The UNIVERSE clinical trial

The first and only randomized study of a DOAC for use in children with congenital heart disease as thromboprophylaxis post Fontan3

Objective

To examine the use of a novel oral suspension formulation of XARELTO® in children 2 to 8 years old with single ventricle physiology who had the Fontan procedure within 4 months before enrollment2,3

Design2,3

  • Randomized
  • Multicenter
  • Open-label
  • Active-controlled
  • 2-part (A and B), phase 3 study

Parts A and B

Part A: Assessed PK and PD of XARELTO® in young children to determine a dose to approximate the drug exposure achieved in adults with XARELTO® 10 mg QD

Part B: Evaluated the safety and efficacy of XARELTO® vs aspirin for thromboprophylaxis post-Fontan procedure for 12 months

UNIVERSE clinical trial study design2,3

UNIVERSE clinical trial study design for direct oral anticoagulant (DOAC) in childrenUNIVERSE clinical trial study design for direct oral anticoagulant (DOAC) in children
Outcomes

Primary efficacy outcome:

any thrombotic event, venous or arterial

Principal safety outcome:

major bleeding events

Secondary safety outcomes:

nonmajor and trivial/minimal bleeding

Inclusion criteria
  • Children aged 2 to 8 years with single ventricle
  • Within 4 months post-Fontan procedure
Main exclusion criteria
  • Thrombosis requiring treatment
  • History of GI disease or surgery associated with impaired absorption
  • Active, or high risk of bleeding contraindicating antiplatelet or anticoagulant therapy, including history of ICH, or contraindication to aspirin or rivaroxaban
  • Chronic NSAID use
  • Platelet count <50 x 109/L at screening
  • Estimated eGFR <30 mL/min/1.73 m2

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

BID = twice daily; DOAC = direct oral anticoagulant; DRC = Data Review Committee; eGFR = estimated glomerular filtration rate; EOT = end of treatment; IDMC = independent data monitoring committee; GI = gastrointestinal; ICH = intracranial hemorrhage; NSAID = non-steroidal anti-inflammatory drug; PD = pharmacodynamics; PK = pharmacokinetics; QD = once daily;
R = randomization.

UNIVERSE clinical trial

Bleeding rates were assessed for XARELTO® vs aspirin1

Principal safety outcome

UNIVERSE trial: bleeding rates for XARELTO® (rivaroxaban) versus aspirin

Major bleeding: The single case of epistaxis (nosebleed) occurred in the rivaroxaban part B group.

Clinically relevant nonmajor bleeding: With rivaroxaban, bleeding events occurred in the lower GI tract, gingival tissue, and skin; with ASA, these events occurred in the lower GI tract, skin and subconjunctival tissue, and one patient developed a hematoma.

Trivial bleeding: The most frequent site of trivial bleeding was the skin in both groups.

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

*Clinically relevant nonmajor bleeding is clinically overt bleeding, which did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Major bleeding is clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, or bleeding at a critical site or with a fatal outcome.

ASA = aspirin; GI = gastrointestinal.

The UNIVERSE clinical trial was not powered for statistical significance

XARELTO® was evaluated for the prevention of thrombotic events in pediatric patients post Fontan2

Rates of primary and secondary efficacy outcomes1,2*
UNIVERSE trial: rates of thrombotic events in patients treated with XARELTO® (rivaroxaban) versus aspirin
EventTreatment arm†
XARELTO®‡
n=64%
n (%)		Aspirin‡
n=34
n (%)
Primary efficacy outcome1 (1.6)3 (8.8)
Ischemic stroke01 (2.9)
Pulmonary embolism1 (1.6)0
Venous thrombosis02 (5.9)

Not powered to test formal hypotheses for efficacy and safety due to the limited availability of the study population and the expected low event rates.2,3

*Efficacy outcomes based on full analysis set: all participants in part A who received ≥1 dose of study drug and all participants in part B who were randomized and received ≥1 dose of study drug. In the rivaroxaban part A group, 1 participant (8%) had a venous thrombotic event on Day 362 of treatment (364 days post-Fontan procedure). This study was not powered for efficacy hypothesis testing (post hoc log-rank test; P=0.095).2

†Part B: randomized 2:1 (XARELTO®: aspirin).

‡Treatment schedule: body weight–adjusted doses of XARELTO® (exposures to match that of 10 mg QD in adults) or aspirin (approximately 5 mg/kg).

QD = once daily.

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REFERENCES: 1. XARELTO® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. McCrindle BW, Michelson AD, Van Bergen AH, et al; UNIVERSE Study Investigators. Thromboprophylaxis for children post-Fontan procedure: insights from the UNIVERSE study. J Am Heart Assoc. 2021;10(22):e021765. 3. Pina LM, Dong X, Zhang L, et al. Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: rationale and design of a prospective, randomized trial (the UNIVERSE study). Am Heart J. 2019;213:97-104.