| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043566 |
| E.1.2 | Term | Thromboembolism |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 in the Main Treatment Period:
from the date of first dose of study drug to Month 3 Visit, or to the date of last dose of study drug plus 3 days if study treatment id discontinued, whichever is earlier. |
|
| E.2.2 | Secondary objectives of the trial |
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,
systemic embolic event (SEE), myocardial infarction (MI), and
asymptomatic intracardiac thrombus identified by cardiac imaging
occurring from randomization to Month 3 Visit.
To compare the safety of edoxaban against SOC with regard to all
bleedings that occur in the Main Treatment Period: from the date of first
dose of study drug to Month 3 Visit, or to the date of last dose of study
drug plus 3 days if study treatment is discontinued, whichever is earlier.
To compare the efficacy of edoxaban against SOC with regard to death
as a result of a TE occurring from randomization to Month 3 Visit.
-Please refer to remaining text in section 2.1.2.1 of the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 criteria may apply:
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 Randomization and must consent to avoid becoming pregnant by using a locally approved contraception method throughout the study. For locally approved contraceptive methods.
5.If the subject has a history of thromboembolic Event (TE) that meets all of the following criteria:
-old,organized and /or resolved per the discretion of the Principal Investigator (confirmed of an old, organized and or resolved TE is not required by any imaging studies and
-The subject is asymptomatic and
- The subject continues to require at least 3 months of anti -coagulation treatment , and
-There is no intracardiac thrombus or thrombi on the screening echo , and
-all other inclusion and exclusion criteria are met. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the study:
1.Subjects with a history of the following up to randomization
-symptomatic venous or arterial/TE.
-Asymptomatic venous or arterial TE found by routine imaging.
-Asymptomatic intracardiac thrombosis confirmed by an echocardiogram during study screening period.Note: Valid
echocardiograms are defined here as 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. Subjects with a contraindication to the use of heparin (UFH or LMWH)
and/or VKA.
5.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.
6.Administration of rifampin is prohibited during the study and subjects
on concomitant use of rifampin are excluded.
7a.Subjects with severe hepatic impairment or hepatic disease associated with coagulopathy ( e.g. acute hepatitis, chronic active hepatitis, and cirrhosis)
b) subjects with ALT >5 × the upper limit of normal (ULN) or total bilirubin (TBL) >2 × ULN with direct bilirubin >20% of the total at Screening.
c) Subjects with aPTT>50 seconds or international normalised ratio [INR] >2.0 nor related to anticoagulation therapy at screening.
8.Subjects with estimated glomerular filtration rate (eGFR) <30% of
normal for age and size.
9.Subjects with stage 2 hypertension defined as blood pressure (BP)
systolic and/or diastolic confirmed >99th percentile plus 5 mmHg.
10.Subjects with thrombocytopenia (thrombocytes <50 × 109/L).
11.Subjects with Fontan procedure with a history of or signs/symptoms
suggestive of protein-losing enteropathy.
12.Subjects with a life expectancy less than the expected study duration
(3 months).
13.Subjects who are known to be pregnant or breastfeeding.
14. Subjects who are not using an approved method of contraception.
15.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 including contraindicated medications identified.
16.Subject who participated in another interventional clinical study or treated with an
experimental therapy with less than a 30-day washout period prior to
the Screening Visit.
17. If any imaging is performed prior to randomization and results show a newly detected unorganized thrombus, these subjects are NOT eligible for the study.
18. Hypersensitivity to the active ingredient or to any of the excipients of any components of the trial treatment.
19.Patients with a history of thrombosis who are diagnosed with anti-phospholipid syndrome who are triple positive (for lupus anticoagulant, anti cardiolipin antibodies , and anti- beta 2-glycoprotein I antibodies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary safety endpoint is a combination of major bleeding events
and CRNM bleeding events per ISTH definition occurring during the Main
Treatment Period: from the date of first dose of study drug to Month 3
Visit, or to the date of last dose of study drug if study treatment is
discontinued. |
|
| E.5.1.1 | 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 for the Main Treatment Period will be summarized by
treatment group.
-The incidence and annualized event rate of other secondary safety and
efficacy endpoints of for the extension Period will be summarized for
the edoxaban treatment group.
Exploratory Analysis:
-Quality of life will be assessed using validated questionnaires.
Please refer to remainder text on pages 31 &32 of the protocol. |
|
| E.5.2 | Secondary end point(s) |
Point (repeat as necessary)
-All bleeding events occurring during the Main Treatment Period, from
the date of first dose of study drug to Month 3 Visit, or to the date of last
dose of study drug if study treatment is discontinued.
-A combination of major and CRNM bleedings from the day after Month 3
Visit to the date of the last dose of study medication plus 30 days for
subjects who participate in the Extension Period.
-All bleeding events from the day after the Month 3 Visit to the date of
last dose of study medication plus 30 days for subjects who participate
in the Extension Period.
The secondary efficacy endpoints are:
-The combination of symptomatic TE in the systemic arterial or venous
pathways including DVT, PE, stroke, intracardiac thrombus,SEE and MI,
and asymptomatic intracardiac thrombus identified by cardiac imaging,
that occur from randomization to Month 3 Visit.
- Deaths as a result of TE that occurs from randomization to Month 3
Visit.
-All-cause mortality from randomization to Month 3 Visit.
-The combination of symptomatic TE in the systemic arterial or venous
pathways and asymptomatic intracardiac thrombus identified by cardiac
imaging, that occur from the day after the Month 3 Visit to the date of
the last dose of study drug plus 30 days for subjects who participate in
the Extension Period.
-Deaths as a result of TE that occurs from the day after Month 3 Visit to
the date of the last dose of study drug plus 30 days for subjects who
participate in the Extension Period.
-All-cause mortality from the day after the Month 3 Visit to the date of
the last dose of study drug plus 30 days for subjects who participate in
the Extension Period.
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. |
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Canada |
| Croatia |
| Egypt |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Lebanon |
| Poland |
| Russian Federation |
| Spain |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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