Randomized, Placebo-Controlled Phase 2b Study to Evaluate the
Safety and Efficacy of Recombinant Human Lecithin Cholesterol
Acyltransferase in Acute ST-Segment-Elevation Myocardial
Infarction: Results of REAL-TIMI 63B

J 2022

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B

BONACA, M. P., D. A. MORROW, B. A. BERGMARK, D. D. BERG, J. A. C. LIMA et. al.

Basic information

Original name

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B

Authors

BONACA, M. P. (guarantor), D. A. MORROW, B. A. BERGMARK, D. D. BERG, J. A. C. LIMA, U. HOFFMANN, Y. KATO, M. T. LU, J. KUDER, S. A. MURPHY, Jindřich ŠPINAR (203 Czech Republic, belonging to the institution), T. OUDE OPHUIS, R. G. KISS, J. LOPEZ-SENDON, O. AVERKOV, S. B. WHEATCROFT, J. KUBICA, J. CARLOS NICOLAU, R. H. M. FURTADO, L. ABUHATZIRA, B. HIRSHBERG, S. A. OMAR, A. L. VAVERE, Y. T. CHANG, R. T. GEORGE and M. S SABATINE.

Edition

Circulation, PHILADELPHIA, LIPPINCOTT WILLIAMS & WILKINS, 2022, 0009-7322

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 37.800

RIV identification code

RIV/00216224:14110/22:00126848

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1161/CIRCULATIONAHA.122.059325

UT WoS

000854165700007

Keywords in English

acyltransferases; cholesterol ester transfer proteins; lipoproteins_HDL; ST elevation myocardial infarction

Abstract

V originále

BACKGROUND: 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 lecithincholesterol 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. METHODS: REAL-TIMI 63B (A Randomized, Placebo-controlled Phase 2b Study to Evaluate the Safety and Efficacy of MED16012 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. RESULTS: 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 (MED16012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: 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.

Citovat

BONACA, M. P., D. A. MORROW, B. A. BERGMARK, D. D. BERG, J. A. C. LIMA, U. HOFFMANN, Y. KATO, M. T. LU, J. KUDER, S. A. MURPHY, Jindřich ŠPINAR, T. OUDE OPHUIS, R. G. KISS, J. LOPEZ-SENDON, O. AVERKOV, S. B. WHEATCROFT, J. KUBICA, J. CARLOS NICOLAU, R. H. M. FURTADO, L. ABUHATZIRA, B. HIRSHBERG, S. A. OMAR, A. L. VAVERE, Y. T. CHANG, R. T. GEORGE and M. S SABATINE. Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B. Circulation. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS, 2022, vol. 146, No 12, p. 907-916. ISSN 0009-7322. Available from: https://dx.doi.org/10.1161/CIRCULATIONAHA.122.059325.

@article{2223861,
   author = {Bonaca, M. P. and Morrow, D. A. and Bergmark, B. A. and Berg, D. D. and Lima, J. A. C. and Hoffmann, U. and Kato, Y. and Lu, M. T. and Kuder, J. and Murphy, S. A. and Špinar, Jindřich and Oude Ophuis, T. and Kiss, R. G. and LopezandSendon, J. and Averkov, O. and Wheatcroft, S. B. and Kubica, J. and Carlos Nicolau, J. and Furtado, R. H. M. and Abuhatzira, L. and Hirshberg, B. and Omar, S. A. and Vavere, A. L. and Chang, Y. T. and George, R. T. and Sabatine., M. S},
   article_location = {PHILADELPHIA},
   article_number = {12},
   doi = {http://dx.doi.org/10.1161/CIRCULATIONAHA.122.059325},
   keywords = {acyltransferases; cholesterol ester transfer proteins; lipoproteins_HDL; ST elevation myocardial infarction},
   language = {eng},
   issn = {0009-7322},
   journal = {Circulation},
   title = {Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B},
   url = {https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059325?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed},
   volume = {146},
   year = {2022}
}

TY  - JOUR
ID  - 2223861
AU  - Bonaca, M. P. - Morrow, D. A. - Bergmark, B. A. - Berg, D. D. - Lima, J. A. C. - Hoffmann, U. - Kato, Y. - Lu, M. T. - Kuder, J. - Murphy, S. A. - Špinar, Jindřich - Oude Ophuis, T. - Kiss, R. G. - Lopez-Sendon, J. - Averkov, O. - Wheatcroft, S. B. - Kubica, J. - Carlos Nicolau, J. - Furtado, R. H. M. - Abuhatzira, L. - Hirshberg, B. - Omar, S. A. - Vavere, A. L. - Chang, Y. T. - George, R. T. - Sabatine., M. S
PY  - 2022
TI  - Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B
JF  - Circulation
VL  - 146
IS  - 12
SP  - 907-916
EP  - 907-916
PB  - LIPPINCOTT WILLIAMS & WILKINS
SN  - 00097322
KW  - acyltransferases
KW  - cholesterol ester transfer proteins
KW  - lipoproteins_HDL
KW  - ST elevation myocardial infarction
UR  - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059325?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
N2  - BACKGROUND: 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 lecithincholesterol 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. METHODS: REAL-TIMI 63B (A Randomized, Placebo-controlled Phase 2b Study to Evaluate the Safety and Efficacy of MED16012 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. RESULTS: 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 (MED16012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: 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.
ER  -

BONACA, M. P., D. A. MORROW, B. A. BERGMARK, D. D. BERG, J. A. C. LIMA, U. HOFFMANN, Y. KATO, M. T. LU, J. KUDER, S. A. MURPHY, Jindřich ŠPINAR, T. OUDE OPHUIS, R. G. KISS, J. LOPEZ-SENDON, O. AVERKOV, S. B. WHEATCROFT, J. KUBICA, J. CARLOS NICOLAU, R. H. M. FURTADO, L. ABUHATZIRA, B. HIRSHBERG, S. A. OMAR, A. L. VAVERE, Y. T. CHANG, R. T. GEORGE and M. S SABATINE. Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B. \textit{Circulation}. PHILADELPHIA: LIPPINCOTT WILLIAMS \&{} WILKINS, 2022, vol.~146, No~12, p.~907-916. ISSN~0009-7322. Available from: https://dx.doi.org/10.1161/CIRCULATIONAHA.122.059325.

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