease who have a need for anticoagulation.
Interventions
DRUGApixaban
Specified dose on specified days
Specified dose on specified days
Specified dose on specified days
Sponsors
Pediatric Heart Network
Pfizer
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Males and Females, 28 days to \< 18 years of age, inclusive * Congenital or acquired heart diseases requiring chronic anticoagulation for thromboprophylaxis (eg, single ventricle physiology including all 3 stages of palliation, dilated cardiomyopathy, Kawasaki disease with coronary aneurysms, and pulmonary hypertension) * Eligible participants include those who newly start anticoagulants and those who are currently on VKA or LMWH or other anticoagulants for thromboprophylaxis * Able to tolerate enteral medication \[eg, by mouth, nasogastric tube, or gastric tube\] * Participants 28 days to \< 3 months must be able to tolerate oral/nasogastric tube (NGT)/gastric tube (GT) feeds for at least 5 days prior to randomization
Exclusion criteria
* Recent thromboembolic events less than 6 months prior to enrollment * Weight \< 3 kg * Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the time of enrollment * Artificial heart valves and mechanical heart valves * Known inherited bleeding disorder or coagulopathy (e.g. hemophilia, von Willebrand disease, etc.) * Active bleeding at the time of enrollment * Any major bleeding other than perioperative in the preceding 3 months * Known intracranial congenital vascular malformation or tumor * Confirmed diagnosis of a GI ulcer * Known antiphospholipid syndrome (APS). Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participants with adjudicated major or CRNM bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding satisfies one or more of the following criteria: fatal bleeding, clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS, or bleeding that requires surgical intervention in an operating suite, including interventional radiology. CRNM bleeding satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition or bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Maximum Observed Concentration (Tmax) | From first dose up to 6 months after first dose | — |
| The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death | From randomization to 2 days after last dose (Up to approximately 12 months) | The number of participants with thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, pulmonary embolism (PE), stroke, other arterial or venous thromboembolic events, etc.) and thromboembolic event-related death detected by imaging or clinical diagnosis. Death and thromboembolic events are adjudicated by a blinded, independent events adjudication committee (EAC) |
| The Number of Participants With Adjudicated Major Bleeding | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participants with adjudicated major bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding is defined as bleeding that satisfies one or more of the following criteria: * fatal bleeding * clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period * bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS * bleeding that requires surgical intervention in an operating suite, including interventional radiology |
| The Number of Participants With Adjudicated CRNM Bleeding | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participants with adjudicated clinically relevant non-major (CRNM) bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. CRNM bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: * overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition * bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room |
| The Number of Participants With All Adjudicated Bleeding | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participants with all adjudicated bleeding events |
| The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participants with drug discontinuation due to adverse effects, intolerability, or bleeding. |
| The Number of Participant Deaths in the Study | From first dose to 2 days after last dose (Up to approximately 12 months) | The number of participant deaths in the study. |
| Maximum Observed Concentration (Cmax) | From first dose up to 6 months after first dose | — |
| Trough Observed Concentration (Cmin) | From first dose up to 6 months after first dose | — |
| Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | From first dose up to 6 months after first dose | — |
| Anti-FXa Activity | From first dose up to 6 months after first dose | Anti-FXa Activity was measured to assess participant plasma apixaban levels. 125 participants received at least one dose of apixaban and had anti-FXa samples collected that contributed measurements to at least one of the timepoints below. |
| Chromogenic FX Assay (Apparent FX Level) | From first dose up to 6 months after first dose | Chromogenic FX was measured to assess (apparent) FX levels in participants and inhibition of FXa by apixaban. 125 participants received at least one dose of apixaban and had chromogenic FX assay samples collected that contributed measurements to at least one of the timepoints below. |
| The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | from randomization up to 12 months after randomization | Subjects' quality of life was measured using the PedsQL instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. PedsQL consists of 23 items scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or for the child report for younger children ages 5-7, a 3-point Likert scale: 0 (Not at all), 2 (Sometimes), and 4 (A lot). Scores are reverse scored and transformed to a 0-100 scale as follows: 0=100, 1=75, 3=25, 4=0. Higher scores indicate a better HRQOL and/or lower problems. |
| Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | from randomization up to 12 months after randomization | Subjects' quality of life was measured using the KIDCLOT instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. KIDCLOT Parent inventory uses a 5 point Likert scale from 1 (N/A), 2 (Never), 3 (Rarely), 4 ( Now and then), 5 (Often). Child inventory uses a 4 point Likert scale 1 (N/A), 2 (Never), 3 (Now and then), 5 (Always). Values are scores as follows 1=0, 2=1, 3=2, 4=3, 5=4. Score interpretation is 0 to 100 percent IMPACT of anticoagulation on a child's life therefore, higher scores indicates a more negative effect. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Finland, Germany, Israel, Italy, Mexico, Russia, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
192 participants were randomized and 188 received treatment
Participants by arm
| Arm | Count |
|---|---|
| Apixaban Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first.
