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

Wun T, Soulieres D, Frelinger AL, Krishnamurti L, Novelli EM, Kutlar A, Ataga KI, Knupp CL, McMahon LE, Strouse JJ, Zhou C, Heath LE, Nwachuku CE, Jakubowski JA, Riesmeyer JS, Winters KJ - J Hematol Oncol (2013)

Bottom Line: 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.In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, Davis Cancer Center, 4501 X St,, Ste, 3016, Sacramento, CA, 95817, USA. twun@ucdavis.edu

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.

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Related in: MedlinePlus

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
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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

Mentions: The study consisted of 2 phases (Phase A and Phase B) (Figure 1) and employed an adaptive design with decisions about dose allocations made as the trial progressed. During each phase, patients were randomized to prasugrel or placebo in a 2:1 manner and stratified by sickle-cell genotype (HbSS, HbS-β+-thalassemia and HbS-β0-thalassemia genotype patients in one stratum, and HbSC genotype patients in another stratum). We stratified in this way because some data [18,19], though not all [10,14], suggest more pronounced platelet activation in patients with HbSS than HbSC. In addition, our limited studies showed no difference in platelet activation between Hb S-β+-thalassemia and HbSS patients [10]. Patients underwent screening (Visit 0) and returned to the site for Visit 1 (0 to 10 days after screening), Visit 2 (10 ± 2 days after Visit 1), and Visit 3 (30 ± 3 days after Visit 1). Patients were contacted by phone for Visit 4 (30 days after last dose of study drug) to collect information on adverse events (AEs) and serious adverse events (SAEs).


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

Wun T, Soulieres D, Frelinger AL, Krishnamurti L, Novelli EM, Kutlar A, Ataga KI, Knupp CL, McMahon LE, Strouse JJ, Zhou C, Heath LE, Nwachuku CE, Jakubowski JA, Riesmeyer JS, Winters KJ - J Hematol Oncol (2013)

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
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585853&req=5

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
Mentions: The study consisted of 2 phases (Phase A and Phase B) (Figure 1) and employed an adaptive design with decisions about dose allocations made as the trial progressed. During each phase, patients were randomized to prasugrel or placebo in a 2:1 manner and stratified by sickle-cell genotype (HbSS, HbS-β+-thalassemia and HbS-β0-thalassemia genotype patients in one stratum, and HbSC genotype patients in another stratum). We stratified in this way because some data [18,19], though not all [10,14], suggest more pronounced platelet activation in patients with HbSS than HbSC. In addition, our limited studies showed no difference in platelet activation between Hb S-β+-thalassemia and HbSS patients [10]. Patients underwent screening (Visit 0) and returned to the site for Visit 1 (0 to 10 days after screening), Visit 2 (10 ± 2 days after Visit 1), and Visit 3 (30 ± 3 days after Visit 1). Patients were contacted by phone for Visit 4 (30 days after last dose of study drug) to collect information on adverse events (AEs) and serious adverse events (SAEs).

Bottom Line: 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.In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, Davis Cancer Center, 4501 X St,, Ste, 3016, Sacramento, CA, 95817, USA. twun@ucdavis.edu

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.

Show MeSH
Related in: MedlinePlus