An Open-Label, Study to Evaluate safety and efficacy of Edoxaban tosylate in children with heart disease at risk of a blood clot.

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2017-000475-90-HU
• Date of registration: 23/11/2017
• Prospective Registration: Yes
• Primary sponsor: Daiichi Sankyo Inc
• Public title: An Open-Label, Study to Evaluate safety and efficacy of Edoxaban tosylate in children with heart disease at risk of a blood clot.
• Scientific 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.
• Date of first enrolment: 22/01/2018
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000475-90
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Canada, Croatia, Egypt, France, Germany, Hungary, India, Israel, Italy, Lebanon, Poland, Russian Federation, Spain, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Clinical Trial Information Contact
• Affiliation: Daiichi Sankyo Inc

• Name: Clinical Trial Information Contact
• Affiliation: Daiichi Sankyo Inc

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must satisfy all of the following criteria to be eligible for the study:

1.Children with cardiac diseases who are at risk for thromboembolic complications and require at least 3 months antithrombotic anticoagulant prophylaxis. Either one of the following:
a.Children with cardiac disease who have a history of cardiac shunt occlusion/thrombosis, with shunt still in place (secondary prevention).
OR
b.Children with cardiac disease who require (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.1 Some examples of cardiac conditions at risk of thrombosis are Fontan surgery, heart failure, and Kawasaki disease, and Blalock-Taussig and Glenn surgery.

2.Male or female children 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.

3.Subject and/or parent(s)/legal guardian(s) or legally acceptable representative is informed and provides signed consent for the child to participate in the study with edoxaban treatment. Pediatric subjects 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.

4.Female subjects of childbearing potential must test negative for pregnancy at Screening and must consent to avoid becoming pregnant by using a locally approved contraception method throughout the study. For locally approved contraceptive methods.
Are the trial subjects under 18? yes
Number of subjects for this age range: 150
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects who meet any of the following criteria will be disqualified from entering the study:

1.Subjects with evidence of symptomatic venous or arterial thrombosis and/or asymptomatic intracardiac thrombosis confirmed by a transthoracic echocardiogram during study screening period.Note: Valid echocardiograms are images taken within 5 weeks prior to Randomization Visit.

2.Subjects with mechanical heart valves.

3.Subjects with active bleeding or high risk of bleeding contraindicating treatment with anticoagulant.

4.Co-administration of antithrombotic therapy is contraindicated in edoxaban arm and SOC arm except for low dose aspirin defined as 1 to 5 mg/kg/day with maximum of 100 mg/day.

5.Subjects with hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk (aPTT >50 seconds or international normalized ratio [INR] >2.0 not related to anticoagulation therapy) or ALT >5 × the upper limit of normal (ULN) or total bilirubin (TBL) >2 × ULN with direct bilirubin >20% of the total at Screening.

6.Subjects with estimated glomerular filtration rate (eGFR) <30% of normal for age and size.

7.Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or diastolic confirmed >99th percentile plus 5 mmHg.

8.Subjects with thrombocytopenia (thrombocytes <50 × 109/L).

9.Subjects with Fontan procedure with a history of or signs/symptoms suggestive of protein-losing enteropathy.

10.Subjects with a life expectancy less than the expected study duration (3 months).

11.Subjects who are known to be pregnant or breastfeeding.

12.Subjects with any condition that, as judged by the Investigator, would place the subject at increased risk of harm if he/she participated in the study.

13.Subjects with a contraindication to the use of heparin and/or VKA (UFH or LMWH) and/or VKA


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

thromboembolism
MedDRA version: 20.0 Level: LLT Classification code 10043566 Term: Thromboembolism System Organ Class: 100000004866

Intervention(s)

Trade Name: Lixiana 15 mg film-coated tablets
Product Code: DU176B
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: EDOXABAN (as anhydrous free form
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Trade Name: Lixiana 30 mg film-coated tablets
Product Code: DU176B
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: EDOXABAN (as anhydrous free form)
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Product Name: Edoxaban
Product Code: DU176B
Pharmaceutical Form: Granules for oral suspension
INN or Proposed INN: EDOXABAN (as anhydrous free form)
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Trade Name: Clexane® Syringes 2,000 IU (20 mg)/0.2 ml solution for injection
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ENOXAPARIN SODIUM
CAS Number: 9041-08-1
Concentration unit: anti-Xa IU anti-Xa activity International Unit(s)
Concentration type: equal
Concentration number: 2,000-

Trade Name: Clexane® Syringes 4,000 IU (40 mg)/0.4 ml solution for injection
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ENOXAPARIN SODIUM
CAS Number: 9041-08-1
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 4,000-

Trade Name: Clexane® Syringes 6,000 IU (60 mg)/0.6 ml solution for injection
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ENOXAPARIN SODIUM
CAS Number: 9041-08-1
Concentration unit: IU international unit(s)
Concentr

Primary Outcome(s)

Primary end point(s): The primary safety endpoint is a combination of major bleeding events and CRNM bleeding events per ISTH definition occurring on treatment (ie, during treatment or within 3 days of completing or interrupting or stopping study treatment during the first 3-month treatment period).

