Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03395639
• Collaborator: (none)
• Enrollment: 168
• Locations: 48
• Arms: 2
• Actual Duration (Months): 42.6
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A committee will judge the safety and effectiveness of edoxaban and the regular treatment (standard of care).

All children in the study will receive free treatment. They will have a 2 in 3 chance to receive edoxaban, and a 1 in 3 chance to receive the standard of care for preventing blood clots.

The study will find out if edoxaban is safer and more effective than the standard of care.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Disease	Drug: Edoxaban; Drug: Standard of Care (SOC)	Phase 3

Detailed Description

The primary objective is to compare the safety of edoxaban with the standard of care (SOC) in pediatric subjects with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis with regard to the combination of major and clinically relevant non-major (CRNM) bleeding per International Society on Thrombosis and Haemostasis [ISTH] definition.

The key secondary objective is to compare the efficacy of edoxaban against SOC with regard to the development of symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways including deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus and myocardial infarction (MI), and asymptomatic intracardiac thrombus identified by cardiac imaging.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: An Open-label, Randomised, Parallel-group, Multicentre, Observational Trial to Evaluate Safety and Efficacy of Edoxaban Tosylate in Children From 38 Weeks Gestational Age to Less Than 18 Years of Age With Cardiac Diseases at Risk of Thromboembolic Events
• Actual Study Start Date: May 15, 2018
• Actual Primary Completion Date: Dec 3, 2021
• Actual Study Completion Date: Dec 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban Two out of three participants will be randomized for treatment with edoxaban solution or tablets	Drug: Edoxaban; Edoxaban 15 mg or 30 mg tablets for participants 12 to <18 years of age, or 60 mg edoxaban suspension (dosed as mg/kg) for participants under 12 years of age (and optionally, 12 or older), for oral administration; Other Names: Lixiana Savaysa
Active Comparator: Standard of Care (SOC) One out of three participants will be randomized for treatment with the institution's SOC regimen	Drug: Standard of Care (SOC); Standard of care could include low molecular weight heparin (LMWH) and/or VKA according to the clinical site's SOC treatment regimen; Other Names: Warfarin/heparin Enoxaparin

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period [Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier]

   Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.

Secondary Outcome Measures

1. Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period [Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier]

   Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).

2. Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period [Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier]

   Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).

3. Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period [Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier]

   Death due to any cause (all-cause mortality) was assessed.

4. Number of Participants With Adjudicated Bleeding Events During the Extension Period [Month 4 up to Month 13]

   Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.

5. Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period [Month 4 up to Month 13]

   Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).

6. Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period [Month 4 up to Month 13]

   Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).

7. Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period [Month 4 up to Month 13]

   Death due to any cause (all-cause mortality) was assessed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Day to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Is a child with cardiac disease who is at risk for thromboembolic complications and requires at least 3 months antithrombotic anticoagulant prophylaxis

Either one of the following:

1. a child with cardiac disease who has a history of cardiac shunt occlusion/thrombosis, with shunt still in place (secondary prevention).

OR

1. a child with cardiac disease who requires (including those already taking, and those not yet taking) anticoagulation for primary prevention of TE.

Cardiac conditions known to significantly increase the risk of thrombosis (hence, indications for primary TE prevention) are defined in Antithrombotic Therapy and Prevention of Thrombosis. Some examples of cardiac conditions at risk of thrombosis are Fontan surgery, heart failure, Kawasaki disease, and Blalock-Taussig and Glenn surgery.

• Is a male or female child between 1 and <18 years of age (children between 38 weeks gestational age and 1 year of age will be included in the study, however, only after the safety and efficacy data of 50 subjects between 1 and <18 years of age in the edoxaban arm have been evaluated at the end of the 3-month treatment period)

• Has parent(s)/legal guardian(s) or legally acceptable representative who is informed and provides signed consent for the child, to participate in the study with edoxaban treatment. Pediatric participants with appropriate intellectual maturity will be required to sign an assent form in addition to the signed informed consent from the parent(s)/legal guardian(s) or any legally acceptable representative.

