Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial Fibrillation

Abstract Introduction : The primary objective of this phase II study was to assess the safety of different dose regimens of DU-176b, an oral direct factor Xa inhibitor, in patients with non-valvular atrial fibrillation (AF). Methods : This was a randomized, parallel group, multicenter, multinational, double-blind DU-176b and open-label warfarin safety study in patients with AF (CHADS2 index ≥ 2). Patients were randomly assigned to receive either one of four fixed dose regimens of DU-176b (30 mg qd, 30 mg bid, 60 mg qd or 60 mg bid) or warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0–3.0. for 12 weeks. Investigators, sponsor and study subjects were blinded to DU-176b dose but not to the identity of DU-176b vs. warfarin. Investigators adjusted warfarin doses based on INR values obtained in local laboratories. The INR was determined weekly for 4 weeks and every two weeks thereafter. The primary outcomes were the occurrence of centrally adjudicated major and/or clinically relevant non-major bleeding event, and elevated liver enzymes and/or bilirubin. Secondary outcomes included major adverse cardiovascular events (MACE), a composite of stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular condition or cardiovascular death, as well as all other adverse events, including all bleeding events. Results : A total of 1,146 patients were randomized. There were no clinically relevant differences between treatment groups with respect to the demographic data and baseline characteristics. Mean age was 65±8.7 years, 63.3% of patients had a CHADS2 index of 2 and 64.40% were warfarin naïve. The DU-176b 60 mg bid treatment arm was prematurely terminated during the study based on a recommendation by the Independent Data Monitoring Committee (DMC). A total of 180 patients were randomized to this group at the time. The incidence of major and clinically relevant non-major bleeding events was significantly higher in both the DU-176b 60 mg bid and 30 mg bid groups than in those given warfarin. The incidence of major and clinically relevant non-major bleeding events in the DU-176b 30 mg qd and 60 mg qd groups was similar to that in warfarin-treated patients. The time in therapeutic range (TTR) for warfarin-experienced patients was 50.1% and for warfarin naïve patients was 41.8%. There were no significant differences in the number (%) of subjects with persistently elevated ALT, AST, or bilirubin values across the treatment groups. The incidence of stroke was similar across treatment groups (Table). DU-176b 30 mg qd N=235 DU-176b 60 mg qd N=234 DU-176b 30 mg bid N=244 DU-176b 60 mg bid N=180 Warfarin qd N=250 Bleeding, n (%) (95% CI) Major+CR non-major 7 (3.0) (1.2–6.0) 11 (4.7) (2.4–8.3) 19 (7.8) (4.8–11.9)a 19 (10.6) (6.5–16.0)b 8 (3.2) (1.4–6.2) Major 0 (0) (0–1.6) 1 (0.4) (0–2.4) 5 (2.0) (0.7–4.7) 6 (3.3) (1.2–7.1)a 1 (0.4) (0–2.2) All 13 (5.5) (3.0–9.3) 19 (8.1) (5.0–12.4) 32 (13.1) (9.1–18.0) 33 (18.3) (13.0–24.8)b 20 (8.0) (5.0–12.1) Stroke, n (%) (95% CI) 1 (0.4) (0–2.3) 1 (0.4) (0–2.4) 2 (0.8) (0.1–2.9) 2 (1.1) (0.1–4.0) 4 (1.6) (0.4–4.0) Conclusions : DU-176b 30 mg qd and 60 mg qd dose regimens had a safety profile similar to warfarin in patients with AF. Patients treated with the DU-176b 30 mg bid or 60 mg bid regimens had more bleeding events than occurred with warfarin. These results suggest that the DU-176b 30 mg qd or 60 mg qd regimens are safe and well tolerated. A Phase III trial is needed to determine whether DU-176b will provide a suitable replacement for warfarin in AF patients. CR, clinically relevant. aP<0.05, bP=0.002 to warfarin.

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