Trial Summary
LANCELOT ACS
Title: Lesson from Antagonizing the Cellular Effect of Thrombin–Acute Coronary Syndromes
Trial Sponsor: Eisai, Inc.
Year Presented: 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 09/23/2010
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: NOTHING TO DISCLOSE
Reviewer: Christopher P. Cannon, M.D., F.A.C.C.
Reviewer Disclosure: CONSULTING FEES/HONORARIA: Novartis, Alnylam, BMS EQUITY I
Description:
Atopaxar is a novel protease-activated receptor-1 (PAR-1) antagonist (formerly known as E5555) that has shown promising results in early clinical studies. The LANCELOT ACS trial was a phase II trial designed to study the safety and efficacy of atopaxar in patients admitted with acute coronary syndrome (ACS).
Hypothesis:
Atopaxar would be safe and efficacious, as compared with placebo, in the treatment of patients admitted with ACS.
Drugs/Procedures Used:
Patients presenting with ACS were randomized in a 1:1:1:1 fashion to receive either placebo, or atopaxar 400 mg loading dose followed by 50 mg daily maintenance dose, atopaxar 400 mg loading dose followed by 100 mg daily maintenance dose, or atopaxar 400 mg loading dose followed by 200 mg daily maintenance dose.
Concomitant Medications:
Aspirin (97%), thienopyridine (82%), statin (88%), beta-blocker (85%), and glycoprotein IIb/IIIa inhibitor (15%)
Principal Findings:
A total of 603 patients were randomized, 142 to placebo, 156 to atopaxar 50 mg daily, 157 to atopaxar 100 mg daily, and 148 to atopaxar 200 mg daily. Baseline characteristics were fairly similar between the four arms. About 22% had diabetes mellitus, 27% had prior myocardial infarction (MI), 3% had prior stroke, and 5% had known peripheral arterial disease.
The primary endpoint of major bleeding (as defined in the CURE trial) was noted to be similar between the placebo, atopaxar 50 mg, 100 mg, and 200 mg arms, respectively (0% vs. 0.6% vs. 3.2% vs. 1.4%, p = 0.28).The rate of major bleeding for all doses of atopaxar combined was 1.8% vs. 0% for placebo (p = 0.18). CURE-defined minor bleeding was also similar for placebo versus the three ascending doses of atopaxar (2.2% vs. 0.7% vs. 2.6% vs. 0.7%, p = 0.81). Similar results were noted when analyzed by the Thrombolysis in Myocardial Infarction (TIMI) definitions for major, minor, and minimal bleeding. The incidence of cardiovascular death, stroke, MI, or recurrent ischemia was similar between the four arms (7.8% vs. 3.9% vs. 10.8% vs. 9.5%, p = 0.26). The incidence of ischemia, as detected by 48-hour Holter monitoring, was lower in the combined atopaxar arm, as compared with placebo (18.7% vs. 28.1%, p = 0.02).
Platelet function studies demonstrated a dose-dependent inhibition of platelet aggregation (as measured with 15 µM of thrombin receptor-activated peptide) with the 50 mg, 100 mg, and 200 mg maintenance doses of atopaxar (77% vs. 90% vs. 95% at 2 weeks, and 63% vs. 79% vs. 97% at 8 weeks). Significant inhibition of platelet aggregation with the loading dose of 400 mg was seen within 1-3 hours of administration (74%).
There was a dose-related increase in the incidence of alanine aminotransferase ≥3 x upper limit of normal (ULN) with higher doses of atopaxar (2.2% vs. 2.2% vs. 5.5%) compared with placebo (2.5%). Mean QTc was higher across the three atopaxar doses (410.9 vs. 414.4 vs. 417.8 msec), as compared with placebo (409.4 msec), although no malignant arrhythmias or syncope were noted.
Interpretation:
The results of the phase II LANCELOT ACS trial demonstrate the safety of atopaxar in terms of major bleeding in patients with ACS, as compared with placebo (on a background of aspirin and a thienopyridine), although higher doses were associated with a higher incidence of transaminitis and QTc prolongation. The trial was underpowered to study clinical outcomes, but they seemed to be similar between the placebo and atopaxar arms. A high level of platelet aggregation inhibition was achieved with the 400 mg loading dose within 1-3 hours of administration, and this was sustained with the maintenance doses in a dose-response fashion. Similar safety and efficacy results were noted in the recently presented and published J-LANCELOT trial in Japanese patients with ACS, coronary artery disease, or high-risk clinical characteristics.
Atopaxar is a PAR-1 antagonist, and thus, has a novel mechanism of antiplatelet action. Further phase III trials are awaited. Clinical outcomes trials with another PAR-1 antagonist, vorapaxar, are also underway.
Study Design:
Blinded. Parallel. Placebo Controlled. Randomized.
Primary Endpoints:
Major bleeding, as per CURE definition
Patient Population:
Male or female; ages 18-80 years
Presenting with features of unstable angina or non-ST-elevation MI
At least one of the following:
o Troponin T or I or creatine kinase-myocardial band ≥ULN
o ECG changes compatible with ischemia (i.e., ST depression at least 1 mm in two contiguous leads or T-wave inversion >3 mm or any dynamic ST shift or transient ST elevation)
o Randomization and treatment ≤72 hours of the onset of symptoms
Number of enrollees: 603
Duration of follow-up: 12 weeks
Mean patient age: 61 years (median)
Percentage female: 32%
Exclusions:
Increased risk of bleeding, anemia (hemoglobin <10 g/dl), thrombocytopenia (<100 x 103/μL), history of pathological intracranial findings
Planned elective major surgery
Planned use of oral anticoagulants (e.g., warfarin), fibrinolytics, or regular nonsteroidal anti-inflammatory drugs
Known hepatic disease or creatinine clearance <30 ml/min