• If a female subject of childbearing potential, tests negative for pregnancy at Screening and consents to avoid becoming pregnant by using a locally approved contraception method throughout the study

Exclusion Criteria:

• Has evidence of symptomatic venous or arterial thrombosis and/or asymptomatic intracardiac thrombosis confirmed by a transthoracic echocardiogram during study screening period

• Has mechanical heart valve(s)

• Has active bleeding or high risk of bleeding contraindicating treatment with anticoagulant

• Takes antithrombotic therapy (other than low-dose aspirin) that is not protocol-related

• Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded

• Has any hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk

• Has estimated glomerular filtration rate (eGFR) <30% of normal for age and size

• Has stage 2 hypertension defined as blood pressure systolic and/or diastolic confirmed

99th percentile plus 5 mmHg

• Has thrombocytopenia or life expectancy less than three months

• Has had Fontan procedure with a history of or signs/symptoms suggestive of protein-losing enteropathy

• Is pregnant or breastfeeding

• Has a contraindication to the use of heparin and/or vitamin K antagonist (VKA)

• Has any condition that, as judged by the Investigator, would place the participant at increased risk of harm if he/she participated in the study, including contraindicated medications identified in the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Cardon Childrens Medical Center	Mesa	Arizona	United States	85202
3	Cedars Sinai Medical Center (ECG)	Los Angeles	California	United States	90048
4	University of California-San Francisco Department of Pediatrics - Hematology/Oncology	San Francisco	California	United States	94158
5	University of Florida College of Medicine	Gainesville	Florida	United States	32610
6	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
7	Rush University Medical Center	Chicago	Illinois	United States	60612
8	Ochsner Medical Center	New Orleans	Louisiana	United States	70121
9	Novant Health Heart and Vascular institute	Charlotte	North Carolina	United States	28204
10	East Carolina Heart Institute @ ECU	Greenville	North Carolina	United States	27834
11	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
12	OU Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
13	University of Virginia Health System	Charlottesville	Virginia	United States	22903
14	Seattle Children's Research Institute	Seattle	Washington	United States	98105
15	Kepler Universitätsklinikum Med Campus IV	Linz		Austria	4020
16	McMaster Children's Hospital	Hamilton	Ontario	Canada	L8N 3Z5
17	CHU Sainte-Justine	Montréal	Quebec	Canada	H3T 1C5
18	McGill University Health Centre/Glen Site/Montreal Children's Hospital	Pierrefonds	Quebec	Canada	H9H 4Y6
19	University Hospital Center Zagreb	Zagreb		Croatia	10000
20	Zagazig University Hospital	Zagazig	Al Sharkeya	Egypt	44519
21	Alexandria Clinical Research Center, Faculty of Medicine	Alexandria		Egypt	21131
22	Kasr Elainy School of Medicine, Abo Elreesh Hospital (Japanese Hospital), Ali Basha Ibrahim ST Faculty of Medicine Cairo University	Cairo		Egypt	11562
23	Ain Shams University Hospital	Cairo		Egypt	11566
24	Suez Canal University Hospital	Ismailia		Egypt	41522
25	Hôpital Des Enfants, Bâtiment Modulaire	Toulouse cedex 9	Haute Garonne	France	31059
26	Pediatric and Congenital Cardiology and Pulmonology Department; Arnaud De Villeneuve University Hospital	Montpellier	Herault	France	34295
27	Pediatric Cardiology Department, Hospital Necker Enfants Malades, APHP, Université Paris Descartes	Paris	Paris Cedex 15	France	75015
28	Gottsegen Gyorgy Orszagos Kardiologiai Intezet	Budapest		Hungary	1096
29	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged		Hungary	6720
30	Nirmal Hospital Private Limited	Sūrat	Gujarat	India	395002
31	Institute of Child Health	Kolkata		India	700017
32	Soroka University Medical Center	Be'er Sheva		Israel	8410101
33	Hadassah University Hospital - Ein Kerem	Jerusalem		Israel	9112001
34	Sheba Medical Center	Ramat Gan		Israel	5265601
35	Children's Heart Centre at the American University of Beirut Medical Center	Beirut		Lebanon	11-0236
36	Hotel Dieu de France Hospital	Beirut		Lebanon	166830
37	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
38	Erciyes University Medical Faculty, Department of Children Hospital	Edirne	Kayseri	Turkey	38039
39	Hacettepe University Medical Faculty	Ankara		Turkey	06100
40	Istanbul University Istanbul Medical Faculty	Istanbul		Turkey	34093
41	Ege University Faculty of Medicine Department of Child Health and Diseases	İzmir		Turkey	35040
42	Izmir-Dr. Behçet Uz. Pediatric Diseases and Surgery Training and Research Hospital- Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi	İzmir		Turkey	35210
43	Communal Institution Dnipropetrovsk Regional Pediatric Clinical Hospital of Dnipropetrovsk Regional Council, State Institution Dnipropetrovsk Medical Academy of MoH of Ukraine	Dnipro		Ukraine	49100
44	Communal Healthcare Institution Regional Pediatric Clinical Hospital, Kharkiv National Medical University	Kharkiv		Ukraine	61093
45	Vynnitsa Regional Children Clinical Hospital Policlinic Dept	Vinnytsia		Ukraine	21000
46	Royal Brompton Hospital	London	Greater London	United Kingdom	SW3 6HP
47	Glenfield Hospital	Leicester	Leicestershire	United Kingdom	LE3 9QP
48	Ward 2B, Royal Hospital for Children	Glasgow	Strathclyde	United Kingdom	G51 4TF

