SAN DIEGO, CA—In a small Phase 2 study presented at the 53rd American Society of Hematology’s Annual Meeting and Exposition, once-daily prasugrel 5mg for 30 days showed some promise of decreasing pain in patients with sickle-cell disease (SCD).
Prasugrel is an oral P2Y12 ADP receptor antagonist FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous intervention. Platelet activation may play a role in the pathogenesis of complications related to SCD. Ted Wun, MD, of the University of California, Sacramento, and colleagues, performed a randomized, double-blind, adaptive Phase 2 multicenter study of prasugrel in adult patients with SCD since older trials studying the potential of antiplatelet agents to lessen the incidence and severity of pain in SCD have been uncertain.
The study had a 2:1 prasugrel:placebo randomization ratio. The primary endpoint was safety of prasugrel compared to placebo, measured by the incidence of hemorrhagic events requiring medical intervention. Secondary endpoints consisted of clinical efficacy, defined as frequency and severity of pain related to SCD recorded in patient pain diaries, and pharmacodynamic effects assessed by VerifyNow P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI).
Forty-one patients were randomized to receive prasugrel; 21 to receive placebo. Mean age of trial participants was 32.9 years in the prasugrel group and 31.5 in the placebo group; 51.2% and 42.8% of patients were female, respectively. Sixty percent of patients in the prasugrel group and 61.9% in the placebo group were HbSS, 5% and 4.8% were HbS/b0thalassemia, 10% and 9.5% were HbS/b+thalassemia, and 25% and 23.8% were HbSC, respectively. Subsequently, one of the patients with HbSC was found not to have SCD but instead had only b-thalassemia trait.
Eighteen patients (44%) who received prasugrel and nine patients (43%) who received placebo had received hydroxyurea prior to receiving study drug. The aforementioned characteristics, along with pain intensity (average pain score on a scale of 0 to 9 over seven days prior to receiving study drug), were balanced between treatment arms. At 30 days, 96% of the patients in the prasugrel group and 93% in the placebo group had complete diaries.
Median and mean pain rate (percentage of days with pain) and intensity in the prasugrel arm compared to placebo did not reach statistical significance. The proportion of pain episodes requiring medical intervention occurred in nine patients (22.5%) treated with prasugrel, five of whom reported the pain in their diary; all were reported by the investigator. In the placebo arm, seven patients (36.8%) required medical attention, four of whom noted the pain in their diary; again, all were investigator-reported. This difference was not statistically significant (P=0.348) A measurable platelet inhibition occurred as determined by both VN PRU and VASP PRI; no dose escalation was needed.
Prasugrel was generally well tolerated, Dr. Wun said. Eight patients receiving prasugrel experienced hemorrhagic adverse events (AEs; 19.5%) (in six of these patients, the AEs were possibly related to study drug [14.6%]); one patient (5.3%) receiving placebo experienced a hemorrhagic AE. No hemorrhagic events required medical intervention, and there were no hemorrhagic serious AEs. Compared with the placebo arm, patients in the prasugrel arm had a higher rate of hemorrhagic AEs; all were self-limited and predominantly mild.
Despite the study’s small size and short duration, the data suggest signal of some efficacy for prasugrel when measured by pain rate, Dr. Wun concluded, adding that they provide justification for a Phase 3 study of prasugrel adequately powered to ascertain effects on pertinent clinical outcomes, including pain rate, severity, and frequency of vaso-occlusive crisis.