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

Primary Purpose

Thrombosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Rivaroxaban

Acetylsalicylic Acid

About this trial

This is an interventional prevention trial for Thrombosis focused on measuring Thromboembolism, Fontan Procedure, Children

Eligibility Criteria

2 Years - 8 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Rivaroxaban

Acetylsalicylic Acid

Arm Description

Outcomes

Primary Outcome Measures

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.

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.

Plasma Concentration of Rivaroxaban at Day 1 (1.5-4 Hours Postdose)

Plasma Concentration of Rivaroxaban at Day 4 (Up to 3 Hours Predose)

Plasma Concentration of Rivaroxaban at Day 4 (0.5-1.5 Hours Postdose)

Plasma Concentration of Rivaroxaban at Day 4 (1.5-4 Hours Postdose)

Plasma Concentration of Rivaroxaban at Day 4 (6-8 Hours Postdose)

Plasma Concentration of Rivaroxaban at Month 3 (Up to 3 Hours Predose)

Plasma Concentration of Rivaroxaban at Month 3 (0.5-1.5 Hours Postdose)

Plasma Concentration of Rivaroxaban at 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.

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.

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.

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.

Absolute PT at Day 4 (0.5-1.5 Hours Postdose)

Absolute PT at Day 4 (1.5-4 Hours Postdose)

Absolute PT at Day 4 (6-8 Hours Postdose)

Absolute PT at Month 3 (Up to 3 Hours Predose)

Absolute PT at Month 3 (0.5-1.5 Hours Postdose)

Absolute PT at 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.

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.

aPTT at 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.

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.

aPTT at Day 4 (6-8 Hours Postdose)

aPTT at Month 3 (Up to 3 Hours Predose)

aPTT at Month 3 (0.5-1.5 Hours Postdose)

aPTT at 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.

Anti-FXa at Day 1 (1.5-4 Hours Postdose)

Anti-FXa at Day 4 (6-8 Hours Postdose)

Anti-FXa at Month 3 (Up to 3 Hours Predose)

Anti-FXa at Month 3 (0.5-1.5 Hours Postdose)

Anti-FXa at Month 3 (2.5-4 Hours Postdose)

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT02846532

First Posted

July 25, 2016

Last Updated

March 2, 2022

Sponsor

Janssen Research & Development, LLC

Collaborators

Bayer

1. Study Identification

Unique Protocol Identification Number

NCT02846532

Brief Title

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

Acronym

UNIVERSE

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

November 16, 2016 (Actual)

Primary Completion Date

July 16, 2020 (Actual)

Study Completion Date

July 16, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

Collaborators

Bayer

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Thrombosis

Keywords

Thromboembolism, Fontan Procedure, Children

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

112 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rivaroxaban

Arm Type

Experimental

Arm Title

Acetylsalicylic Acid

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Rivaroxaban

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Acetylsalicylic Acid

Intervention Description

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

Primary Outcome Measure Information:

Title

Percentage of Participants With Any Thrombotic Event (Venous or Arterial and Symptomatic or Asymptomatic)

Description

Time Frame

Up to 12 months

Title

Plasma Concentration of Rivaroxaban at Day 1 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 1: 0.5-1.5 hours postdose

Title

Plasma Concentration of Rivaroxaban at Day 1 (1.5-4 Hours Postdose)

Description

Time Frame

Day 1: 1.5-4 hours postdose

Title

Plasma Concentration of Rivaroxaban at Day 4 (Up to 3 Hours Predose)

Description

Time Frame

Day 4: Up to 3 hours predose

Title

Plasma Concentration of Rivaroxaban at Day 4 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 4: 0.5-1.5 hours postdose

Title

Plasma Concentration of Rivaroxaban at Day 4 (1.5-4 Hours Postdose)

Description

Time Frame

Day 4: 1.5-4 hours postdose

Title

Plasma Concentration of Rivaroxaban at Day 4 (6-8 Hours Postdose)

Description

Time Frame

Day 4: 6-8 hours postdose

Title

Plasma Concentration of Rivaroxaban at Month 3 (Up to 3 Hours Predose)

Description

Time Frame

Month 3: Up to 3 hours predose

Title

Plasma Concentration of Rivaroxaban at Month 3 (0.5-1.5 Hours Postdose)

Description

Time Frame

Month 3: 0.5-1.5 hours postdose

Title

Plasma Concentration of Rivaroxaban at Month 3 (2.5-4 Hours Postdose)

Description

Time Frame

Month 3: 2.5-4 hours postdose

Title

Percentage of Participants With Bleeding Events

Description

Time Frame

Up to 12 months

Title

Absolute Prothrombin Time (PT) at Day 1 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 1: 0.5-1.5 hours postdose

Title

Absolute PT at Day 1 (1.5-4 Hours Postdose)

Description

Time Frame

Day 1: 1.5-4 hours postdose

Title

Absolute PT at Day 4 (Up to 3 Hours Predose)

Description

Time Frame

Day 4: Up to 3 hours predose

Title

Absolute PT at Day 4 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 4: 0.5-1.5 hours postdose

Title

Absolute PT at Day 4 (1.5-4 Hours Postdose)

