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
Overview
- Phase
- Phase 3
- Intervention
- Rivaroxaban
- Conditions
- Thrombosis
- Sponsor
- Janssen Research & Development, LLC
- Enrollment
- 112
- Primary Endpoint
- Percentage of Participants With Any Thrombotic Event (Venous or Arterial and Symptomatic or Asymptomatic)
- Status
- Completed
- Last Updated
- last year
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.
Investigators
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
Arms & Interventions
Rivaroxaban
Intervention: Rivaroxaban
Acetylsalicylic Acid
Intervention: Acetylsalicylic Acid
Outcomes
Primary Outcomes
Percentage of Participants With Any Thrombotic Event (Venous or Arterial and Symptomatic or Asymptomatic)
Time Frame: Up to 12 months
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.
Plasma Concentration of Rivaroxaban at Day 1 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Day 1 (1.5-4 Hours Postdose)
Time Frame: 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.
Absolute PT at Day 4 (6-8 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Day 4 (Up to 3 Hours Predose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Day 4 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Day 4 (1.5-4 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Day 4 (6-8 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Month 3 (Up to 3 Hours Predose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Month 3 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Plasma Concentration of Rivaroxaban at Month 3 (2.5-4 Hours Postdose)
Time Frame: 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.
Percentage of Participants With Bleeding Events
Time Frame: Up to 12 months
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.
Absolute Prothrombin Time (PT) at Day 1 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Absolute PT at Day 1 (1.5-4 Hours Postdose)
Time Frame: 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.
Absolute PT at Day 4 (Up to 3 Hours Predose)
Time Frame: 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.
Absolute PT at Day 4 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Absolute PT at Day 4 (1.5-4 Hours Postdose)
Time Frame: 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.
Absolute PT at Month 3 (Up to 3 Hours Predose)
Time Frame: 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.
Absolute PT at Month 3 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Absolute PT at Month 3 (2.5-4 Hours Postdose)
Time Frame: 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.
Activated Partial Thromboplastin Time (aPTT) at Day 1 (0.5-1.5 Hours Postdose)
Time Frame: 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.
aPTT at Day 1 (1.5-4 Hours Postdose)
Time Frame: 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.
aPTT at Day 4 (Up to 3 Hours Predose)
Time Frame: 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.
aPTT at Day 4 (0.5-1.5 Hours Postdose)
Time Frame: 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.
aPTT at Day 4 (1.5-4 Hours Postdose)
Time Frame: 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.
aPTT at Day 4 (6-8 Hours Postdose)
Time Frame: 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.
aPTT at Month 3 (Up to 3 Hours Predose)
Time Frame: 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.
aPTT at Month 3 (0.5-1.5 Hours Postdose)
Time Frame: 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.
aPTT at Month 3 (2.5-4 Hours Postdose)
Time Frame: 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.
Anti-FXa at Day 1 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Anti-FXa at Day 1 (1.5-4 Hours Postdose)
Time Frame: 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.
Anti-FXa at Day 4 (6-8 Hours Postdose)
Time Frame: 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.
Anti-FXa at Month 3 (Up to 3 Hours Predose)
Time Frame: 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.
Anti-FXa at Month 3 (0.5-1.5 Hours Postdose)
Time Frame: 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.
Anti-FXa at Month 3 (2.5-4 Hours Postdose)
Time Frame: 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.
Secondary Outcomes
- Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)(Up to 12 months)