Participants weighing between \>/= 3 and \< 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight.
Children randomized to the apixaban arm of the study weighing \>/= 35 kg will be administered apixaban 5 mg twice daily (BID). | 129 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) Participants receive thromboprophylaxis with VKA or LMWH for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first.
Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, Participants having difficulty with VKA may switch to LMWH. | 63 |
| Total | 192 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-Treatment Period | Participant no longer meets study criteria | 1 | 0 |
| Pre-Treatment Period | Participant withdrew consent | 2 | 1 |
| Treatment Period | Adverse Event | 6 | 1 |
| Treatment Period | Lost to Follow-up | 0 | 1 |
| Treatment Period | Participant withdrew consent | 1 | 0 |
Baseline characteristics
| Characteristic | Apixaban | Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Total |
|---|---|---|---|
| Age, Continuous | 7.96 Years STANDARD_DEVIATION 4.553 | 7.56 Years STANDARD_DEVIATION 4.408 | 7.83 Years STANDARD_DEVIATION 4.499 |
| Age, Customized 12 YEARS - < 18 YEARS | 32 Participants | 15 Participants | 47 Participants |
| Age, Customized 28 DAYS - < 2 YEARS | 8 Participants | 3 Participants | 11 Participants |
| Age, Customized 2 YEARS - < 6 YEARS | 40 Participants | 22 Participants | 62 Participants |
| Age, Customized 6 YEARS - < 12 YEARS | 49 Participants | 23 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 14 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 105 Participants | 47 Participants | 152 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) White | 109 Participants | 51 Participants | 160 Participants |
| Sex: Female, Male Female | 67 Participants | 23 Participants | 90 Participants |
| Sex: Female, Male Male | 62 Participants | 40 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 126 | 0 / 62 |
| other Total, other adverse events | 68 / 126 | 36 / 62 |
| serious Total, serious adverse events | 26 / 126 | 13 / 62 |
Outcome results
Primary
Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events
The number of participants with adjudicated major or CRNM bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding satisfies one or more of the following criteria: fatal bleeding, clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS, or bleeding that requires surgical intervention in an operating suite, including interventional radiology. CRNM bleeding satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition or bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room.
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events | 1 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events | 3 Participants |
Secondary
Anti-FXa Activity
Anti-FXa Activity was measured to assess participant plasma apixaban levels. 125 participants received at least one dose of apixaban and had anti-FXa samples collected that contributed measurements to at least one of the timepoints below.