Description

Time Frame

Day 4: 1.5-4 hours postdose

Title

Absolute PT at Day 4 (6-8 Hours Postdose)

Description

Time Frame

Day 4: 6-8 hours postdose

Title

Absolute PT at Month 3 (Up to 3 Hours Predose)

Description

Time Frame

Month 3: Up to 3 hours predose

Title

Absolute PT at Month 3 (0.5-1.5 Hours Postdose)

Description

Time Frame

Month 3: 0.5-1.5 hours postdose

Title

Absolute PT at Month 3 (2.5-4 Hours Postdose)

Description

Time Frame

Month 3: 2.5-4 hours postdose

Title

Activated Partial Thromboplastin Time (aPTT) at Day 1 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 1: 0.5-1.5 hours postdose

Title

aPTT at Day 1 (1.5-4 Hours Postdose)

Description

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.

Time Frame

Day 1: 1.5-4 hours postdose

Title

aPTT at Day 4 (Up to 3 Hours Predose)

Description

Time Frame

Day 4: Up to 3 hours predose

Title

aPTT at Day 4 (0.5-1.5 Hours Postdose)

Description

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.

Time Frame

Day 4: 0.5-1.5 hours postdose

Title

aPTT at Day 4 (1.5-4 Hours Postdose)

Description

Time Frame

Day 4: 1.5-4 hours postdose

Title

aPTT at Day 4 (6-8 Hours Postdose)

Description

Time Frame

Day 4: 6-8 hours postdose

Title

aPTT at Month 3 (Up to 3 Hours Predose)

Description

Time Frame

Month 3: Up to 3 hours predose

Title

aPTT at Month 3 (0.5-1.5 Hours Postdose)

Description

Time Frame

Month 3: 0.5-1.5 hours postdose

Title

aPTT at Month 3 (2.5-4 Hours Postdose)

Description

Time Frame

Month 3: 2.5-4 hours postdose

Title

Anti-FXa at Day 1 (0.5-1.5 Hours Postdose)

Description

Time Frame

Day 1: 0.5-1.5 hours postdose

Title

Anti-FXa at Day 1 (1.5-4 Hours Postdose)

Description

Time Frame

Day 1: 1.5-4 hours postdose

Title

Anti-FXa at Day 4 (6-8 Hours Postdose)

Description

Time Frame

Day 4: 6-8 hours postdose

Title

Anti-FXa at Month 3 (Up to 3 Hours Predose)

Description

Time Frame

Month 3: Up to 3 hours predose

Title

Anti-FXa at Month 3 (0.5-1.5 Hours Postdose)

Description

Time Frame

Month 3: 0.5-1.5 hours postdose

Title

Anti-FXa at Month 3 (2.5-4 Hours Postdose)

Description

Time Frame

Month 3: 2.5-4 hours postdose

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Up to 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

8 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Research & Development, LLC Clinical Trial

Organizational Affiliation

Janssen Research & Development, LLC

Official's Role

Study Director

Facility Information:

City

Los Angeles

State/Province

California

Country

United States

City

Gainesville

State/Province

Florida

Country

United States

City

Oak Lawn

State/Province

Illinois

Country

United States

City

Indianapolis

State/Province

Indiana

Country

United States

City

Iowa City

State/Province

Iowa

Country

United States

City

Baltimore

State/Province

Maryland

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Minneapolis

State/Province

Minnesota

Country

United States

City

Omaha

State/Province

Nebraska

Country

United States

City

Durham

State/Province

North Carolina

Country

United States

City

Cincinnati

State/Province

Ohio

Country

United States

City

Hershey

State/Province

Pennsylvania

Country

United States

City

Philadelphia

State/Province

Pennsylvania

Country

United States

City

Memphis

State/Province

Tennessee

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Salt Lake City

State/Province

Utah

Country

United States

City

Milwaukee

State/Province

Wisconsin

Country

United States

City

Buenos Aires

Country

Argentina

City

Cordoba

Country

Argentina

City

Brussel

Country

Belgium

City

Gent

Country

Belgium

City

Leuven

Country

Belgium

City

Curitiba

Country

Brazil

City

Porto Alegre

Country

Brazil

City

São Paulo

Country

Brazil

City

Vancouver

State/Province

British Columbia

Country

Canada

City

Toronto

State/Province

Ontario

Country

Canada

City

Montreal

State/Province

Quebec

Country

Canada

City

Fukuoka

Country

Japan

City

Kitakyushu-shi,

Country

Japan

City

Setagaya-ku

Country

Japan

City

Shizuoka-shi, Shizuoka

Country

Japan

City

Kuala Lumpur

Country

Malaysia

City

Mexico

Country

Mexico

City

Leiden

Country

Netherlands

City

Rotterdam

Country

Netherlands

City

Utrecht

Country

Netherlands

City

A Coruña

Country

Spain

City

Barcelona

Country

Spain

City

Bilbao

Country

Spain

City

Madrid

Country

Spain

City

Valencia

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

34558312

Citation

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. Erratum In: J Am Heart Assoc. 2021 Dec 21;10(24):e020766.

Results Reference

derived

Links:

URL

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ERF update upload receipt

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

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