| 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 |
| Blood clot (s) in the vein |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066899 |
| E.1.2 | Term | Venous 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 demonstrate the non-inferiority of edoxaban to standard of care (SOC; including low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors) in the treatment and secondary prevention of VTE in pediatric subjects with regard to the composite efficacy endpoint (ie, symptomatic recurrent VTE, death as result of VTE, and no change or extension of thrombotic burden) during the first 3-month treatment period.
|
|
| E.2.2 | Secondary objectives of the trial |
- To compare edoxaban vs SOC:
during the first 3-month treatment period as regards:
• a combination of major and CRNM bleedings occurring during or within 3 days of completing, interrupting or stopping treatment
• the individual components of the composite efficacy endpoints
from first to the last dose + 30 days as regards:
• the occurrence of DVT, catheter-related thrombosis, PE, sinovenous thrombosis
• a combination of major and CRNM bleedings, symptomatic recurrent VTE, and death due to VTE
• all bleedings
• a composite combination of major and CRNM bleedings
from randomization to the last dose + 30 days as regards:
• the composite efficacy endpoint
• all-cause mortality
- To characterize the multiple dose PK of edoxaban and to assess the effect of certain covariates on the edoxaban PK
- To evaluate the relationship between edoxaban exposure and safety and efficacy
- To characterize the effect of edoxaban on biomarkers of coagulation
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study:
1. Male or female pediatric subjects between birth (defined as 38 weeks gestational age) and less than 18 years of age at the time of consent.
2. Pediatric subjects with the presence of documented VTE confirmed by appropriate diagnostic imaging and requiring anticoagulant therapy for at least 90 days.
3. Subjects must have received at least 5 days of heparin (LMWH or SP Xa inhibitors or UFH according to the edoxaban label for VTE treatment) therapy prior to randomization to treat the newly identified index VTE. In addition, prior to being randomized to edoxaban or SOC, subjects initially treated with VKA are
recommended to have an INR < 2.5.
4. 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.
5. Female subjects who have menarche must test negative for pregnancy at Screening and must consent to avoid becoming pregnant by using an approved contraception method throughout the study. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the
study:
1. Subjects with active bleeding or high risk of bleeding contraindicating treatment with LMWH, SP Xa inhibitors, VKAs, or direct oral anticoagulants (DOACs; identified high risk of bleeding during prior experimental administration of DOACs).
2. Subjects who have been or are being treated with thrombolytic agents, thrombectomy or insertion of a caval filter for the newly identified index VTE.
3. Administration of antiplatelet therapy is contraindicated in both arms except for low dose aspirin defined as 1-5 mg/Kg/day with maximum of 100 mg/day.
4. Administration of rifampin is prohibited during the study and subjects on concomitant use of rifampin are excluded.
5a. Subjects with severe hepatic impairment or hepatic disease associated with coagulopathy (eg acute hepatitis, chronic active hepatitis, and cirrhosis).
b. Subjects with ALT > 5 × the upper limit of normal (ULN) or total bilirubin > 2 × ULN with direct bilirubin > 20% of the total at Screening Visit.
c. Subjects with aPTT > 50 seconds or international normalized ratio [INR] > 2.0 not related to anticoagulation therapy.
6. Subjects with estimated glomerular filtration rate (GFR) < 30% of normal for age and size as determined by the Schwartz formula.
7. Subjects with stage 2 hypertension defined as blood pressure (BP) systolic and/or diastolic confirmed > 99th percentile + 5 mmHg.
8. Subject with thrombocytopenia < 50 × 109/L at Screening Visit. Subjects with a history of heparin-induced thrombocytopenia may be enrolled in the study at the Investigator’s discretion.
9. Life expectancy less than the expected study treatment duration (3 months).
10. Subjects who are known to be pregnant or breastfeeding.
11. 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 in Appendix 17.4
12. Subjects who participated in another interventional clinical study or were treated with an experimental therapy with less than a 30-day washout period prior to identifying the qualifying index VTE.
13. Hypersensitivity to the active ingredient or to any of the excipients of any components of the trial treatment.
14. Patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the composite endpoint consisting of incidence of symptomatic recurrent venous thromboembolic disease, death as result of VTE, and no change or extension of thrombotic burden (as defined in the protocol) during the first 3-months period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include:
A composite endpoint consisting of the incidence of symptomatic recurrent venous thromboembolic disease, death as a result of VTE, and no change or extension of thrombotic burden from randomization to the date of the last dose
of study drug + 30 days.
The individual components of the primary efficacy endpoint during the first 3 month period:
Symptomatic recurrent VTE
Death as a result of VTE
No change or extension of thrombotic burden.
All-cause mortality from randomization to last dose + 30 days.
The DVT, Catheter-related thrombosis, PE, and sinovenous thrombosis events within and after the first 3-month treatment period.
Net Clinical Outcome Endpoint:
Composite of symptomatic recurrent VTE events, death as a result of VTE, and major and CRNM bleeding that occurred from the date of the first dose of study drug to the date of last dose of study drug + 30 days.
Safety Endpoints:
The safety endpoints are:
A combination of major and clinically relevant non- major (CRNM) bleedings occurring during treatment or within 3 days of completing or interrupting or stopping study during the first 3- month treatment period.
All bleedings from first to the last dose + 30 days.
A combination of major and CRNM bleedings from first to the last dose + 30 days.
Pharmacokinetic and Pharmacodynamic Endpoints:
Approximately, the first 12 subjects of each age cohort (total of approximately 60 subjects) randomized to the edoxaban treatment arm
will participate in the multiple-dose PK/PD assessment on Day 5
Pharmacokinetics:
Using population PK analysis, the following PK parameters will be estimated: apparent systemic
clearance (CL/F) and apparent volume ofdistribution (V/F) of edoxaban.
Pharmacodynamics:
The following biomarkers of coagulation will be
estimated: PT, aPTT, anti-FXa for edoxaban treatment arm. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoints:
3 month treatment period
randomization to last dose + 30 days
Net Clinical Outcome:
first dose of study drug to the date of last dose of study drug + 30 days
Safety Endpoints:
during treatment or within 3 days of completing or interrupting or stopping study during the first 3- month treatment period. From first to the last dose + 30 days
PK/PD endpoints:
Day of the fifth dose of edoxaban (Day 5+3 days)
Pre-dose sample.
Post-dose sample can be taken either:
any time between 1.0 to 3 hours post-dose
or
any time between 5 to 8 hours post-dose |
|
| 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 | 43 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Croatia |
| Czech Republic |
| Denmark |
| Egypt |
| El Salvador |
| France |
| Germany |
| Greece |
| Guatemala |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Kenya |
| Korea, Democratic People's Republic of |
| Lebanon |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Panama |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
