Rivaroxaban for Children Aged Over 2 Years With Giant Coronary Artery Aneurysms After Kawasaki Disease

Official title

Rivaroxaban Versus Warfarin for Thromboprophylaxis in Children Aged Over 2 Years With Giant Coronary Artery Aneurysms After Kawasaki Disease: a Multicenter, Open-label, Parallel, Exploratory, Randomized Controlled Trial

Overview

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 aged over 2 years with giant coronary artery aneurysms after Kawasaki disease

Detailed 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. In the previous pilot study, this optimized dosing regimen demonstrated a favorable feasibility among 11 Chinese pediatric patients aged over 2 years with giant coronary artery aneurysm after Kawasaki disease, with no thrombosis or major bleeding over 6 months.

This study is a multicenter, open-label, exploratory, randomized controlled trial to evaluate the feasibility, safety and effectiveness of rivaroxaban for thromboprophylaxis in children aged over 2 years with giant coronary artery aneurysms after Kawasaki disease, following the 15 mg-equivalent dosing regimen. Participants will be randomly assigned to the control or experimental groups. Randomization ratio will be 2:1. 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 between warfarin and rivaroxaban

Interventions

• 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
• Drug Aspirin or Clopidogrel
  Aspirin \[3 \~5mg/(kg·d) once daily\] or Clopidogrel \[1.0 mg/kg; once daily\]
• Drug Warfarin
  Warfarin 0.05\~0.12 mg/(kg·d) once daily. INR should maintain within 1.5 to 2.5

Primary outcome measures

• Composite of new thrombosis in coronary arteries, major bleeding, clinically relevant non-major bleeding event or major adverse cardiovascular event [Time frame: From Day 1 of treatment to the third month after treatment initiation]

Secondary outcome measures (12)

• Occurrence of new thrombosis in coronary arteries [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Time to first new thrombosis in coronary arteries [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Composite of Major bleeding or Clinically relevant non-major bleeding event [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Occurrence of major bleeding [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Occurrence of clinically relevant non-major bleeding (CRNM) [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Occurence of patient important bleeding, no intervention (PIBNI) [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Occurence of minor bleeding [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Occurrence of major adverse cardiovascular event [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Time to major adverse cardiovascular event [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Any adverse events [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Plasma concentration of rivaroxaban at specific timepoints [Time frame: From Day 1 of treatment to the third month after treatment initiation]
• Anti-factor Xa activity at specific timepoints [Time frame: From Day 1 of treatment to the third month after treatment initiation]

Eligibility criteria

Inclusion criteria

• 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;
• Anticoagulant with antiplatelet drug therapy for anti-thromboprophylaxis is recommended for the next 3 months;
• Participant should be able to tolerate oral feeding, nasogastric or gastric feeding;
• Children aged ≥ 2 years

Exclusion criteria

• Active bleeding or bleeding risk contraindicating anticoagulant therapy
• With history of venous thromboembolism or risk factors related with venous thromboembolism, like congenital heart disease, carcinoma, central venous catheter or long-term immobilization.
• Thrombus within giant coronary aneurysm was confirmed by previous imaging examinations, including two-dimensional echocardiography, computed tomography angiography in coronary artery or coronary angiography
• An eGFR <30mL/min/1.73 m2 (For children younger than 1 year, serum creatinine results above 97.5th percentile)
• Platelet count < 100 x 109/L
• 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
• Sustained uncontrolled hypertension defined as systolic and/or diastolic blood pressure >95 th age percentile
• 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)
• Concomitant use of strong inducers of CYP3A4, including but not limited to rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine
• Hypersensitivity or any other contraindications listed in the local labeling for the comparator treatment or experimental treatment
• Inability to cooperate with the study procedures and follow-up visits
• Refuse to provide informed consent eGFR, estimated glomerular filtration rate; ULN, upper level of normal; TB, total bilirubin; CYP3A4, cytochrome P450 isoenzyme 3A4

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

China · 1 center

• Children's Hospital of Fudan University — Shanghai

Identifiers

NCT: NCT05643651 · 2022-399

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