TY - JOUR
T1 - Effect of infusion of high-density lipoprotein mimetic containing recombinant apolipoprotein A-I Milano on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial
T2 - A randomized clinical trial
AU - Nicholls, Stephen J.
AU - Puri, Rishi
AU - Ballantyne, Christie M.
AU - Jukema, J. Wouter
AU - Kastelein, John J.P.
AU - Koenig, Wolfgang
AU - Wright, R. Scott
AU - Kallend, David
AU - Wijngaard, Peter
AU - Borgman, Marilyn
AU - Wolski, Kathy
AU - Nissen, Steven E.
N1 - Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nicholls reports receiving research support from AstraZeneca, Amgen Inc, Anthera, Eli Lilly, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi Regeneron, and LipoScience and consulting and honoraria from AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr Puri received consulting fees from Cerenis, Sanofi Aventis, and Amgen Inc. Dr Ballantyne received grant/research support (all significant [>$10 000] and paid to her institution) from Abbott Diagnostic, Amarin, Amgen Inc, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, the National Institutes of Health, the American Heart Association, and the American Dental Association and received consulting fees from Abbott Diagnostics, Amarin, Amgen Inc, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc, Merck, Novartis, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Dr Jukema has received research grant support from and/or was a speaker (with or without lecture fees) at continuing medical education–credited meetings that were sponsored by Amgen, Anthera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Programme. Dr Kastelein received personal consulting fees from Sanofi, Affiris, Akarna Therapeutics, Amgen Inc, CSL Behring, Regeneron, Staten Biotech, Madrigal, The Medicines Company, Kowa, Lilly, Esperion, Gemphire, Ionis Pharmaceuticals, and Akcea Pharmaceuticals. Dr Koenig reports receiving personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, GSK, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen and grants and nonfinancial support from Roche Diagnostics, Beckmann, Singulex, and Abbott. Dr Wright is a consultant for The Medicines Company, Boehringer-Ingelheim, AstraZeneca, Sanofi Regeneron, and Gilead. Drs Kallend and Wijngaard are employees of The Medicines Company. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen Inc, Cerenis, Eli Lilly, Esperion, Pfizer, The Medicines Company, Takeda, and Orexigen. Dr Nissen is involved in these clinical trials, but receives no personal remuneration for his participation. Dr Nissen consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. No other disclosures are reported. Funding/Support: The study was funded by The Medicines Company. Role of the Funder/Sponsor: The sponsor, The Medicines Company, participated actively in designing the study in collaboration with the steering committee, developed the protocol that was written by the steering committee, provided logistical support during the trial in terms of site management in collaboration with C5Research, and performed all site monitoring. The sponsor maintained the trial database. After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research, where statistical analyses were performed by an independent statistician, Kathy Wolski, MPH. The results reported in the article are the results of the analyses performed by Ms Wolski. The lead academic investigator (S.J.N.) wrote the manuscript and is responsible for the accuracy and completeness of the data and the analyses. While the steering committee and coordinating center had confidentiality agreements with the sponsor, the study contract specified that a copy of the study database be provided to C5Research for independent analysis. While employees of the sponsor are coauthors of the article, they provided a review of the drafts. The academic authors had unrestricted rights to publish the results. The manuscript was modified after consultating with the coauthors. The final decision on content was exclusively retained by the academic authors.
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/9
Y1 - 2018/9
N2 - IMPORTANCE Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. OBJECTIVE To determine the effect of infusingMDCO-216 on coronary atherosclerosis progression. DESIGN, SETTING, AND PARTICIPANTS This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. MAIN OUTCOMES AND MEASURES The primary efficacy measurewas the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measureswere the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patientswhodemonstrated plaque regression. Safety and tolerabilitywere also evaluated. RESULTS Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93men[76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5]mg/dL [to convert to millimoles per liter, multiply by0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levelswere comparable with the placebo andMDCO-216 (68.6 vs 70.5mg/dL; difference, -2.5mg/dL; 95%CI, -10.1 to 5.0; P = .51).Areduction in high-density lipoprotein cholesterol levelswas observed inMDCO, but not placebo patients (-3.3 vs 3.0mg/dL [to convert to millimoles per liter, multiply by0.0259]; difference, -6.3mg/dL; 95%CI, -8.5 to -4.1; P < .001). Percent atheroma volume, whichwas adjusted for baseline values, decreased0.94%with the placebo and0.21% withMDCO-216 (difference,0.73%; 95%CI, -0.07 to 1.52; P = .07). Normalized TAVdecreased 7.9mm3 with the placebo and 6.4mm3 withMDCO-216 (difference, 1.6mm3; 95%CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8mm3 with the placebo and 2.2mm3 with MDCO-216 (difference0.4mm3; 95%CI, -4.4 to 3.5; P = .83).Asimilar percentage of patients demonstrated a regression of PAV(67.2%vs 55.8%; P = .21) and TAV(68.9%vs 71.2%; P = .79) in the placebo andMDCO-216 groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy.
AB - IMPORTANCE Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. OBJECTIVE To determine the effect of infusingMDCO-216 on coronary atherosclerosis progression. DESIGN, SETTING, AND PARTICIPANTS This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. MAIN OUTCOMES AND MEASURES The primary efficacy measurewas the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measureswere the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patientswhodemonstrated plaque regression. Safety and tolerabilitywere also evaluated. RESULTS Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93men[76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5]mg/dL [to convert to millimoles per liter, multiply by0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levelswere comparable with the placebo andMDCO-216 (68.6 vs 70.5mg/dL; difference, -2.5mg/dL; 95%CI, -10.1 to 5.0; P = .51).Areduction in high-density lipoprotein cholesterol levelswas observed inMDCO, but not placebo patients (-3.3 vs 3.0mg/dL [to convert to millimoles per liter, multiply by0.0259]; difference, -6.3mg/dL; 95%CI, -8.5 to -4.1; P < .001). Percent atheroma volume, whichwas adjusted for baseline values, decreased0.94%with the placebo and0.21% withMDCO-216 (difference,0.73%; 95%CI, -0.07 to 1.52; P = .07). Normalized TAVdecreased 7.9mm3 with the placebo and 6.4mm3 withMDCO-216 (difference, 1.6mm3; 95%CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8mm3 with the placebo and 2.2mm3 with MDCO-216 (difference0.4mm3; 95%CI, -4.4 to 3.5; P = .83).Asimilar percentage of patients demonstrated a regression of PAV(67.2%vs 55.8%; P = .21) and TAV(68.9%vs 71.2%; P = .79) in the placebo andMDCO-216 groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy.
UR - http://www.scopus.com/inward/record.url?scp=85052738253&partnerID=8YFLogxK
U2 - 10.1001/jamacardio.2018.2112
DO - 10.1001/jamacardio.2018.2112
M3 - Article
C2 - 30046837
AN - SCOPUS:85052738253
VL - 3
SP - 806
EP - 814
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 9
ER -