A large study in kids from birth to 18 years of age that have a clot in their lungs, limbs, to test a new drug (edoxaban) compared to current drugs used for treatment and to prevent further clots in your body

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2018/01/011249
• Date of registration: 10-01-2018
• Prospective Registration: Yes
• Primary sponsor: Daiichi Sankyo Inc
• Public title: A large study in kids from birth to 18 years of age that have a clot in their lungs, limbs, to test a new drug (edoxaban) compared to current drugs used for treatment and to prevent further clots in your body
• 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: 30-01-2018
• Target sample size: 274
• Recruitment status: Open to Recruitment
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=22178
• Study type: Interventional
• Study design: Randomized, Parallel Group, Active Controlled Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:Centralized Blinding and masking:Open Label
• Phase: Phase 3

Countries of recruitment

Argentina, Brazil, Bulgaria, Canada, Chile, Croatia, Czech Republic, Denmark, Egypt, France, Germany, Hungary, India, Israel, Italy, Kenya, Lebanon, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Serbia , Singapore, Slovenia, Spain, Taiwan, Thailand, Turkey, Ukraine, United States of America

Contacts

• Name: Suneela Thatte
• Affiliation: IQVIA RDS (India) Private Limited

• Name: Suneela Thatte
• Affiliation: IQVIA RDS (India) Private Limited

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 berequired 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


Exclusion criteria: 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 Ã? the upper limit of normal (ULN) or total bilirubin > 2 Ã? 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 Ã? 109/L at Screening Visit. Subjects with a history of heparin induced thrombocytopenia may be enrolled in the study at the Investigatorâ??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:

Health Condition(s) or Problem(s) studied

Health Condition 1: I824- Acute embolism and thrombosis of deep veins of lower extremity

Intervention(s)

Intervention1: Intervention
Edoxaban Treatment arm

: (12 to 18 years old) will receive tablets (15 and/or 30 mg strength. Orally once a day for 3 months (with option for extended treatment for additional 9 months ).

Subjects younger than 12 years of age will receive edoxaban granules for oral suspension. In each cohort, doses will be selected to elicit target exposures comparable to those achieved from adult doses of 60 mg if no dose adjustment needed.
Dosing regimen will be determined from Phase 1 single dose study U157 and population based PK.

Control Intervention1: Comparator
Standard of Care (SoC)Treatment Arm
: SoC treatment will be dispensed to the subject on a monthly visit
schedule. Subjects will receive SOC anticoagulant according to the siteâ??s SOC treatment, as follows (alone or combination):
- LMWH (alone or followed with VKA)
- SP Xa inhibitors (alone or followed with VKA)
- Vitamin K antagonist (VKA)In case of centrally sourced SOC treatment, the Sponsor will only provide enoxaparin as LMWH, fondaparinux as SP Xa inhibitor, or warfarin as VKA with limited presentations. The subject will be treated with enoxaparin or fondaparinux or warfarin/heparin, with the following suggestion:
- Enoxaparin â?? Subjects will be treated with enoxaparin alone or can be switched to warfarin anytime during the study treatment period.
- Enoxaparin will be provided as solution for subcutaneous (SC) injection in pre-filled syringes with only 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL concentration or in multiple dose vials (300 mg/3.0 mL) for injection.
- Fondaparinux â?? Subjects will be treated with fondaparinux alone or can be switched to warfarin anytime during the study treatment period.
- Fondaparinux will be supplied as solution for SC injection in pre-filled sy

Primary Outcome(s)

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.

Timepoint: 3 months

Secondary Outcome(s)

- To compare edoxaban against SOC with regard to the composite efficacyendpoint as described in the primary objective from randomization to the lastdose plus 30 days.Timepoint: first to the last dose plus 30 days

- To characterize the effect of edoxaban on biomarkers of coagulation (ie, prothrombin time [PT], activated partial thromboplastin time [aPTT], and anti-activated factor X [anti-FXa]).Timepoint: During the entire study

- To compare edoxaban against SOC with regard to composite combination of major and CRNM bleedings from first to the last dose plus 30 days.Timepoint: first to the last dose plus 30 days.

- To evaluate the relationship between edoxaban exposure and safety (such as bleeding) and efficacy (thromboembolic events).



Timepoint: During the entire study

- To compare edoxaban against SOC with regard to a combination of major and CRNM bleedings and symptomatic recurrent VTE, and death as result of VTE which occur from first to the last dose plus 30 days.



Timepoint: first to last dose plus 30 days

- To compare edoxaban against SOC with regard to all bleedings which occur from first to the last dose plus 30 daysTimepoint: first to the last dose plus 30 days

- To compare edoxaban against SOC with regard to all-cause mortality from randomization to the last dose plus 30 days.Timepoint: randomization to the last dose plus 30 days.

- To characterize the multiple dose pharmacokinetics of edoxaban in pediatric subjects at Day 5 using population pharmacokinetic (PK) analysis (apparent systemic clearance [CL/F] and apparent volume of distribution [V/F]) and to assess the effect of covariates such as age, body weight, and renal function on the PK of edoxaban.Timepoint: Day 5

- To compare edoxaban against SOC with regard to individual components of the composite efficacy endpoints as described in the primary objective during the first 3-month treatment period.Timepoint: 3 months

- To compare edoxaban against SOC with regard to occurrence of DVT, catheter-related thrombosis, sinovenous thrombosis within and after thefirst 3-month treatment periodTimepoint: 3 months

- To compare edoxaban against SOC with regard to the combination of major and clinically relevant non-major (CRNM) bleedings occurring during treatment or within 3 days of completing or interrupting or stopping study treatment during the first 3-month treatment period.Timepoint: During treatment or within 3 days of completing or interrupting or stopping study treatment during the first 3-month treatment period.

Secondary ID(s)

DU176b-D-U312 Protocol Version 3.0, IN1 dated 16-AUG-2019

Source(s) of Monetary Support

Daiichi Sankyo, Inc. 399 Thornall Street Edison, NJ 08837 United States

Secondary Sponsor(s)

Quintiles Research India Pvt Ltd

Ethics review

Status: Approved
Approval date: 14/02/2017
Contact:

Nirmal Hospital Private limited Ethics Committee, Nirmal Hospital Pvt ltd, Ring Road, Surat 395002, Gujarat, India

Status: Approved
Approval date: 24/08/2017
Contact:

Ethics Committee, Sir Ganga Ram Hospital, Sir Ganga Ram Hospital, Marg, Rajinder Nagar, New Delhi - 110060, India

Status: Approved
Approval date: 04/09/2017
Contact:

HM Patel Centre for Medical Care and Education Karamsad

Status: Approved
Approval date: 05/08/2019
Contact:

Institutional Ethics Committee Christian Medical College & Hospital Ludhiana â?? 141008, Punjab, India. Institutional Ethics Committee

Status: Not Approved
Approval date:
Contact:

Institutional Ethics committee (IEC) Department of Pharmacology, Government Medical College, Nagpur-440003, Maharashtra, India

Status: Not Approved
Approval date:
Contact:

Institutional Ethics Committee- Clinical Studies, Indraprastha Apollo Hospitals, New Delhi, Mathura Roads, Sarita Vihar, Delhi- 2110076, India

Status: Not Approved
Approval date:
Contact:

Institutional Ethics Committee, Institute of Child Health, 11. Dr. Biresh Guha Street, Kolkata 700017, West Bengal, India.