Rivaroxaban for Children With Giant Coronary Artery Aneurysms After Kawasaki Disease

Kawasaki Disease Clinical Trial

Official title:

Rivaroxaban Versus Warfarin for Thromboprophylaxis in Children With Giant Coronary Artery Aneurysms After Kawasaki Disease: a Multicenter, Open-label, Parallel, Exploratory, Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05643651
• Other study ID #: KD-GCAA-RW
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: March 1, 2024
• Est. completion date: March 1, 2026

Study information

• Verified date: January 2024
• Source: Children's Hospital of Fudan University
• Contact: Fang Liu, MD
• Phone: 18017590880
• Email: liufang[@]fudan.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Based on population pharmacokinetic model-based simulation, a 15 mg-equivalent, age-, and bodyweight-adjusted dosing regimen for Chinese children with giant coronary artery aneurysms after acute Kawasaki disease was proposed. This exploratory trial aims to evaluate the feasibility, safety and effectiveness of rivaroxaban compared to warfarin for thromboprophylaxis in children with giant coronary artery aneurysms after Kawasaki disease

Description:

Lifelong anticoagulant treatment is required in children with giant coronary artery aneurysm after Kawasaki disease, imposing social and psychologic burdens on patients and parents. Rivaroxaban is a potential oral anticoagulant in this population. Considering the impact of ethnic difference and growth development, we proposed a Chinese-specific, optimized dosing regimen based on model- and clinical evidence-informed precision dosing.

This study is a multicenter, open-label, exploratory, randomized controlled trial to evaluate the feasibility, safety and effectiveness of rivaroxaban for thromboprophylaxis in Chinese children with giant coronary artery aneurysms after Kawasaki disease, following the 15 mg-equivalent, age-, and bodyweight-adjusted dosing regimen. Participants will be randomly assigned to the control or experimental groups. Randomization ratio will be 1:1. The control group will receive warfarin plus aspirin or clopidogrel, and the experimental group will receive Rivaroxaban plus aspirin or clopidogrel. Baseline characteristics, treatment effect outcomes, bleeding events, adverse events and compliance of intervention of each participant will be collected.

Because this is an exploratory study and the low incidence of giant coronary artery aneurysm in children with Kawasaki disease, the study plans to recruit 100 participants. The aims include:

• The feasibility

• The safety and efficacy profile of the optimized, 15 mg-equivalent dosing regimen

• The group differences in safety and treatment effect for antithromboprophylaxis between warfarin and rivaroxaban

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: March 1, 2026
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

Inclusion Criteria:

1. Giant coronary artery aneurysm(s) in any coronary artery after acute stage of Kawasaki disease. Giant coronary artery aneurysm(s) should be confirmed by two-dimensional echocardiography and meet the diagnostic criteria of Z-score =10 or coronary artery internal diameter =8mm;

2. Anticoagulant with antiplatelet drug therapy for antithromboprophylaxis is recommended for the next 6 months;

3. Participant should be able to tolerate oral feeding, nasogastric or gastric feeding;

4. Children aged 1 Month to<18 years, bodyweight = 2600g.

Exclusion Criteria:

1. Active bleeding or bleeding risk contraindicating anticoagulant therapy

2. With history of venous thromboembolism or risk factors related with venous thromboembolism, like congenital heart disease, carcinoma, central venous catheter or long-term immobilization.

3. Thrombus within giant coronary aneurysm was confirmed by previous imaging examinations, including two-dimensional echocardiography, computed tomography angiography in coronary artery or coronary angiography

4. If taking warfarin before recruitment, INR should reach the target range (1.5-2.5) in three consecutive tests in the past month, and each test at least one week apart.

5. An eGFR <30mL/min/1.73 m2 (For children younger than 1 year, serum creatinine results above 97.5th percentile)

6. Platelet count < 100 x 109/L

7. Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or alanine aminotransferase > 5x ULN or total bilirubin > 2x ULN with direct bilirubin > 20% of the total

8. Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure >95 th age percentile

9. Concomitant use of strong inhibitors of both CYP3A4 and P-glycoprotein, including but not limited to all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically (fluconazole is allowed)

10. Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine

11. Hypersensitivity or any other contraindications listed in the local labeling for the comparator treatment or experimental treatment

12. Inability to cooperate with the study procedures and follow-up visits

13. Refuse to provide informed consent eGFR, estimated glomerular filtration rate; ULN, upper level of normal; TB, total bilirubin (TB); CYP3A4, cytochrome P450 isoenzyme 3A4

Related Conditions & MeSH terms

• Aneurysm
• Coronary Aneurysm
• Coronary Artery Aneurysm
• Kawasaki Disease
• Mucocutaneous Lymph Node Syndrome

