A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Ted Wun, Denis Soulieres, Andrew L Frelinger, Lakshmanan Krishnamurti, Enrico M Novelli, Abdullah Kutlar, Kenneth I Ataga, Charles L Knupp, Lillian E McMahon, John J Strouse, Chunmei Zhou, Lori E Heath, Chuke E Nwachuku, Joseph A Jakubowski, Jeffrey S Riesmeyer, Kenneth J Winters, Ted Wun, Denis Soulieres, Andrew L Frelinger, Lakshmanan Krishnamurti, Enrico M Novelli, Abdullah Kutlar, Kenneth I Ataga, Charles L Knupp, Lillian E McMahon, John J Strouse, Chunmei Zhou, Lori E Heath, Chuke E Nwachuku, Joseph A Jakubowski, Jeffrey S Riesmeyer, Kenneth J Winters

Abstract

Background: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.

Methods: The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients.

Results: There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.

Conclusions: Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

Figures

Figure 1
Figure 1
Adaptive study design Phase A and Phase B. Decisions about dose allocations were made as the trial progressed. If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5-mg daily prasugrel, the dose was to be escalated to 7.5 mg. Dotted line denotes dose escalation plan per protocol; no dose escalation occurred occur during the study
Figure 2
Figure 2
Patient distribution. A total of 62 patients were randomly assigned to treatment (prasugrel [41], placebo [21]) and were included in the Intent-to-Treat (ITT) analysis set
Figure 3
Figure 3
Patient-reported days with pain and pain intensity. A. Proportion of patients reporting pain on 0, >0 to 25, >25 to 50, >50 to 75, >75 to <100, or 100% of study days. B. Proportion of patients with average pain intensity of 0, >0 to 2, >2 to 4, >4 to 6, or >6 to 8. Prasugrel = black bars; placebo = grey bars
Figure 4
Figure 4
Pharmacodynamic effects of prasugrel on platelet function. A. Platelet Inhibition: VerifyNow® P2Y12. B. VASP platelet reactivity index. The bottom and top of the box are the 25th and 75th percentile, the solid line in the box is median and the dotted line is mean, the ends of the whiskers are 10th and 90th percentile
Figure 5
Figure 5
Effect of prasugrel vs. placebo on biomarkers of disease-related platelet activation. A. Percent of platelets positive for platelet surface P-selectin, B. Plasma soluble P-selectin, C. Serum TXB2, D. plasma soluble CD40L. Prasugrel = black bars; placebo = grey bars. Results are mean ± SD

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