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm that have anti-FXa samples collected
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Apixaban | Anti-FXa Activity | Day 1 (4 HRS POSTDOSE) | 147.69 ng/mL | Standard Error 7.243 |
| Apixaban | Anti-FXa Activity | Week 2 (PREDOSE) | 86.24 ng/mL | Standard Error 7.652 |
| Apixaban | Anti-FXa Activity | Week 2 (2 HRS POSTDOSE) | 242.34 ng/mL | Standard Error 18.966 |
| Apixaban | Anti-FXa Activity | Month 3 (2 HRS POSTDOSE) | 228.88 ng/mL | Standard Error 14.263 |
| Apixaban | Anti-FXa Activity | Month 6 (PREDOSE) | 66.93 ng/mL | Standard Error 6.532 |
Secondary
Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU))
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm with available pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1460 ng • h/mL | Geometric Coefficient of Variation 61.2 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1840 ng • h/mL | Geometric Coefficient of Variation 20.7 |
| Participants Weight Range 12 to < 18 kg | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1610 ng • h/mL | Geometric Coefficient of Variation 49.6 |
| Participants Weight Range 18 to < 25 kg | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1760 ng • h/mL | Geometric Coefficient of Variation 38.3 |
| Participants Weight Range 25 to < 35 kg | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1840 ng • h/mL | Geometric Coefficient of Variation 43.3 |
| Participants Weight Range ≥ 35 kg | Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU)) | 1630 ng • h/mL | Geometric Coefficient of Variation 37.3 |
Secondary
Chromogenic FX Assay (Apparent FX Level)
Chromogenic FX was measured to assess (apparent) FX levels in participants and inhibition of FXa by apixaban. 125 participants received at least one dose of apixaban and had chromogenic FX assay samples collected that contributed measurements to at least one of the timepoints below.
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm that have have chromogenic FX assay samples collected
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Day 1 (PREDOSE) | 58.87 Percent | Standard Error 2.368 |
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Day 1 (4 HRS POSTDOSE) | 18.90 Percent | Standard Error 1.205 |
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Week 2 (PREDOSE) | 35.88 Percent | Standard Error 1.973 |
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Week 2 (2 HRS POSTDOSE) | 21.26 Percent | Standard Error 1.68 |
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Month 3 (2 HRS POSTDOSE) | 18.25 Percent | Standard Error 0.97 |
| Apixaban | Chromogenic FX Assay (Apparent FX Level) | Month 6 (PREDOSE) | 36.57 Percent | Standard Error 1.943 |
Secondary
Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score
Subjects' quality of life was measured using the KIDCLOT instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. KIDCLOT Parent inventory uses a 5 point Likert scale from 1 (N/A), 2 (Never), 3 (Rarely), 4 ( Now and then), 5 (Often). Child inventory uses a 4 point Likert scale 1 (N/A), 2 (Never), 3 (Now and then), 5 (Always). Values are scores as follows 1=0, 2=1, 3=2, 4=3, 5=4. Score interpretation is 0 to 100 percent IMPACT of anticoagulation on a child's life therefore, higher scores indicates a more negative effect.
Time frame: from randomization up to 12 months after randomization
Population: All randomized English speaking participants 6 years and older taking apixaban or warfarin with both baseline and post baseline questionnaire scores. Parent inventory includes only participants age \>= 34 weeks old.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE CHILD REPORTED - 6 MONTHS | 24.35 Score on a scale | Standard Deviation 12.887 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE CHILD REPORTED - 6 MONTHS | 22.81 Score on a scale | Standard Deviation 13.38 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE CHILD REPORTED - 12 MONTHS | 22.50 Score on a scale | Standard Deviation 11.787 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE CHILD REPORTED - 12 MONTHS | 21.52 Score on a scale | Standard Deviation 13.251 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE PARENT REPORTED - 6 MONTHS | 37.97 Score on a scale | Standard Deviation 20.493 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE PARENT REPORTED - 6 MONTHS | 32.32 Score on a scale | Standard Deviation 17.06 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE PARENT REPORTED - 12 MONTHS | 38.37 Score on a scale | Standard Deviation 18.874 |