Secondary Objective: -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 during the first 3-month treatment period plus 3 days and occurring from randomization to the last dose plus 30 days.
-To compare the efficacy of edoxaban against SOC with regard to death as a result of a TE occurring from randomization to the last dose plus 30 days.
-To compare edoxaban against SOC with regard to the composite combination of major and CRNM bleedings from first to the last dose plus 30 days.
-To compare the safety of edoxaban against SOC with regard to all bleedings which occur from first to the last dose plus 30 days.
Please refer to remaining text on page 4 of the protocol Version 1.0 dated 27 June 2017.

Timepoint(s) of evaluation of this end point: 3 month treatment period.
Analysis of Primary Safety Endpoint:
-A descriptive statistical analysis will be performed for the primary safety endpoint, ie, the composite of major and CRNM bleeding events which occurred on-treatment from the date of first study treatment to the Month 3 Visit plus 3 days. An event will be considered an “on-treatment” event if it occurred while on study drug or within 3 days of randomized study drug interruption or discontinuation. This analysis will be based on CEC adjudication results.
Please refer to remainder text on page 15 of the protocol

Main Objective: The primary objective is to compare the safety of edoxaban with the 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) bleedings per International Society on Thrombosis and Haemostasis [ISTH] definition occurring on treatment (ie, during treatment or within 3 days of completing, interrupting or stopping study treatment during the first 3-month treatment period).

Secondary Outcome(s)

Secondary end point(s): The secondary safety endpoints are:
-A combination of major and CRNM bleedings from first to the last dose plus 30 days.

-All bleeding events from first dose to the last dose plus 30 days.

-All bleeding events occurring on-treatment (during treatment or within 3 days of completing or interrupting or stopping study treatment during the first 3-month treatment period).

The secondary efficacy endpoints are:
-The combination of symptomatic TE in the systemic arterial or venous pathways including DVT, PE, stroke, intracardiac thrombus and MI, and asymptomatic intracardiac thrombus identified by cardiac imaging, which occur from randomization to 3 months of treatment plus 3 days.

-The combination of symptomatic TE in the systemic arterial or venous pathways including DVT, PE, stroke, intracardiac thrombus and MI, and asymptomatic intracardiac thrombus identified by cardiac imaging, which occur from randomization to the date of the last dose of study drug plus 30 days.

-Deaths as a result of TE which occurs from randomization to the date of the last dose of study drug plus 30 days.

-All-cause mortality from randomization to last dose plus 30 days.

Pharmacokinetic (PK)/Pharmacodynamic (PD)/Biomarker Endpoint(s)
-Plasma concentrations of edoxaban and its metabolite, D21-2393, will be assessed in subjects who receive at least 1 dose of edoxaban treatment and have measurable concentrations of edoxaban and/or D21-2393. Population PK analysis will be conducted to characterize the PK profiles of edoxaban in this target subject population.

-The PD biomarkers of coagulation, PT, aPTT, and anti-activated Factor X (FXa) will be assessed as secondary endpoints in edoxaban-treated subjects.

-Other biomarkers may be tested related to coagulation and/or edoxaban’s mechanism of action.

Timepoint(s) of evaluation of this end point: Analysis of Secondary Safety and Efficacy Endpoints:
-The incidence, annualized event rate, and rate difference between edoxaban and SOC treatment groups of other secondary safety and efficacy endpoints will be summarized by treatment group.
-The incidence, annualized event rate, and rate difference of the safety and efficacy endpoints of Main Treatment Period and period of previous anticoagulant regimen will be summarized.

Exploratory Analysis:
-Quality of life will be assessed using validated questionnaires.
-Intrapatient safety (Investigator reported bleeding) and efficacy (Investigator reported TE) during treatment period will be compared with the previous 3-month pre-randomization period of anticoagulant regimen.
Please refer to remainder text on pages 15 &16 of the protocol.

Secondary ID(s)

2017-000475-90-GB

DU176b-C-U313

Source(s) of Monetary Support

Daiichi Sankyo Inc

Ethics review

Status: Approved
Approval date: 15/01/2018
Contact: