Pharmacokinetic, Pharmacodynamic, Safety, and Efficacy Study of Rivaroxaban for Thromboprophylaxis in Pediatric Participants 2 to 8 Years of Age After the Fontan Procedure (UNIVERSE)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT02846532 |
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Recruitment Status :
Completed
First Posted : July 27, 2016
Results First Posted : March 28, 2022
Last Update Posted : March 28, 2022
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Sponsor:
Janssen Research & Development, LLC
Collaborator:
Bayer
Information provided by (Responsible Party):
Janssen Research & Development, LLC
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Thrombosis | Drug: Rivaroxaban Drug: Acetylsalicylic Acid | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 112 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Prevention |
| 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 |
| Actual Study Start Date : | November 16, 2016 |
| Actual Primary Completion Date : | July 16, 2020 |
| Actual Study Completion Date : | July 16, 2020 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Rivaroxaban |
Drug: Rivaroxaban
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. |
| Experimental: Acetylsalicylic Acid |
Drug: Acetylsalicylic Acid
Participants will receive 5 milligram per kilogram (mg/kg) of acetylsalicylic acid once daily up to 12 months in Part B. |
Primary Outcome Measures :
- 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.
- 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 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.
- 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 Outcome Measures :
- Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 12 months ]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.
Information from the National Library of Medicine
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| Ages Eligible for Study: | 2 Years to 8 Years (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02846532
Locations
| United States, California | |
| Los Angeles, California, United States | |
| United States, Florida | |
| Gainesville, Florida, United States | |
| United States, Illinois | |
| Oak Lawn, Illinois, United States | |
| United States, Indiana | |
| Indianapolis, Indiana, United States | |
| United States, Iowa | |
| Iowa City, Iowa, United States | |
| United States, Maryland | |
| Baltimore, Maryland, United States | |
| United States, Massachusetts | |
| Boston, Massachusetts, United States | |
| United States, Minnesota | |
| Minneapolis, Minnesota, United States | |
| United States, Nebraska | |
| Omaha, Nebraska, United States | |
| United States, North Carolina | |
| Durham, North Carolina, United States | |
| United States, Ohio | |
| Cincinnati, Ohio, United States | |
| United States, Pennsylvania | |
| Hershey, Pennsylvania, United States | |
| Philadelphia, Pennsylvania, United States | |
| United States, Tennessee | |
| Memphis, Tennessee, United States | |
| United States, Texas | |
| Houston, Texas, United States | |
| United States, Utah | |
| Salt Lake City, Utah, United States | |
| United States, Wisconsin | |
| Milwaukee, Wisconsin, United States | |
| Argentina | |
| Buenos Aires, Argentina | |
| Cordoba, Argentina | |
| Belgium | |
| Brussel, Belgium | |
| Gent, Belgium | |
| Leuven, Belgium | |
| Brazil | |
| Curitiba, Brazil | |
| Porto Alegre, Brazil | |
| São Paulo, Brazil | |
| Canada, British Columbia | |
| Vancouver, British Columbia, Canada | |
| Canada, Ontario | |
| Toronto, Ontario, Canada | |
| Canada, Quebec | |
| Montreal, Quebec, Canada | |
| Japan | |
| Fukuoka, Japan | |
| Kitakyushu-shi,, Japan | |
| Setagaya-ku, Japan | |
| Shizuoka-shi, Shizuoka, Japan | |
| Malaysia | |
| Kuala Lumpur, Malaysia | |
| Mexico | |
| Mexico, Mexico | |
| Netherlands | |
| Leiden, Netherlands | |
| Rotterdam, Netherlands | |
| Utrecht, Netherlands | |
| Spain | |
| A Coruña, Spain | |
| Barcelona, Spain | |
| Bilbao, Spain | |
| Madrid, Spain | |
| Valencia, Spain | |
Sponsors and Collaborators
Janssen Research & Development, LLC
Bayer
Investigators
| Study Director: | Janssen Research & Development, LLC Clinical Trial | Janssen Research & Development, LLC |
Study Documents (Full-Text)
Documents provided by Janssen Research & Development, LLC:
Documents provided by Janssen Research & Development, LLC:
Study Protocol [PDF] July 27, 2017
Statistical Analysis Plan [PDF] May 16, 2019
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Janssen Research & Development, LLC |
| ClinicalTrials.gov Identifier: | NCT02846532 |
| Other Study ID Numbers: |
CR108075 39039039CHD3001 ( Other Identifier: Janssen Research & Development, LLC ) 2015-002610-76 ( EudraCT Number ) |
| First Posted: | July 27, 2016 Key Record Dates |
| Results First Posted: | March 28, 2022 |
| Last Update Posted: | March 28, 2022 |
| Last Verified: | February 2022 |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Janssen Research & Development, LLC:
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Thromboembolism Fontan Procedure Children |
Additional relevant MeSH terms:
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Thrombosis Embolism and Thrombosis Vascular Diseases Cardiovascular Diseases Aspirin Rivaroxaban Factor Xa Inhibitors Antithrombins Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anticoagulants |
Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Fibrinolytic Agents Fibrin Modulating Agents Platelet Aggregation Inhibitors Cyclooxygenase Inhibitors Antipyretics |