| Apixaban | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE PARENT REPORTED - 12 MONTHS | 31.10 Score on a scale | Standard Deviation 16.021 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE PARENT REPORTED - 12 MONTHS | 33.61 Score on a scale | Standard Deviation 17.943 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE CHILD REPORTED - 6 MONTHS | 26.45 Score on a scale | Standard Deviation 12.114 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE PARENT REPORTED - 6 MONTHS | 39.02 Score on a scale | Standard Deviation 17.932 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE CHILD REPORTED - 6 MONTHS | 22.57 Score on a scale | Standard Deviation 16.049 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE PARENT REPORTED - 12 MONTHS | 39.36 Score on a scale | Standard Deviation 16.057 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | BASELINE CHILD REPORTED - 12 MONTHS | 25.32 Score on a scale | Standard Deviation 11.719 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE PARENT REPORTED - 6 MONTHS | 37.94 Score on a scale | Standard Deviation 20.626 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score | POST BASELINE CHILD REPORTED - 12 MONTHS | 18.01 Score on a scale | Standard Deviation 10.408 |
Secondary
Maximum Observed Concentration (Cmax)
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm with available pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Maximum Observed Concentration (Cmax) | 185 ng/mL | Geometric Coefficient of Variation 48.8 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Maximum Observed Concentration (Cmax) | 218 ng/mL | Geometric Coefficient of Variation 23.4 |
| Participants Weight Range 12 to < 18 kg | Maximum Observed Concentration (Cmax) | 222 ng/mL | Geometric Coefficient of Variation 39.6 |
| Participants Weight Range 18 to < 25 kg | Maximum Observed Concentration (Cmax) | 244 ng/mL | Geometric Coefficient of Variation 30.7 |
| Participants Weight Range 25 to < 35 kg | Maximum Observed Concentration (Cmax) | 249 ng/mL | Geometric Coefficient of Variation 37.7 |
| Participants Weight Range ≥ 35 kg | Maximum Observed Concentration (Cmax) | 203 ng/mL | Geometric Coefficient of Variation 35.9 |
Secondary
The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)
Subjects' quality of life was measured using the PedsQL instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. PedsQL consists of 23 items scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or for the child report for younger children ages 5-7, a 3-point Likert scale: 0 (Not at all), 2 (Sometimes), and 4 (A lot). Scores are reverse scored and transformed to a 0-100 scale as follows: 0=100, 1=75, 3=25, 4=0. Higher scores indicate a better HRQOL and/or lower problems.
Time frame: from randomization up to 12 months after randomization
Population: All randomized English speaking participants 2 years and older with both baseline and post baseline questionnaire scores
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY CHILD - BASELINE | 66.15 Score on a scale | Standard Deviation 30 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY CHILD - BASELINE | 65.34 Score on a scale | Standard Deviation 22.13 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY CHILD - MONTH 12 | 70.31 Score on a scale | Standard Deviation 26.681 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY CHILD - BASELINE | 75.51 Score on a scale | Standard Deviation 27.477 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY PARENT - BASELINE | 63.68 Score on a scale | Standard Deviation 20.727 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY CHILD - MONTH 12 | 73.37 Score on a scale | Standard Deviation 19.998 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY PARENT - MONTH 12 | 66.37 Score on a scale | Standard Deviation 20.811 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY CHILD - MONTH 12 | 80.56 Score on a scale | Standard Deviation 22.408 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY PARENT - BASELINE | 91.41 Score on a scale | Standard Deviation 11.557 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY CHILD - MONTH 12 | 69.46 Score on a scale | Standard Deviation 21.119 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY PARENT - MONTH 12 | 90.30 Score on a scale | Standard Deviation 12.381 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY CHILD - BASELINE | 80.52 Score on a scale | Standard Deviation 23.42 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY PARENT - BASELINE | 79.16 Score on a scale | Standard Deviation 22.571 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY PARENT - MONTH 12 | 70.00 Score on a scale | Standard Deviation 19.56 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY PARENT - MONTH 12 | 79.38 Score on a scale | Standard Deviation 21.012 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY CHILD - MONTH 12 | 80.71 Score on a scale | Standard Deviation 25.48 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY PARENT - BASELINE | 61.44 Score on a scale | Standard Deviation 30.804 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY CHILD - BASELINE | 87.39 Score on a scale | Standard Deviation 22.994 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY PARENT - MONTH 12 | 64.03 Score on a scale | Standard Deviation 29.567 