A Phase 3, Open-Label, Study to Evaluate Pharmacokinetics and Pharmacodynamics of Edoxaban and to compare the safety and efficacy of Edoxaban with standard of care treatment in Paediatric Patients confirmed as requiring treatment for a blood clot

• Register: EUCTR
• Last refreshed on: 14 November 2016
• Main ID: EUCTR2016-000991-49-ES
• Date of registration: 10/11/2016
• Prospective Registration: No
• Primary sponsor: Daiichi Sankyo, Inc.
• Public title: A Phase 3, Open-Label, Study to Evaluate Pharmacokinetics and Pharmacodynamics of Edoxaban and to compare the safety and efficacy of Edoxaban with standard of care treatment in Paediatric Patients confirmed as requiring treatment for a blood clot
• Scientific title: A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER, CONTROLLED TRIAL TO EVALUATE THE PHARMACOKINETICS AND PHARMACODYNAMICS OF EDOXABAN AND TO COMPARE THE EFFICACY AND SAFETY OF EDOXABAN WITH STANDARD OF CARE ANTICOAGULANT THERAPY IN PEDIATRIC SUBJECTS FROM BIRTH TO LESS THAN 18 YEARS OF AGE WITH CONFIRMED VENOUS THROMBOEMBOLISM (VTE)
• Date of first enrolment: 05/11/2016
• Target sample size: 274
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000991-49
• 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

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czech Republic, Denmark, Egypt, France, Germany, Greece, 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, Thailand, 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 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 < 2.0.

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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 274
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 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. 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 > 2 × ULN with direct bilirubin > 20% of the total at Screening Visit.

5. Subjects with glomerular filtration rate (GFR) < 30% of normal for age and size as determined by the Schwartz formula.

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

7. 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.

8. Life expectancy less than the expected study treatment duration (3 months).

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

10. 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.


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

Health Condition(s) or Problem(s) studied

venous thromboembolism
MedDRA version: 19.0 Level: LLT Classification code 10066899 Term: Venous thromboembolism System Organ Class: 100000004866

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

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: millilitre(s)/gram
Concentration type: equal
Concentration number: 60-

Pharmaceutical Form: Solution for injection

Product Name: fondaparinux
Pharmaceutical Form: Solution for infusion in pre-filled syringe
INN or Proposed INN: FONDAPARINUX SODIUM
CAS Number: 114870-03-0
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: range
Concentration number: 5.0-12.5

Pharmaceutical Form: Tablet

Primary Outcome(s)

Secondary Objective: - 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

Main Objective: 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.

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.

Timepoint(s) of evaluation of this end point: 3 month treatment period

Secondary Outcome(s)

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 0.5 to 2 hours post-dose
or
any time between 3 to 8 hours post-dose

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:
Will apply only in the 60 subjects in front-end multiple dose assessment

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.

Secondary ID(s)

DU176b-D-U312

2016-000991-49-HU

Source(s) of Monetary Support

Daiichi Sankyo, Inc.