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

NCT03395639 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: DU176b-C-U3132017-000475-90
• Study Type: interventional
• Target: 168
• Locations: 14 countries
• Sites: 48

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.

Conditions

Cardiac Disease

Keywords

Children; Pediatrics; Cardiac disease with potential for thromboembolic complications; Prophylactic treatment; Anticoagulant drugs

Outcome Measures

Primary Outcomes (1)

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

  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.

  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

Secondary Outcomes (7)

• 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

• 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

• 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

• Number of Participants With Adjudicated Bleeding Events During the Extension Period

  Month 4 up to Month 13

• 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

Study Arms (2)

Edoxaban

EXPERIMENTAL

Two out of three participants will be randomized for treatment with edoxaban solution or tablets

Drug: Edoxaban

Standard of Care (SOC)

ACTIVE COMPARATOR

One out of three participants will be randomized for treatment with the institution's SOC regimen

Drug: Standard of Care (SOC)

Interventions

Edoxaban DRUG

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

Also known as: Lixiana, Savaysa

Edoxaban

Standard of Care (SOC) DRUG

Standard of care could include low molecular weight heparin (LMWH) and/or VKA according to the clinical site's SOC treatment regimen

Also known as: Warfarin/heparin, Enoxaparin

Standard of Care (SOC)

Eligibility Criteria

• Age: 1 Day - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (48)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Cardon Childrens Medical Center

Mesa, Arizona, 85202, United States

Location

Cedars Sinai Medical Center (ECG)

Los Angeles, California, 90048, United States

Location

University of California-San Francisco Department of Pediatrics - Hematology/Oncology

San Francisco, California, 94158, United States

Location

University of Florida College of Medicine

Gainesville, Florida, 32610, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Ochsner Medical Center

New Orleans, Louisiana, 70121, United States

Location

Novant Health Heart and Vascular institute

Charlotte, North Carolina, 28204, United States

Location

East Carolina Heart Institute @ ECU

Greenville, North Carolina, 27834, United States

Location

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

OU Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22903, United States

Location

Seattle Children's Research Institute

Seattle, Washington, 98105, United States

Location

Kepler Universitätsklinikum Med Campus IV

Linz, 4020, Austria

Location

McMaster Children's Hospital

Hamilton, Ontario, L8N 3Z5, Canada

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

McGill University Health Centre/Glen Site/Montreal Children's Hospital

Pierrefonds, Quebec, H9H 4Y6, Canada

Location

University Hospital Center Zagreb

Zagreb, 10000, Croatia

Location

Zagazig University Hospital

Zagazig, Al Sharkeya, 44519, Egypt

Location

Alexandria Clinical Research Center, Faculty of Medicine

Alexandria, 21131, Egypt

Location

Kasr Elainy School of Medicine, Abo Elreesh Hospital (Japanese Hospital), Ali Basha Ibrahim ST Faculty of Medicine Cairo University

Cairo, 11562, Egypt

Location

Ain Shams University Hospital

Cairo, 11566, Egypt

Location

Suez Canal University Hospital

Ismailia, 41522, Egypt

Location

Hôpital Des Enfants, Bâtiment Modulaire

Toulouse, Haute Garonne, 31059, France

Location

Pediatric and Congenital Cardiology and Pulmonology Department; Arnaud De Villeneuve University Hospital

Montpellier, Herault, 34295, France

Location

Pediatric Cardiology Department, Hospital Necker Enfants Malades, APHP, Université Paris Descartes

Paris, Paris Cedex 15, 75015, France

Location

Gottsegen Gyorgy Orszagos Kardiologiai Intezet

Budapest, 1096, Hungary

Location

Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont

Szeged, 6720, Hungary

Location

Nirmal Hospital Private Limited

Surat, Gujarat, 395002, India

Location

Institute of Child Health

Kolkata, 700017, India

Location

Soroka University Medical Center

Beersheba, 8410101, Israel

Location

Hadassah University Hospital - Ein Kerem

Jerusalem, 9112001, Israel

Location

Sheba Medical Center

Ramat Gan, 5265601, Israel

Location

Children's Heart Centre at the American University of Beirut Medical Center

Beirut, 11-0236, Lebanon

Location

Hotel Dieu de France Hospital

Beirut, 166830, Lebanon

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Erciyes University Medical Faculty, Department of Children Hospital

Edirne, Kayseri, 38039, Turkey (Türkiye)

Location

Hacettepe University Medical Faculty

Ankara, 06100, Turkey (Türkiye)

Location

Istanbul University Istanbul Medical Faculty

Istanbul, 34093, Turkey (Türkiye)

Location

Ege University Faculty of Medicine Department of Child Health and Diseases

Izmir, 35040, Turkey (Türkiye)

Location

Izmir-Dr. Behçet Uz. Pediatric Diseases and Surgery Training and Research Hospital- Izmir Dr. Behcet Uz Cocuk Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi

Izmir, 35210, Turkey (Türkiye)

Location

Communal Institution Dnipropetrovsk Regional Pediatric Clinical Hospital of Dnipropetrovsk Regional Council, State Institution Dnipropetrovsk Medical Academy of MoH of Ukraine

Dnipro, 49100, Ukraine

Location

Communal Healthcare Institution Regional Pediatric Clinical Hospital, Kharkiv National Medical University

Kharkiv, 61093, Ukraine

Location

Vynnitsa Regional Children Clinical Hospital Policlinic Dept

Vinnytsia, 21000, Ukraine

Location

Royal Brompton Hospital

London, Greater London, SW3 6HP, United Kingdom

Location

Glenfield Hospital

Leicester, Leicestershire, LE3 9QP, United Kingdom

Location

Ward 2B, Royal Hospital for Children

Glasgow, Strathclyde, G51 4TF, United Kingdom

Location

Related Publications (1)

• Portman MA, Jacobs JP, Newburger JW, Berger F, Grosso MA, Duggal A, Tao B, Goldenberg NA; ENNOBLE-ATE Trial Investigators. Edoxaban for Thromboembolism Prevention in Pediatric Patients With Cardiac Disease. J Am Coll Cardiol. 2022 Dec 13;80(24):2301-2310. doi: 10.1016/j.jacc.2022.09.031. Epub 2022 Oct 31.

  PMID: 36328157 DERIVED

MeSH Terms

Conditions

Heart Diseases

Interventions

edoxaban; Standard of Care; Warfarin; Heparin; Enoxaparin

Condition Hierarchy (Ancestors)

Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Glycosaminoglycans; Polysaccharides; Carbohydrates; Heparin, Low-Molecular-Weight

Results Point of Contact

• Title: Contact for Clinical Trial Information
• Organization: Daiichi Sankyo

CTRinfo@dsi.com

908-992-6400

Study Officials

• Clinical Study Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2018
• First Posted: January 10, 2018
• Study Start: May 15, 2018
• Primary Completion: December 3, 2021
• Study Completion: December 3, 2021
• Last Updated: July 26, 2022
• Results First Posted: July 26, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

ES (1); GB (3); UA (3); FR (3); TU (5); EG (5); HU (2); US (14); IN (2); AU (1); CA (3); CR (1); IL (3); LE (2)