Intervention

Drug:
• Rivaroxaban Oral Tablet [Xarelto]
Administered in an age- and bodyweight-adjusted, 15 mg-equivalent dose regimen proposed by model- and clinical evidence-informed precision dosing
• Aspirin or Clopidogrel
Aspirin [3 ~5mg/(kg·d) once daily] or Clopidogrel [0.2~1.0 mg/kg(<2 years old),1 mg/kg(=2 years old); once daily]
• Warfarin
Warfarin 0.05~0.12 mg/(kg·d) once daily. INR should maintain within 1.5 to 2.5

Locations

Country	Name	City	State
China	Children's Hospital of Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Fudan University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Plasma concentration of rivaroxaban at specific timepoint	For experimental group, plasma concentration of rivaroxaban concentration will be measured by high performance liquid chromatography tandem mass spectrometer if necessary.	From enrollment to the 6th month after treatment
Other	Anti-factor Xa activity at specific timepoint	For experimental group, anti-factor Xa activity will be measured by rivaroxaban calibrated chromogenic anti-factor Xa assay if necessary.	From enrollment to the 6th month after treatment
Primary	The number of coronary arteries with new thrombosis	It is count data. Every echocardiography conducted during study period will be assessed by masked sonographer. The masked sonographers will assess whether new thrombosis occurs in coronary arteries, and recorded the number of involved coronary arteries.	From enrollment to the 6th month after treatment
Secondary	Time to discovering new thrombosis in coronary arteries	It is time to event data. Every echocardiography conducted during study period will be assessed by masked sonographer. The masked sonographers will assess whether new thrombosis occurs in coronary arteries, and recorded the time to discovering new thrombosis in coronary arteries.	From enrollment to the 6th month after treatment
Secondary	Occurrence of major adverse cardiovascular event	It is binary variable. Major adverse cardiovascular event (MACE) includes unstable angina, acute myocardial infarction, stroke, hospitalization for heart failure, unplanned revascularization, cardiovascular death. If any of the MACEs occur during the study period, it will be recorded as 1; otherwise, it will be recorded as 0. The definition of each MACE refers to the following guidelines and consensus: 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Fourth universal definition of myocardial infarction, and 2023 ESC Guidelines for the management of acute coronary syndromes.	From enrollment to the 6th month after treatment
Secondary	Time to major adverse cardiovascular event	It is time to event data. Major adverse cardiovascular event (MACE) includes unstable angina, acute myocardial infarction, stroke, hospitalization for heart failure, unplanned revascularization, cardiovascular death. If any of the MACEs occur during the study period, the time to MACE will be recorded. The definition of each MACE refers to the following guidelines and consensus: 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Fourth universal definition of myocardial infarction, and 2023 ESC Guidelines for the management of acute coronary syndromes.	From enrollment to the 6th monthFrom enrollment to the 6th month after treatment
Secondary	Composite of Major bleeding or Clinically relevant non-major bleeding event	It is a binary variable. Major bleeding is defined as 1.Fatal bleeding; 2.Clinically overt bleeding associated with a decrease in Hgb of =20 g/L (2 g/dL) in a 24-h period; 3.Critical site bleeding, such as retroperitoneal, pulmonary, pericardial, intracranial, or otherwise involves the central nervous system; 4.Bleeding that requires an intervention via an invasive procedure; 5.Overt bleeding for which a reversal agent is administered.; Clinically relevant non-major bleeding event is defined as 1.Bleeding that results in a medical or procedural intervention not meeting major bleeding criteria, including a medication change (reducing, holding, or changing anticoagulation or addition of new medication) ; 2.Bleeding that results in hospitalization or increased level of care; 3.Overt bleeding for which a blood product is administered, and does not meet the criteria for major bleeding	From enrollment to the 6th month after treatment
Secondary	Any adverse events	It is a text variable. If any adverse events( including durg allergy, severe infection, hepatic dysfunction, renal dysfunction, hypertension, fatigue, abdominal pain or others) occur will be reported to the data and safety monitoring board. The detail of adverse event will be recorded, including classification of adverse event, time of occurrence, symptoms, treatment, resolution time, and outcome.	From enrollment to the 6th month after treatment
Secondary	Discontinuation anticoagulant due to regression of coronary artery lesions	It is a binary variable. During study period, researchers will assess and recommend to discontinue anticoagulant if coronary artery lesions regress, which will be confirmed by echocardiography, coronary artery computerized tomography angiography, or coronary artery angiography.	From enrollment to the 6th month after treatment
Secondary	Changes in Z-score of each coronary artery aneurysms	This is a repeated measurement. On day 0, an initial echocardiography will be performed by masked sonographer to assess coronary artery lesions. The maximum internal diameter of coronary artery lesion will be measured and recorded. With data of height, bodyweight and internal diameter, Z-score will be calculated according to Dallaire et. al (Journal of the American Society of Echocardiography, 2011, 24(1).) If multiple coronary artery aneurysms exists, internal diameter and Z-score will be measured, calculated and recorded separately. Repeated echocardiographies will be conducted at each scheduled visit (30±5 days?60±5 days?90±5 days?120±5 days?150±5 days?180±5 days).	From enrollment to the 6th month after treatment