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

• Study Director: Clinical Study Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 3, 2019

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT03395639
• Other Study ID Numbers: DU176b-C-U313; 2017-000475-90
• First Posted: Jan 10, 2018
• Last Update Posted: Jul 26, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo, Inc.: Children; Pediatrics; Cardiac disease with potential for thromboembolic complications; Prophylactic treatment; Anticoagulant drugs
• Additional relevant MeSH terms: Heart Diseases; Heparin; Enoxaparin; Warfarin; Edoxaban

Study Results

Participant Flow

Recruitment Details	A total of 168 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment; 167 participants received treatment and were included in the modified Intent to Treat and Safety Populations.
Pre-assignment Detail	All subjects at the Screening Visit were assessed for international normalized ratio (INR) and activated partial thromboplastin time (aPTT) and evaluated at the local laboratory.

Arm/Group Title	Main Treatment Period: Edoxaban	Main Treatment Period: Standard of Care (SOC)	Extension Period: Edoxaban Only
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
Period Title: Main Treatment Period (0 to 4 Months)
STARTED	110	58	0
Modified Intent to Treat Population	109	58	0
COMPLETED	107	55	0
NOT COMPLETED	3	3	0
Period Title: Main Treatment Period (0 to 4 Months)
STARTED	0	0	147
COMPLETED	0	0	144
NOT COMPLETED	0	0	3

Baseline Characteristics

Arm/Group Title	Edoxaban	Standard of Care (SOC)	Total
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.	Total of all reporting groups
Overall Participants	110	58	168
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.7 (4.8)	7.3 (5.1)	7.6 (4.9)
Age, Customized (Count of Participants)
0 to 6 months	1 0.9%	3 5.2%	4 2.4%
6 months to <2 years	7 6.4%	5 8.6%	12 7.1%
2 to <6 years	33 30%	17 29.3%	50 29.8%
6 to <12 years	41 37.3%	17 29.3%	58 34.5%
12 to <18 years	28 25.5%	16 27.6%	44 26.2%
Sex: Female, Male (Count of Participants)
Female	38 34.5%	21 36.2%	59 35.1%
Male	72 65.5%	37 63.8%	109 64.9%
Race/Ethnicity, Customized (Count of Participants)
Asian	6 5.5%	3 5.2%	9 5.4%
Black or African American	4 3.6%	3 5.2%	7 4.2%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Native Hawaiian/Pacific Islander	2 1.8%	1 1.7%	3 1.8%
White	80 72.7%	39 67.2%	119 70.8%
Other	10 9.1%	7 12.1%	17 10.1%
Unknown	8 7.3%	5 8.6%	13 7.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period
Description	Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.
Time Frame	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier

Outcome Measure Data

Analysis Population Description

Adjudicated bleeding events were assessed in participants in the Safety Analysis Set within the Main Treatment Period.

Arm/Group Title	Edoxaban	Standard of Care (SOC)
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.
Measure Participants	109	58
Major or CRNM bleeding events	1 0.9%	1 1.7%
Major bleeding events	0 0%	0 0%
All bleeding events (Major, CRNM, minor)	4 3.6%	2 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Edoxaban, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Other
	Comments	Difference in adjudicated major or CRNM bleeding rates were assessed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Annualized rate difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Edoxaban, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Other
	Comments	Difference in adjudicated major bleeding rates were assessed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Annualized rate difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Edoxaban, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Other
	Comments	Difference in all adjudicated bleeding (major, CRNM, minor) rates were assessed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Annualized rate difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period
Description	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
Time Frame	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier

Outcome Measure Data

Analysis Population Description

Symptomatic thromboembolic events were assessed in participants in the Safety Analysis Set within the Main Treatment Period.

