A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease
Bibliographic record
Abstract
Abstract Abstract 847FN2 Introduction: Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). 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. Results: Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). Conclusions: Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".