An Adaptive-Design Dose-Ranging Study Of Pd 0348292, A New Oral Factor Xa Inhibitor, For Thromboprophylaxis After Total Knee Replacement Surgery.

Abstract Introduction: A challenge for dose-ranging trials of a new anticoagulant is to minimize subject risk for venous thromboembolism (VTE) and major bleeding while exploring the efficacy and safety of a wide dose range of the study drug. This study utilized an adaptive design to evaluate PD 0348292 across a 100-fold dose range for the prevention of VTE in subjects after total knee replacement (TKR) surgery. Methods: Adult subjects who had undergone unilateral TKR were randomized to 1 of 6 treatments: double-blind oral PD 0348292 (0.1, 0.3, 0.5, 1.0, or 2.5 mg qd) or open-label subcutaneous enoxaparin (30 mg bid) in a 1:1:1:1:1:2 ratio, respectively. PD 0348292 and enoxaparin were initiated 6 to 8 hours and 12 to 24 hours after surgery, respectively; both were continued for 6 to 14 days. The primary efficacy outcome was the incidence of VTE (proximal or distal deep vein thrombosis assessed by bilateral venography, and/or pulmonary embolism) as adjudicated by an independent central imaging laboratory. The primary safety endpoint was the incidence of total bleeding. The adaptive design allowed for the discontinuation of doses of PD 0348292 due to excessive VTE or major bleeding, and the addition of higher doses (4 and 10 mg qd), based on acceptable major bleeding. The decision to discontinue and/or add doses was based upon pre-specified interim assessments of the incidence of VTE and major bleeding by an independent Data Monitoring Committee (DMC) via model-based dose-response analysis (logistic regression). Results: A total of 1411 subjects were randomized at 99 sites in 16 countries; 1389 were treated with at least 1 dose of study drug; and 749 (53.1%) were evaluable for primary efficacy analysis. As a result of DMC assessments, 3 lower dose groups of PD 0348292 (0.1, 0.3, and 0.5 mg qd) were discontinued, and 2 higher dose groups (4 and 10 mg qd) were added during the study. The observed incidence of VTE was 37.1%, 37.1%, 28.8%, 19.2%, 14.3%, 1.4%, and 11.1% for PD 0348292 doses of 0.1, 0.3, 0.5, 1.0, 2.5, 4.0, and 10.0 mg qd, respectively, compared with 18.1% for enoxaparin. The dose response for PD 0348292 was statistically significant (P < 0.001). Based on the dose-response model for efficacy, the dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention in TKR subjects was estimated to be 1.16 (95% CI, 0.56, 2.41) mg qd. Overall, PD 0348292 and enoxaparin were well tolerated. No deaths and no unexpected adverse events were reported. A dose-related increase in the incidence of total bleeding, driven mainly by minor bleeding, was observed with PD 0348292, but was not statistically significant (P = 0.2464). The PD 0348292 dose-response relationship for major bleeding was relatively flat and was not statistically significant (P = 0.6040). Observed incidence of major bleeding ranged from 0% to 1.5% across the PD 0348292 dose range studied, compared with 0.8% for enoxaparin. Three of the 5 reported major bleeding events in PD 0348292 subjects occurred at the surgical site, compared with 2 out of 3 in enoxaparin subjects. Conclusion: The adaptive design utilized in this study enabled comparison of a wide dose range of PD 0348292 (0.1 to 10.0 mg qd) to enoxaparin 30 mg bid in TKR surgical subjects using a single study. Modeling of the efficacy data provided an estimate of a dose of PD 0348292 that was equivalent to enoxaparin 30 mg bid for VTE prevention. The adaptive design and modeling allowed use of approximately 2.5-fold fewer subjects than would have a traditional parallel-arm, pairwise-comparison study design.