Pharmacokinetic, Pharmacodynamic, Safety, and Efficacy Study of Rivaroxaban for Thromboprophylaxis in Pediatric Participants 2 to 8 Years of Age After the Fontan Procedure

Study Overview
=================
Brief Summary
-----------------
The Purpose of this study is to characterize the single and multiple-dose pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/ PD) profiles after oral rivaroxaban therapy administered to pediatric participants 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment (Part A) and to evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched to rivaroxaban 10 milligram [mg] once daily in adults) compared to acetylsalicylic acid (ASA), given once daily (approximately 5 milligram per kilogram [mg/kg]) for thromboprophylaxis in pediatric participants 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.

Detailed Description
-----------------
Part A: This part includes a 12-day Initial PK, PD, and Safety Assessment Period. Participants in Part A will not participate in Part B. Randomization in Part B of this study will begin once the cumulative data from the Initial PK, PD, and Safety Assessment Period in Part A are deemed acceptable by the Independent Data Monitoring Committee. Part A of the study will consist of an up to 21-day Screening Period, a 12-day Initial PK, PD, and Safety Assessment Period, a 12-month Open-Label Treatment Period, and a 30-day Follow-Up phone contact. Part B: Participants will be randomly assigned to two treatment groups and randomization ratio will be 2:1 for rivaroxaban and ASA. ASA will be used as control. There will be an up to a 21-day Screening Period, a 12 month Open-Label Treatment Period and a 30-day Follow-Up phone contact.

Official Title
-----------------
A Prospective, Open-Label, Active-Controlled Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Rivaroxaban for Thromboprophylaxis in Pediatric Subjects 2 to 8 Years of Age After the Fontan Procedure

Conditions
-----------------
Thrombosis

Intervention / Treatment
-----------------
* Drug: Rivaroxaban
* Drug: Acetylsalicylic Acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be considered to be clinically stable by the investigator and able to tolerate oral or enteral administration of a suspension formulation and oral/enteral feedings Satisfactory initial post-Fontan transthoracic echocardiographic Screening as defined in the Post-Fontan Echocardiographic Examination Research Protocol Parent/legally acceptable representative must sign an informed consent form (ICF) and child assent will also be provided, if applicable, according to local requirements Exclusion Criteria: Evidence of thrombosis, including those that are asymptomatic confirmed by post-Fontan procedure transthoracic echocardiogram, or other imaging techniques, during the Screening period of the study History of gastrointestinal disease or surgery associated with clinically relevant impaired absorption History of or signs/symptoms suggestive of protein-losing enteropathy Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant therapy, including a history of intracranial bleeding Platelet count less than (<)50*10^9/Liters (L) at Screening Estimated glomerular filtration rate (eGFR) <30 milliliters per minute per 1.73 meter square (mL/min/1.73m^2) Known clinically significant liver disease

