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Background: From the results of various experimental studies, increasing evidence has been accumulated that the activity of the Na+/H+ exchanger (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform on the cardiac myocyte plasma membrane and has been shown to reduce myocardial cell death and limit infarct size in experimental infarct models. Objective: The objective of the ESCAMI trial is to investigate the tolerability and cardioprotective efficacy of eniporide as an adjunct to reperfusion therapy in patients with acute myocardial infarction (AMI) compared to reperfusion therapy alone. Methods: In this phase II dose-finding trial, patients with AMI ≤6 h in duration and ST elevation in at least two leads are randomized to receive either eniporide or placebo as an adjunctive therapy to thrombolysis or primary percutaneous transluminal coronary angioplasty (PTCA). Eniporide or placebo has to be administered as a 10-min infusion before the initiation of the reperfusion therapy. The primary efficacy end point is the cumulative release of α-hydroxybutyrate dehydrogenase (area under the curve from 0 to 72 h). A total of 10 blood samples are taken over 72 h (baseline, 4, 8, 12, 16, 24, 36, 48, 60 and 72 h) and analyzed by a central laboratory. In addition, other cardiac markers, including creatine kinase (CK), CK-MB and troponin T and I are examined. Secondary target variables include relevant cardiovascular events within 6 weeks and total mortality up to 6 months. Resolution of ST segment elevation is measured at 90 and 180 min after the start of thrombolysis and immediately and 90 min after PTCA. The combined clinical end point at 6 weeks consists of total mortality, the occurrence of heart failure, cardiogenic shock or sustained ventricular arrhythmia. For the safety evaluation of the new drug, the incidence and type of adverse events is recorded up to 6 weeks. A two-stage adaptive design is employed that allows a reduction in the number of patients treated with ineffective doses compared to conventional dose-finding studies. In stage 1, four doses of eniporide (50, 100, 150 and 200 mg) are compared to placebo. The objective of stage 1 is to obtain some initial evidence of efficacy and to select a subset of doses to be tested in stage 2. A linear trend test is employed to test the efficacy at stage 1. In stage 2, the efficacy of the best two doses selected from stage 1 are compared to placebo. Conclusion: The ESCAMI trial tests a novel pharmacologic agent (eniporide) in patients with AMI and the hypothesis that inhibition of the NHE system before reperfusion can decrease infarct size and improve the clinical outcome. In addition, this trial is designed as a phase II trial and a two-stage design is employed to decrease the number of patients treated with an ineffective dose. This trial will add to our knowledge about the concept of myocardial cell protection by NHE inhibition induced before reperfusion therapy and the potential of this treatment strategy for clinical practice.