Rituximab in Patients with Acute ST-elevation Myocardial Infarction (RITA-MI): an Experimental Medicine Safety Study.

Abstract

AIMS\nIn pre-clinical models of acute myocardial infarction (MI), mature B cells mobilise inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility and pharmacodynamic effect of rituximab given to patients with acute ST elevation MI (STEMI).\n\n\nMETHODS AND RESULTS\nRITA-MI was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48\u2009hours of symptom onset. Four escalating doses (200, 500, 700 and 1000\u2009mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. [NCT : 03072199]. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% CI 93.8-98.8%) depletion of circulating B cells within 30 mins of starting the infusion. Maximal B cell depletion was seen at day 6, which was significantly lower than baseline for all doses (p\u2009<\u20090.001). B cell repopulation at 6\u2009months was dose-dependent, with modulation of returning B cell subsets. Immunoglobulin (IgG, IgM and IgA) levels were not affected during the 6\u2009months of follow-up.\n\n\nCONCLUSIONS\nA single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy.\n\n\nCLINICAL TRIAL REGISTRATION\nNCT03072199 at https://www.clinicaltrials.gov/.\n\n\nTRANSLATIONAL PERSPECTIVE\nSelective depletion of B cells using anti-CD20 antibody has been shown to be beneficial in various pre-clinical models of myocardial infarction with additional supportive clinical observational data. Our research provides the first translational step in using this strategy in patients. We found rituximab to be safe and effective in rapidly and profoundly depleting B cells in patients after an acute myocardial infarction. This work has directly led to the funding and setup of a multi-centre, international, randomised, double-blind, placebo-controlled, phase 2\u2009b clinical trial which should give us an indication of this strategy s clinical efficacy.