Arm/Group Title	Edoxaban	Standard of Care (SOC)
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.
Measure Participants	109	58
Thromboembolic event, Any Event	0 0%	1 1.7%
Deep vein thrombosis	0 0%	1 1.7%
Pulmonary embolism	0 0%	1 1.7%
Stroke	0 0%	0 0%
Systemic embolic event	0 0%	0 0%
Intracardiac thrombus	0 0%	0 0%
Myocardial infarction	0 0%	0 0%
Asymptomatic intracardiac thrombus identified by cardiac imaging	0 0%	0 0%
Death as a result of TE	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period
Description	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
Time Frame	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier

Outcome Measure Data

Analysis Population Description

Death was assessed in participants in the modified Intent to Treat Population within the Main Treatment Period.

Arm/Group Title	Edoxaban	Standard of Care (SOC)
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.
Measure Participants	109	58
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period
Description	Death due to any cause (all-cause mortality) was assessed.
Time Frame	Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier

Outcome Measure Data

Analysis Population Description

Death was assessed in participants in the modified Intent to Treat Population within the Main Treatment Period.

Arm/Group Title	Edoxaban	Standard of Care (SOC)
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.	Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.
Measure Participants	109	58
Count of Participants [Participants]	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With Adjudicated Bleeding Events During the Extension Period
Description	Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding.
Time Frame	Month 4 up to Month 13

Outcome Measure Data

Analysis Population Description

Adjudicated bleeding events were assessed in participants with available data in the Safety Analysis Set within the Extension Period.

Arm/Group Title	Edoxaban
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
Measure Participants	144
Major or CRNM bleeding events	1 0.9%
Major bleeding events	1 0.9%
All bleeding events (Major, CRNM, minor)	4 3.6%

6. Secondary Outcome

Title	Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period
Description	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
Time Frame	Month 4 up to Month 13

Outcome Measure Data

Analysis Population Description

Symptomatic thromboembolic events were assessed in participants with available data in the Safety Analysis Set within the Extension Period.

Arm/Group Title	Edoxaban
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
Measure Participants	144
Thromboembolic event, Any Event	4 3.6%
Deep vein thrombosis	0 0%
Pulmonary embolism	0 0%
Stroke	2 1.8%
Systemic embolic event	0 0%
Intracardiac thrombus	0 0%
Myocardial infarction	2 1.8%
Asymptomatic intracardiac thrombus identified by cardiac imaging	0 0%
Death as a result of TE	0 0%

7. Secondary Outcome

Title	Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period
Description	Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
Time Frame	Month 4 up to Month 13

Outcome Measure Data

Analysis Population Description

Death was assessed in participants with available data in the modified Intent to Treat Population within the Extension Period.

Arm/Group Title	Edoxaban
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
Measure Participants	144
Count of Participants [Participants]	0 0%

8. Secondary Outcome

Title	Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period
Description	Death due to any cause (all-cause mortality) was assessed.
Time Frame	Month 4 up to Month 13

Outcome Measure Data

Analysis Population Description

Death was assessed in participants with available data in the modified Intent to Treat Population within the Extension Period.

Arm/Group Title	Edoxaban
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
Measure Participants	144
Count of Participants [Participants]	2 1.8%