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY CHILD - BASELINE | 69.85 Score on a scale | Standard Deviation 20.871 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY PARENT - BASELINE | 60.29 Score on a scale | Standard Deviation 29.558 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY PARENT - BASELINE | 65.61 Score on a scale | Standard Deviation 16.625 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY PARENT - MONTH 12 | 58.69 Score on a scale | Standard Deviation 29.56 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY CHILD - MONTH 12 | 68.24 Score on a scale | Standard Deviation 24.367 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY PARENT - BASELINE | 65.57 Score on a scale | Standard Deviation 27.342 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY CHILD - MONTH 12 | 91.77 Score on a scale | Standard Deviation 10.896 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY PARENT - MONTH 12 | 68.20 Score on a scale | Standard Deviation 24.037 |
| Apixaban | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY CHILD - BASELINE | 69.64 Score on a scale | Standard Deviation 15.512 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY PARENT - MONTH 12 | 66.17 Score on a scale | Standard Deviation 28.067 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY CHILD - BASELINE | 60.71 Score on a scale | Standard Deviation 17.374 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY CHILD - MONTH 12 | 64.81 Score on a scale | Standard Deviation 22.327 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY PARENT - BASELINE | 65.42 Score on a scale | Standard Deviation 18 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | GENERAL-SPECIFIC MODULE ASSESSED BY PARENT - MONTH 12 | 70.32 Score on a scale | Standard Deviation 21.949 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY CHILD - BASELINE | 64.70 Score on a scale | Standard Deviation 18.465 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY CHILD - MONTH 12 | 63.44 Score on a scale | Standard Deviation 19.836 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY CHILD - BASELINE | 85.68 Score on a scale | Standard Deviation 15.857 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY CHILD - MONTH 12 | 86.27 Score on a scale | Standard Deviation 16.4 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY CHILD - BASELINE | 78.44 Score on a scale | Standard Deviation 23.39 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY CHILD - MONTH 12 | 81.37 Score on a scale | Standard Deviation 30.689 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY CHILD - BASELINE | 60.31 Score on a scale | Standard Deviation 34.162 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY CHILD - MONTH 12 | 60.31 Score on a scale | Standard Deviation 38.333 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY CHILD - BASELINE | 53.24 Score on a scale | Standard Deviation 20.382 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY CHILD - MONTH 12 | 53.53 Score on a scale | Standard Deviation 26.796 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY CHILD - BASELINE | 63.55 Score on a scale | Standard Deviation 28.998 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY CHILD - MONTH 12 | 57.28 Score on a scale | Standard Deviation 38.948 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY PARENT - BASELINE | 67.71 Score on a scale | Standard Deviation 22.668 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | HEART PROBLEMS AND TREATMENT ASSESSED BY PARENT - MONTH 12 | 69.00 Score on a scale | Standard Deviation 23.688 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY PARENT - BASELINE | 85.27 Score on a scale | Standard Deviation 17.325 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT II ASSESSED BY PARENT - MONTH 12 | 83.80 Score on a scale | Standard Deviation 18.915 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY PARENT - BASELINE | 79.66 Score on a scale | Standard Deviation 22.958 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | PERCEIVED PHYSICAL APPEARANCE ASSESSED BY PARENT - MONTH 12 | 74.33 Score on a scale | Standard Deviation 26.998 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY PARENT - BASELINE | 56.27 Score on a scale | Standard Deviation 33.997 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | TREATMENT ANXIETY ASSESSED BY PARENT - MONTH 12 | 57.77 Score on a scale | Standard Deviation 34.199 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY PARENT - BASELINE | 61.60 Score on a scale | Standard Deviation 25.807 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COGNITIVE PROBLEMS ASSESSED BY PARENT - MONTH 12 | 58.53 Score on a scale | Standard Deviation 33.432 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL) | COMMUNICATION ASSESSED BY PARENT - BASELINE | 67.33 Score on a scale | Standard Deviation 28.257 |
Secondary
The Number of Participant Deaths in the Study
The number of participant deaths in the study.
