Summary

• The selection of the 20-mg once-daily dose for XARELTO in the ROCKET AF study was based primarily on the results of the 2 phase 2, dose-ranging studies evaluating XARELTO for the treatment of acute, symptomatic deep vein thrombosis (DVT).^1-3
  • These studies demonstrated that once and twice-daily doses from 20 mg to 60 mg per day were comparable, based on efficacy and safety results. Based on this data, the lowest dose of 20 mg once daily was chosen for further assessment.
• Since AF patients differ from the DVT treatment patient population (i.e., AF patients tend to be older and have decreased renal function), simulations using the population model developed for DVT treatment were conducted to predict the pharmacokinetics (PK) in patient with AF.^4,5
  • Simulations showed that the plasma concentration-time profile for patients in the anticipated AF patient population with normal renal function who receive 20 mg once daily was similar to the estimated plasma concentration-time profile for patients in the DVT treatment population who receive the same dose.⁵
• Dose selection for ROCKET AF was also supported by a phase 1 study demonstrating inhibition of XARELTO pharmacodynamic effects at 24 hours after dosing (i.e., inhibition of factor Xa activity).⁶
• Additional citations identified during a literature search are included in the References section for your review.^7-11

CLINICAL STUDIES

Phase 2, Dose-Ranging Studies

ROCKET AF trial

The ROCKET AF trial was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, non-inferiority study designed to evaluate the efficacy and safety of oral, fixed-dose XARELTO 20 mg once daily (15 mg for patients with creatinine clearance [CrCl] of 30–49 mL/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular AF at moderate-to-high risk for stroke.¹²

The selection of the 20 mg once-daily dose for XARELTO in the ROCKET AF study was based primarily on the results of 2 phase 2, dose-ranging studies evaluating XARELTO for the treatment of acute, symptomatic DVT, which are summarized below.^1-3

• These studies showed that the efficacy results with XARELTO once-daily or twice-daily were comparable to or better than the comparator for DVT treatment. The risk of bleeding was also similar, with no clear difference between once-daily or twice-daily dosing.
• As a result of this data, the lowest dose of 20 mg once daily was chosen for further assessment. Additionally, based on a PK modeling study, 15 mg once daily was chosen to be used in patients with moderate renal impairment (CrCl of 30–49 mL/min).

Phase 2, dose-finding studies for DVT treatment were considered as the dose-finding studies for the phase 3 ROCKET AF study (for prevention of stroke in patients with nonvalvular AF) because the number of strokes in patients with AF would be too low in any phase 2 study to adequately select a dose for subsequent phase 3 studies.^4,5

• A model of DVT treatment was applied to studies of stroke prevention in patients with AF. This model measured thrombus regression after acute, proximal DVT.

ODIXa-DVT Study

The ODIXa-DVT study¹ was a phase 2, dose-finding study to compare safety and efficacy between XARELTO and standard anticoagulation for treatment of acute, proximal DVT. Treatment groups included oral XARELTO (10 mg, 20 mg, or 30 mg twice daily or 40 mg once daily for 12 weeks) and subcutaneous (SC) enoxaparin 1 mg/kg twice daily (for at least 5 days) followed by vitamin K antagonist (VKA) for 12 weeks, dosed to an INR of 2.0 to 3.0. Complete compression ultrasound (CCUS) was performed at baseline to detect proximal DVT. Baseline perfusion lung scan was performed within 72 hours of CCUS and within 36 hours of initiation of study drug. CCUS and perfusion lung scans were performed at day 21 and again at day 84±14. Efficacy and safety results are presented in the tables below.

• The primary efficacy endpoint was improvement in thrombotic burden (defined as ≥4-point reduction in the thrombus score, as measured by CCUS at day 21) in the absence of confirmed, symptomatic extension or recurrence of DVT, confirmed, symptomatic pulmonary embolism (PE), or venous thromboembolism-related death. Please see the table below for study results.
• The primary safety outcome was the incidence of major bleeding, with onset no later than 2 days after the last dose of study drug. Please see the table below for results.

XARELTO was determined to be safe and effective across all dosing groups (ranging from a total daily dose of 20 mg to 60 mg) in treating patients with acute, symptomatic, proximal DVT.

The EINSTEIN-DVT Dose-Ranging Study

The EINSTEIN-DVT Dose-Ranging Study² was a phase 2, dose-ranging study that compared double-blinded, oral XARELTO 20, 30, or 40 mg once daily vs open-label, parenteral unfractionated heparin (started with 5000-IU bolus and 1250-IU/hour infusion) or low molecular weight heparin (SC tinzaparin 175 IU/kg once daily or SC enoxaparin 1.5 mg/kg once daily or SC enoxaparin 1 mg/kg twice daily) followed by an oral VKA (adjusted to target INR of 2.0 to 3.0) for treatment of acute, symptomatic DVT. Treatment was continued for 12 weeks. Compression ultrasound and perfusion lung scans were obtained at baseline and on day 84 (12 weeks). Efficacy and safety results are presented in the tables below.

• The primary efficacy endpoint was the composite of symptomatic recurrent DVT, symptomatic fatal or nonfatal PE, and asymptomatic deterioration in the burden of thrombosis at day 84 (12 weeks). Please see the table below for results.
• The principal safety endpoint was the composite of major and clinically relevant, nonmajor bleeding up to 48 hours after treatment cessation. Secondary safety endpoints were any bleeding, all-cause mortality, and the individual components of the principal safety endpoint. Please see the table below for results.

XARELTO was determined to be safe and effective in the 20-mg, 30-mg, and 40-mg fixed-dose treatment groups of patients with acute, symptomatic DVT, and a dose-dependent response was not apparent. The XARELTO 40-mg dose did not increase the risk for major bleeding or clinically relevant, nonmajor bleeding.

PHARMACOKINETIC MODELING

The patient population enrolled in the ROCKET AF study for stroke prevention in nonvalvular AF is recognized to be different than the population enrolled in the phase 2, dose-finding studies for DVT treatment. Patients with AF tend to be older and tend to have decreased renal function compared to those in the DVT treatment population. Therefore, a population PK model established from the phase 2, dose-finding studies for DVT treatment was used to simulate an AF population by modifying patient demographics to reflect those that would be expected for AF patients.^4,5

• Simulations showed that the plasma concentration-time profile for patients in the anticipated AF population with normal renal function who receive 20 mg once daily was similar to the estimated plasma concentration-time profile for patients in the DVT treatment population who receive the same dose.
• PK simulations also demonstrated that lowering the dose of XARELTO to 15 mg once daily in patients with moderate renal impairment (CrCl ≤50 mL/min) would result in exposures similar to those seen in AF patients with normal renal function or mild renal impairment receiving 20 mg once daily.⁵

PHARMACODYNAMICS

Dose selection for ROCKET AF was also supported by a phase 1, single-blinded, placebo-controlled, dose-escalation study that evaluated the pharmacokinetics and pharmacodynamics of single doses of XARELTO (1.25, 5, 10, 15, 20, 30, 40, 60, or 80 mg) in 108 healthy, white, male subjects.⁶ In this study, factor Xa activities had not completely returned to baseline at 24 hours for doses above 5 mg.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 04 September 2024.