Adverse Events

Time Frame	Adverse events (AEs) were collected from the time of signing the informed consent form up to 30 days after the last dose of study drug, up to 13 months.
Adverse Event Reporting Description	Adverse events (AEs) were defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Arm/Group Title	Main Treatment Period: Edoxaban		Main Treatment Period: Standard of Care (SOC)		Extension Period: Edoxaban Only
Arm/Group Description	Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.		Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site's SOC treatment regimen.		Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
All Cause Mortality
	Main Treatment Period: Edoxaban		Main Treatment Period: Standard of Care (SOC)		Extension Period: Edoxaban Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/109 (0%)		0/58 (0%)		2/144 (1.4%)
Serious Adverse Events
	Main Treatment Period: Edoxaban		Main Treatment Period: Standard of Care (SOC)		Extension Period: Edoxaban Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/109 (4.6%)		3/58 (5.2%)		19/144 (13.2%)
Blood and lymphatic system disorders
Haemolysis	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Immune thrombocytopenia	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Cardiac disorders
Cardiac failure	2/109 (1.8%)		1/58 (1.7%)		0/144 (0%)
Coronary artery thrombosis	1/109 (0.9%)		0/58 (0%)		0/144 (0%)
Atrial thrombosis	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Cardiac disorder	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Coronary artery occlusion	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Myocardial infarction	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Myocardial ischaemia	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Palpitations	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Congenital, familial and genetic disorders
Coarctation of the aorta	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Gastrointestinal disorders
Vomiting	0/109 (0%)		1/58 (1.7%)		1/144 (0.7%)
Gingival bleeding	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Mucous stools	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
General disorders
Non-cardiac chest pain	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Pyrexia	0/109 (0%)		0/58 (0%)		2/144 (1.4%)
Infections and infestations
Abscess limb	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Bronchitis	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Injury, poisoning and procedural complications
Skin laceration	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Soft tissue injury	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Traumatic liver injury	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Investigations
Pulmonary arterial pressure increased	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Metabolism and nutrition disorders
Hyponatraemia	0/109 (0%)		1/58 (1.7%)		0/144 (0%)
Nervous system disorders
Cerebellar infarction	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Cerebral haematoma	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Paraesthesia	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Syncope	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Renal and urinary disorders
Acute kidney injury	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/109 (1.8%)		0/58 (0%)		0/144 (0%)
Pulmonary embolism	0/109 (0%)		1/58 (1.7%)		0/144 (0%)
Dyspnoea	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Epistaxis	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Pulmonary artery stenosis	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Skin and subcutaneous tissue disorders
Petechiae	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Vascular disorders
Haematoma	0/109 (0%)		0/58 (0%)		1/144 (0.7%)
Other (Not Including Serious) Adverse Events
	Main Treatment Period: Edoxaban		Main Treatment Period: Standard of Care (SOC)		Extension Period: Edoxaban Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/109 (46.8%)		24/58 (41.4%)		69/144 (47.9%)
Gastrointestinal disorders
Diarrhoea	3/109 (2.8%)		1/58 (1.7%)		1/144 (0.7%)
Vomiting	3/109 (2.8%)		2/58 (3.4%)		6/144 (4.2%)
General disorders
Pyrexia	5/109 (4.6%)		1/58 (1.7%)		13/144 (9%)
Infections and infestations
Bronchitis	3/109 (2.8%)		0/58 (0%)		3/144 (2.1%)
Upper respiratory tract infection	2/109 (1.8%)		2/58 (3.4%)		7/144 (4.9%)
Nasopharyngitis	4/109 (3.7%)		3/58 (5.2%)		4/144 (2.8%)
Influenza	1/109 (0.9%)		0/58 (0%)		5/144 (3.5%)
Tonsillitis	2/109 (1.8%)		0/58 (0%)		3/144 (2.1%)
Viral infection	0/109 (0%)		1/58 (1.7%)		3/144 (2.1%)
Laryngitis	0/109 (0%)		2/58 (3.4%)		0/144 (0%)
Investigations
Catheterisation cardiac	0/109 (0%)		2/58 (3.4%)		0/144 (0%)
Metabolism and nutrition disorders
Iron deficiency	0/109 (0%)		2/58 (3.4%)		0/144 (0%)
Nervous system disorders
Headache	5/109 (4.6%)		2/58 (3.4%)		9/144 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	14/109 (12.8%)		2/58 (3.4%)		9/144 (6.3%)
Cough	4/109 (3.7%)		2/58 (3.4%)		9/144 (6.3%)
Epistaxis	3/109 (2.8%)		2/58 (3.4%)		6/144 (4.2%)
Rhinorrhoea	4/109 (3.7%)		1/58 (1.7%)		3/144 (2.1%)
Skin and subcutaneous tissue disorders
Ecchymosis	0/109 (0%)		0/58 (0%)		3/144 (2.1%)
Vascular disorders
Haematoma	0/109 (0%)		0/58 (0%)		5/144 (3.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.