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | The Number of Participant Deaths in the Study | 0 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participant Deaths in the Study | 0 Participants |
Secondary
The Number of Participants With Adjudicated CRNM Bleeding
The number of participants with adjudicated clinically relevant non-major (CRNM) bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. CRNM bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: * overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition * bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | The Number of Participants With Adjudicated CRNM Bleeding | 1 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With Adjudicated CRNM Bleeding | 2 Participants |
Secondary
The Number of Participants With Adjudicated Major Bleeding
The number of participants with adjudicated major bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding is defined as bleeding that satisfies one or more of the following criteria: * fatal bleeding * clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period * bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS * bleeding that requires surgical intervention in an operating suite, including interventional radiology
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | The Number of Participants With Adjudicated Major Bleeding | 1 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With Adjudicated Major Bleeding | 1 Participants |
Secondary
The Number of Participants With All Adjudicated Bleeding
The number of participants with all adjudicated bleeding events
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | The Number of Participants With All Adjudicated Bleeding | 47 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With All Adjudicated Bleeding | 23 Participants |
Secondary
The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding
The number of participants with drug discontinuation due to adverse effects, intolerability, or bleeding.
Time frame: From first dose to 2 days after last dose (Up to approximately 12 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding | 7 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding | 1 Participants |
Secondary
The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death
The number of participants with thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, pulmonary embolism (PE), stroke, other arterial or venous thromboembolic events, etc.) and thromboembolic event-related death detected by imaging or clinical diagnosis. Death and thromboembolic events are adjudicated by a blinded, independent events adjudication committee (EAC)
Time frame: From randomization to 2 days after last dose (Up to approximately 12 months)
Population: All randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Apixaban | The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death | Thromboembolic event-related death | 0 Participants |
| Apixaban | The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death | Thromboembolic event | 0 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death | Thromboembolic event-related death | 0 Participants |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death | Thromboembolic event | 0 Participants |
Secondary
Time of Maximum Observed Concentration (Tmax)
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm with available pharmacokinetic data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Apixaban | Time of Maximum Observed Concentration (Tmax) | 2.24 hours |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Time of Maximum Observed Concentration (Tmax) | 2.47 hours |
| Participants Weight Range 12 to < 18 kg | Time of Maximum Observed Concentration (Tmax) | 1.72 hours |
| Participants Weight Range 18 to < 25 kg | Time of Maximum Observed Concentration (Tmax) | 1.74 hours |
| Participants Weight Range 25 to < 35 kg | Time of Maximum Observed Concentration (Tmax) | 1.65 hours |
| Participants Weight Range ≥ 35 kg | Time of Maximum Observed Concentration (Tmax) | 1.85 hours |
Secondary
Trough Observed Concentration (Cmin)
Time frame: From first dose up to 6 months after first dose
Population: All treated participants in the apixaban arm with available pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Trough Observed Concentration (Cmin) | 57.9 ng/mL | Geometric Coefficient of Variation 90.3 |
| Low Molecular Weight Heparin (LMWH)/Vitamin K Antagonists (VKA) | Trough Observed Concentration (Cmin) | 82.7 ng/mL | Geometric Coefficient of Variation 21.5 |
| Participants Weight Range 12 to < 18 kg | Trough Observed Concentration (Cmin) | 64.3 ng/mL | Geometric Coefficient of Variation 69.5 |
| Participants Weight Range 18 to < 25 kg | Trough Observed Concentration (Cmin) | 67.4 ng/mL | Geometric Coefficient of Variation 58.9 |
| Participants Weight Range 25 to < 35 kg | Trough Observed Concentration (Cmin) | 73.1 ng/mL | Geometric Coefficient of Variation 64.7 |
| Participants Weight Range ≥ 35 kg | Trough Observed Concentration (Cmin) | 72.7 ng/mL | Geometric Coefficient of Variation 46.8 |