Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke

被引：117

作者：

Lyden, Patrick ^{[1
]}

Pryor, Kent E. ^{[2
]}

Coffey, Christopher S. ^{[3
]}

Cudkowicz, Merit ^{[4
]}

Conwit, Robin ^{[5
]}

Jadhav, Ashutosh ^{[6
,25
]}

Sawyer, Robert N., Jr. ^{[7
]}

Claassen, Jan ^{[8
,27
]}

Adeoye, Opeolu ^{[9
,28
]}

Song, Shlee ^{[1
]}

Hannon, Peter ^{[10
,30
]}

Rost, Natalia S. ^{[4
]}

Hinduja, Archana ^{[11
,32
]}

Torbey, Michel ^{[11
,32
]}

Lee, Jin-Moo ^{[12
,33
]}

Benesch, Curtis ^{[13
,34
]}

Rippee, Michael ^{[14
,35
]}

Rymer, Marilyn ^{[14
,35
]}

Froehler, Michael T. ^{[15
,36
]}

Clarke Haley, E. ^{[16
,37
]}

Johnson, Mark ^{[17
,39
]}

Yankey, Jon ^{[3
]}

Magee, Kim ^{[3
]}

Qidwai, Julie ^{[3
]}

Levy, Howard ^{[2
]}

Mark Haacke, E. ^{[18
]}

Fawaz, Miller ^{[18
]}

Davis, Thomas P. ^{[19
]}

Toga, Arthur W. ^{[20
]}

Griffin, John H. ^{[21
]}

Zlokovic, Berislav V. ^{[22
,23
]}

Pryor, Kent

Zlokovic, Berslav

Fornal, Kathleen

Conwit, Robin ^{[5
]}

Coull, Bruce

Adams, Harold

Bushnell, Cheryl

Leira, Enrique

Tirschwell, David

Sansing, Lauren

Kasner, Scott

Savitz, Sean

Meschia, James ^{[24
]}

Cloyd, James ^{[24
]}

Gurney, James ^{[24
]}

Lynch, David ^{[24
]}

Martin, Renee ^{[24
]}

Jadhav, Ashutosh ^{[6
,25
]}

Ducruet, Andrew ^{[25
]}

机构：

[1] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[2] ZZ Biotech LLC, Houston, TX USA

[3] Univ Iowa, Iowa City, IA USA

[4] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA

[5] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[6] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA

[7] SUNY Buffalo, Buffalo, NY USA

[8] Columbia Univ, Neurol Inst, New York, NY USA

[9] Univ Cincinnati, Dept Emergency Med, Cincinnati, OH USA

[10] Univ Utah, Salt Lake City, UT USA

[11] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA

[12] Barnes Jewish Hosp, St Louis, MO 63110 USA

[13] Univ Rochester, Med Ctr, Rochester, NY 14642 USA

[14] Univ Kansas Hosp, Kansas City, KS USA

[15] Vanderbilt Univ, Med Ctr, Cerebrovasc Program, Nashville, TN USA

[16] Univ Virginia, Charlottesville, VA USA

[17] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA

[18] MRI Inst Biomed Res, Bingham Farms, MI USA

[19] Univ Arizona, Coll Med, Dept Med Pharmacol, Tucson, AZ USA

[20] Univ Southern Calif Los Angeles, Keck Sch Med, Lab Neuro Imaging, Inst Neuroimaging & Informat, Los Angeles, CA USA

[21] Scripps Res Inst, La Jolla, CA 92037 USA

[22] Univ Southern Calif Los Angeles, Zilkha Neurogenet Inst, Los Angeles, CA USA

[23] Univ Southern Calif Los Angeles, Dept Physiol & Neurosci, Keck Sch Med, Los Angeles, CA USA

[24] DSMB, Los Angeles, CA USA

[25] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA

[26] SUNY Buffalo, Gates Vasc Inst, Buffalo, NY USA

[27] Columbia Univ, Med Ctr, New York Presbyterian Hosp, New York, NY 10027 USA

[28] Univ Cincinnati, Cincinnati, OH 45221 USA

[29] Cedars Sinai Med Ctr, Los Angeles, CA USA

[30] Univ Utah, Salt Lake City, UT 84112 USA

[31] Massachusetts Gen Hosp, Harvard Partners, Boston, MA 02114 USA

[32] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA

[33] Washington Univ, Sch Med, Barnes Jewish Hosp, St Louis, MO 63130 USA

[34] Univ Rochester, Med Ctr, Rochester, NY 14627 USA

[35] Univ Kansas, Med Ctr, Lawrence, KS 66045 USA

[36] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA

[37] Univ Virginia, Charlottesville, VA 22903 USA

[38] Northwestern Mem Hosp, Chicago, IL USA

[39] Univ Texas Southwestern Med Ctr Dallas, Parkland Hlth & Hosp Syst, Dallas, TX 75390 USA

来源：

ANNALS OF NEUROLOGY | 2019年 / 85卷 / 01期

关键词：

THERAPEUTIC WINDOW; ANALOG; NEUROPROTECTION; THROMBOSIS; EXTENDS; CELLS; MICE;

D O I：

10.1002/ana.25383

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. Methods The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 mu g/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. Results Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 mu g/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 +/- 5.8 ml in placebo to 0.8 +/- 2.1 ml in the combined treatment arms (p = 0.066). Interpretation RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 mu g/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confir

引用

页码：125 / 136

页数：12

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