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

NCT02846532 | Completed Phase 3 Results DMC

• 3 other identifiers: CR10807539039039CHD30012015-002610-76
• Study Type: interventional
• Target: 112
• Locations: 10 countries
• Sites: 42

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.

Conditions

Thrombosis

Keywords

Thromboembolism; Fontan Procedure; Children

Outcome Measures

Primary Outcomes (35)

• 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 Outcomes (1)

• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

  Up to 12 months

Study Arms (2)

Rivaroxaban

EXPERIMENTAL

Drug: Rivaroxaban

Acetylsalicylic Acid

EXPERIMENTAL

Drug: Acetylsalicylic Acid

Interventions

Rivaroxaban DRUG

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.

Rivaroxaban

Acetylsalicylic Acid DRUG

Participants will receive 5 milligram per kilogram (mg/kg) of acetylsalicylic acid once daily up to 12 months in Part B.

Acetylsalicylic Acid

Eligibility Criteria

• Age: 2 Years - 8 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead
• Bayer: collaborator

Study Sites (42)

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Los Angeles, California, United States

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Gainesville, Florida, United States

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Oak Lawn, Illinois, United States

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Indianapolis, Indiana, United States

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Iowa City, Iowa, United States

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Baltimore, Maryland, United States

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Boston, Massachusetts, United States

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Minneapolis, Minnesota, United States

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Omaha, Nebraska, United States

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Durham, North Carolina, United States

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Cincinnati, Ohio, United States

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Hershey, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Memphis, Tennessee, United States

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Houston, Texas, United States

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Salt Lake City, Utah, United States

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Milwaukee, Wisconsin, United States

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Buenos Aires, Argentina

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Córdoba, Argentina

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Brussels, Belgium

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Ghent, Belgium

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Leuven, Belgium

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Curitiba, Brazil

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Porto Alegre, Brazil

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São Paulo, Brazil

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Vancouver, British Columbia, Canada

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Toronto, Ontario, Canada

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Montreal, Quebec, Canada

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Fukuoka, Japan

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Kitakyushu-shi, Japan

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Setagaya Ku, Japan

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Shizuoka, Japan

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Kuala Lumpur, Malaysia

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México, Mexico

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Leiden, Netherlands

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Rotterdam, Netherlands

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Utrecht, Netherlands

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A Coruña, Spain

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Barcelona, Spain

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Bilbao, Spain

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Madrid, Spain

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Valencia, Spain

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Related Publications (1)

• McCrindle BW, Michelson AD, Van Bergen AH, Suzana Horowitz E, Pablo Sandoval J, Justino H, Harris KC, Jefferies JL, Miriam Pina L, Peluso C, Nessel K, Lu W, Li JS; UNIVERSE Study Investigators *. Thromboprophylaxis for Children Post-Fontan Procedure: Insights From the UNIVERSE Study. J Am Heart Assoc. 2021 Nov 16;10(22):e021765. doi: 10.1161/JAHA.120.021765. Epub 2021 Sep 24.

  PMID: 34558312 DERIVED

Related Links

• ERF update upload receipt

MeSH Terms

Conditions

Thrombosis; Thromboembolism

Interventions

Rivaroxaban; Aspirin

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: SR DIRECTOR
• Organization: Janssen Research & Development, LLC

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2016
• First Posted: July 27, 2016
• Study Start: November 16, 2016
• Primary Completion: July 16, 2020
• Study Completion: July 16, 2020
• Last Updated: March 30, 2025
• Results First Posted: March 28, 2022

Record last verified: 2025-03

Locations

CA (3); BE (3); JP (4); ME (1); AR (2); BR (3); ES (5); US (17); MY (1); NL (3)