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.

CONCLUSION:

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: A T Cohen, R A Boyd, J W Mandema, L Dicarlo, R Pak, A5571010 Investigators
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 11 Issue 8 Pg. 1503-10 (Aug 2013) ISSN: 1538-7836 [Electronic] England
• PMID: 23782955 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 International Society on Thrombosis and Haemostasis.

Chemical References

• Enoxaparin
• Factor Xa Inhibitors
• N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidiine-1,2-dicarboxamide
• Pyridones
• Pyrrolidines

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Arthroplasty, Replacement, Knee (methods)
• Computer Simulation
• Dose-Response Relationship, Drug
• Enoxaparin (pharmacology)
• Factor Xa Inhibitors
• Female
• Humans
• Male
• Middle Aged
• Probability
• Pyridones (pharmacology)
• Pyrrolidines (pharmacology)
• Thromboembolism (drug therapy, prevention & control)
• Treatment Outcome