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

• ClinicalTrials.gov Identifier: NCT03395639
• Recruitment Status: Completed
• First Posted: January 10, 2018
• Results First Posted: July 26, 2022
• Last Update Posted: July 26, 2022
• Sponsor: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): Daiichi Sankyo, Inc.

Tracking Information

• First Submitted Date: January 4, 2018
• First Posted Date: January 10, 2018
• Results First Submitted Date: June 2, 2022
• Results First Posted Date: July 26, 2022
• Last Update Posted Date: July 26, 2022
• Actual Study Start Date: May 15, 2018
• Actual Primary Completion Date: December 3, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2022)

Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period [ 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 ]

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.

Original Primary Outcome Measures (submitted: January 4, 2018)

• Number of participants with combined bleeding events within the main treatment period [ Time Frame: within 4 months (3-month Main Treatment Period + 30-day follow-up) ]
  Combined bleeding events include major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period
• Number of participants with combined bleeding events during the entire trial (from first to the last dose plus 30 days) [ Time Frame: within 13 months (3-month Main Treatment Period + 9-month Extension Period + 30-day follow-up) ]
  Combined bleeding events include major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring on treatment

Current Secondary Outcome Measures (submitted: July 5, 2022)

• Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period [ 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 ]
  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).
• Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period [ 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 ]
  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).
• Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period [ 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 ]
  Death due to any cause (all-cause mortality) was assessed.
• Number of Participants With Adjudicated Bleeding Events During the Extension Period [ Time Frame: 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.
• Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period [ Time Frame: 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).
• Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period [ Time Frame: 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).
• Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period [ Time Frame: Month 4 up to Month 13 ]
  Death due to any cause (all-cause mortality) was assessed.

Original Secondary Outcome Measures (submitted: January 4, 2018)

• Number of participants with symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways [ Time Frame: within 4 months ]
  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)
• Number of participants with symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways [ Time Frame: within 13 months ]
  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)
• Number of participants who died as a result of TE between randomization and the date of the last dose of study drug plus 30 days [ Time Frame: within 13 months ]
• Number of participants who died as a result of any cause between randomization and the date of the last dose of study drug plus 30 days [ Time Frame: within 13 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Cardiac Disease

Intervention

• 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
• 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

Study Arms

• Experimental: Edoxaban
  Two out of three participants will be randomized for treatment with edoxaban solution or tablets
  Intervention: Drug: Edoxaban
• Active Comparator: Standard of Care (SOC)
  One out of three participants will be randomized for treatment with the institution's SOC regimen
  Intervention: Drug: Standard of Care (SOC)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 20, 2021): 168
• Original Estimated Enrollment (submitted: January 4, 2018): 150
• Actual Study Completion Date: December 3, 2021
• Actual Primary Completion Date: December 3, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

2. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Day to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Canada, Croatia, Egypt, France, Hungary, India, Israel, Lebanon, Spain, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Germany, Italy, Poland, Russian Federation

Administrative Information

• NCT Number: NCT03395639
• Other Study ID Numbers: DU176b-C-U313; 2017-000475-90 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Daiichi Sankyo, Inc.
• Verification Date: July 2022