CPC Clinical Research, Department of Medicine, University of Colorado Anschutz School of Medicine, Aurora (M.P.B.).
TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.A.M., B.A.B., D.D.B., J. Kuder, S.A.M., M.S.S.).
Circulation. 2022 Sep 20;146(12):907-916. doi: 10.1161/CIRCULATIONAHA.122.059325. Epub 2022 Aug 30.
High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction.
REAL-TIMI 63B (A Randomized, Placebo‑controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012.
A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided =0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided =0.30). There was no significant difference in treatment emergent serious adverse events.
Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events.
URL: https://www.
gov; Unique identifier: NCT03578809.
高密度脂蛋白在胆固醇逆向转运中起着关键作用。此外，高密度脂蛋白颗粒可能具有心脏保护作用，并减少心肌损伤时的梗死面积。卵磷脂-胆固醇酰基转移酶是胆固醇逆向转运的限速酶。Medi6012 是一种重组人卵磷脂-胆固醇酰基转移酶，可增加高密度脂蛋白胆固醇。给予卵磷脂-胆固醇酰基转移酶有可能减少急性 ST 段抬高型心肌梗死的梗死面积和消退冠状动脉斑块。
REAL-TIMI 63B（一项随机、安慰剂对照的 2b 期研究，评估 MEDI6012 在急性 ST 段抬高型心肌梗死中的安全性和疗效）是一项多中心、随机、安慰剂对照的 2b 期临床试验。症状发作后 6 小时内发生 ST 段抬高型心肌梗死且计划行经皮介入治疗的患者，按 2:1 的比例随机分为 Medi6012（2 或 6 剂量方案）或安慰剂组，并随访 12 周。主要终点为 10 至 12 周时心脏 MRI 评估的左心室质量百分比梗死面积，主要分析为经皮介入治疗前 TIMI 血流分级 0 至 1 的患者，他们接受了至少 2 剂 Medi6012。次要终点为冠状动脉计算机断层血管造影术从基线到 10 至 12 周的非钙化斑块体积变化，主要分析为接受 Medi6012 全部 6 剂的患者。
共随机分配了 593 例患者。患者中位年龄为 62 岁，77.9%为男性，95.8%为他汀类药物初治患者。症状发作至随机分组的中位时间为 146（四分位距 [IQR]，103-221）分钟，自入院至随机分组的中位时间为 12.7（IQR，6.6-24.0）分钟，首次药物剂量在经皮介入治疗前中位时间为 8（IQR，3-13）分钟。指数心肌梗死在前壁占 69.6%，TIMI 血流分级 0 至 1 占 65.1%。12 周时，治疗组间梗死面积无差异（Medi6012：9.71%，IQR 4.79-16.38；安慰剂：10.48%，[IQR，4.92-16.61]，单侧=0.79）。非钙化斑块体积也无差异（几何均数比，0.96[95%CI，NA-1.10]，单侧=0.30）。治疗中出现的严重不良事件无显著差异。
在急性 ST 段抬高型心肌梗死患者中给予 Medi6012 治疗并未导致 12 周时梗死面积或非钙化斑块体积显著减少。Medi6012 耐受性良好，总体严重不良事件无增加。
