title: An adaptive-design dose-ranging study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery.
abstract: BACKGROUND
  PD 0348292 is an oral, selective, direct and reversible factor Xa inhibitor. This was an adaptive dose-ranging study evaluating a 100-fold PD 0348292 dose range in subjects undergoing total knee replacement (TKR).
  
  
  OBJECTIVE
  To assess the efficacy and safety of a dose range of PD 0348292 relative to enoxaparin for the prevention of venous thromboembolism (VTE).
  
  
  METHODS
  Extensive dose-response modeling and trial simulations were used to select the PD 0348292 dose range for the Phase 2 study. Subjects were randomized to a blinded PD 0348292 dose (0.1 mg qd to 10 mg qd) or open-label enoxaparin (30 mg bid) for 6-14 days after TKR surgery. Efficacy was assessed by mandatory bilateral venography. Results were analyzed using a dose-response modeling approach.
  
  
  RESULTS
  Observed VTE frequency ranged from 1.4-37.1% across PD 0348292 doses and was 18.1% for enoxaparin. The PD 0348292 dose-response relationship for VTE was statistically significant (P < 0.0001). The dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention was estimated to be 1.16 mg (95% CI = 0.56 mg, 2.41 mg) qd. Total bleeding ranged from 4.9% to 13.8% across PD 0348292 doses and was 6.3% with enoxaparin. The dose-response relationship for total bleeding was not statistically significant (P = 0.2464). Overall, PD 0348292 and enoxaparin were well tolerated.
  
  
  CONCLUSIONS
  Characterization of the dose-response relationship for VTE and bleeding using an adaptive Phase 2 study design provided a strong quantitative basis for Phase 3 dose selection.
authors.affiliation: Vascular Medicine, Department of Vascular Surgery, King's College Hospital, London, UK.
authors.forename: A T
authors.initials: AT
authors.lastname: Cohen
authors.forename: R A
authors.initials: RA
authors.lastname: Boyd
authors.forename: J W
authors.initials: JW
authors.lastname: Mandema
authors.forename: L
authors.initials: L
authors.lastname: Dicarlo
authors.forename: R
authors.initials: R
authors.lastname: Pak
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019645:Arthroplasty, Replacement, Knee / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011336:Probability; D011728:Pyridones / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D013923:Thromboembolism / Q000188:drug therapy* / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D017984:Enoxaparin; D065427:Factor Xa Inhibitors; C523986:N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidiine-1,2-dicarboxamide; D011728:Pyridones; D011759:Pyrrolidines
keywords: Dose Response Relationship; Drug; anticoagulants; research design; total knee replacement; venous thromboembolism