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 8 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br> | Drug: Rivaroxaban<br>* Participants will receive oral suspension containing rivaroxaban 1 milligram per milliliter (mg/ml) twice daily in Part A and Part B. Following total daily doses of Rivaroxaban will be administered based on the weight of the participants: 7 to <8 kilogram (kg) will receive 2.2 milligram (mg); 8 to <10 kg will receive 3.2 mg; 10 to<12 kg will receive 3.4 mg; 12 to <20 will receive 4.0 mg and 20 to <30 will receive 5.0 mg.<br>|
| Experimental: Acetylsalicylic Acid<br> | Drug: Acetylsalicylic Acid<br>* Participants will receive 5 milligram per kilogram (mg/kg) of acetylsalicylic acid once daily up to 12 months in Part B.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Any Thrombotic Event (Venous or Arterial and Symptomatic or Asymptomatic) | Thrombotic event was defined as the appearance of a new thrombotic burden within the cardiovascular system on either routine surveillance or clinically indicated imaging, or the occurrence of a clinical event known to be strongly associated with thrombus (such as cardioembolic stroke, pulmonary embolism). The event included ischemic stroke, pulmonary embolism, venous thrombosis, arterial/intracardiac thrombosis, and other thrombosis. | Up to 12 months | 
| Plasma Concentration of Rivaroxaban at Day 1 (0.5-1.5 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 0.5-1.5 hours postdose | 
| Plasma Concentration of Rivaroxaban at Day 1 (1.5-4 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 1.5-4 hours postdose | 
| Plasma Concentration of Rivaroxaban at Day 4 (Up to 3 Hours Predose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: Up to 3 hours predose | 
| Plasma Concentration of Rivaroxaban at Day 4 (0.5-1.5 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 0.5-1.5 hours postdose | 
| Plasma Concentration of Rivaroxaban at Day 4 (1.5-4 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 1.5-4 hours postdose | 
| Plasma Concentration of Rivaroxaban at Day 4 (6-8 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 6-8 hours postdose | 
| Plasma Concentration of Rivaroxaban at Month 3 (Up to 3 Hours Predose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: Up to 3 hours predose | 
| Plasma Concentration of Rivaroxaban at Month 3 (0.5-1.5 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 0.5-1.5 hours postdose | 
| Plasma Concentration of Rivaroxaban at Month 3 (2.5-4 Hours Postdose) | Plasma rivaroxaban concentrations for Parts A and B were assessed. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 2.5-4 hours postdose | 
| Percentage of Participants With Bleeding Events | Bleeding events were categorized into major, clinically relevant non-major bleeding (CRNM), and trivial bleeding events. Major bleeding: overt bleeding and associated with a fall in hemoglobin of 2 gram per deciliter (g/dL) or more; or leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults; or occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or contributing to death. CRNM bleeding: overt bleeding not meeting the criteria for major bleeding but associated with: Medical intervention, or Unscheduled contact with a physician, cessation of study treatment, or Discomfort for the subject such as pain, or Impairment of activities of daily life. Trivial bleeding: any other overt bleeding event that does not meet criteria for CRNM bleeding. | Up to 12 months | 
| Absolute Prothrombin Time (PT) at Day 1 (0.5-1.5 Hours Postdose) | Absolute prothrombin time was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 0.5-1.5 hours postdose | 
| Absolute PT at Day 1 (1.5-4 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 1.5-4 hours postdose | 
| Absolute PT at Day 4 (Up to 3 Hours Predose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average the participants included in the given time-range is presented here. | Day 4: Up to 3 hours predose | 
| Absolute PT at Day 4 (0.5-1.5 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 0.5-1.5 hours postdose | 
| Absolute PT at Day 4 (1.5-4 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 1.5-4 hours postdose | 
| Absolute PT at Day 4 (6-8 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 6-8 hours postdose | 
| Absolute PT at Month 3 (Up to 3 Hours Predose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: Up to 3 hours predose | 
| Absolute PT at Month 3 (0.5-1.5 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 0.5-1.5 hours postdose | 
| Absolute PT at Month 3 (2.5-4 Hours Postdose) | Absolute PT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 2.5-4 hours postdose | 
| Activated Partial Thromboplastin Time (aPTT) at Day 1 (0.5-1.5 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 0.5-1.5 hours postdose | 
| aPTT at Day 1 (1.5-4 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and average of the participants included in the given time-range is presented here. | Day 1: 1.5-4 hours postdose | 
| aPTT at Day 4 (Up to 3 Hours Predose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: Up to 3 hours predose | 
| aPTT at Day 4 (0.5-1.5 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average the participants included in the given time-range is presented here. | Day 4: 0.5-1.5 hours postdose | 
| aPTT at Day 4 (1.5-4 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average for the participants included in the given time-range is presented here. | Day 4: 1.5-4 hours postdose | 
| aPTT at Day 4 (6-8 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 6-8 hours postdose | 
| aPTT at Month 3 (Up to 3 Hours Predose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: Up to 3 hours predose | 
| aPTT at Month 3 (0.5-1.5 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 0.5-1.5 hours postdose | 
| aPTT at Month 3 (2.5-4 Hours Postdose) | aPTT was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 2.5-4 hours postdose | 
| Anti-FXa at Day 1 (0.5-1.5 Hours Postdose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 0.5-1.5 hours postdose | 
| Anti-FXa at Day 1 (1.5-4 Hours Postdose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 1: 1.5-4 hours postdose | 
| Anti-FXa at Day 4 (6-8 Hours Postdose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Day 4: 6-8 hours postdose | 
| Anti-FXa at Month 3 (Up to 3 Hours Predose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: Up to 3 hours predose | 
| Anti-FXa at Month 3 (0.5-1.5 Hours Postdose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 0.5-1.5 hours postdose | 
| Anti-FXa at Month 3 (2.5-4 Hours Postdose) | Anti-FXa was assessed as pharmacodynamic parameter. Each participant was assessed once within the specified time-range and the average of the participants included in the given time-range is presented here. | Month 3: 2.5-4 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs were defined as those adverse events (AEs) that occurred from the first day of study drug to the last day of study drug + 2 days inclusive. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product.AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thromboembolism, Fontan Procedure, Children