A Phase III International Multi-center, Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Nitric Oxide Synthase Inhibition with Tilarginine Acetate Injection in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction,Or, the TRIUMPH Study:Tilarginine Acetate Injection in a Randomized International Study in Unstable AMI Patients / Cardiogenic Shock - TRIUMPH Study

Conditions: It is the intent of the proposed study to further evaluate the safety and efficacy of Tilarginine Acetate Injection as a novel, mortality reducing therapeutic drug for patients with cardiogenic shock complicating acute myocardial infarction.

Registration Number: EUCTR2005-000412-27-AT

Lead Sponsor: Arginox Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 700

Inclusion Criteria

1. Confirmation of Acute MI
Patients will be considered to have an acute MI if they meet both of the following criteria (a and b):
a. Ischemic symptoms for at least 30 minutes AND
b. Electrocardiogram (ECG) changes (at least one of the following):
- Two or more contiguous leads with ST segment elevation
- Evolving Q-waves
- Left bundle branch block (LBBB)
- ST segment depression in at least 2 contiguous leads
In non-ST elevation MI (including old LBBB), cardiac serum markers above the upper limit of normal in the local laboratory must be confirmed prior to study entry.
2. Confirmation of Persistent Cardiogenic Shock at Randomization
Patients must meet all of the following shock criteria (a, b, c and d) at the time of randomization :
a. Peripheral signs of tissue hypoperfusion such as decreased urine output and/or cool extremities AND
b. SBP <100 mm Hg (IABP may be paused for 60 seconds if required and clinically feasible to record a blood pressure <100 mm Hg) despite vasopressor therapy with dopamine dose at least 7 ug/kg/min, or norepinephrine / epinephrine 0.1 ug/kg/min (alone or in any combination that yields 0.1 ug/kg/min) or phenylephrine 0.7 ug/kg/min; AND
c. Evidence of elevated LV filling pressures e.g. that the subject is not hypovolemic. Clinical examples of this would include pulmonary congestion confirmed by clinical examination or chest radiography; a pulmonary capillary wedge pressure (PCWP) =15 mm Hg, determined from pulmonary artery catheterization or by Doppler echocardiography (mitral E wave deceleration time =130ms); a left ventricular end diastolic pressure (LVEDP) at catheterization > 20 mmHg if obtained no more than 3 hours prior to randomization, or an intravenous fluid challenge. The amount of intravenous infusion that is sufficient to exclude hypovolemic will be determined by the clinical status of the subject. Evidence of a sufficient volume infusion includes an increase in central venous pressure (CVP), or development of pulmonary congestion, or resolution of hypotension and shock, AND
d. Left ventricular ejection fraction (LVEF) <40% (measured by left ventriculography or echocardiography).
3. Confirmation of Persistent Cardiogenic Shock Five Minutes Prior to Study Drug Administration
Patients must meet all of the following shock criteria (a, b, and c) within 5 minutes of study drug administration:
a. Continued signs of tissue hypoperfusion such as decreased urine output and/or cool extremities AND
b. SBP <100 mm Hg (IABP may be paused for 60 seconds if required and clinically feasible to record a blood pressure <100 mm Hg) despite vasopressor therapy with dopamine dose at least 7 ug/kg/min, or norepinephrine / epinephrine 0.1 ug/kg/min (alone or in any combination that yields 0.1 ug/kg/min) or phenylephrine 0.7 ug/kg/min; AND
c. no intercurrent volume loss since randomization
4. Confirmed Patency of the Infarct Related Artery (<70% stenosis with any TIMI flow grade)
Infarct related artery patency must be confirmed by coronary angiography. Patency may be established by spontaneous reperfusion, fibrinolytic therapy and/or PCI. Patients with any TIMI flow or no reflow are eligible.
5. Duration of Cardiogenic Shock and time from patency of the IRA
The total duration of cardiogenic shock prior to randomization must be less than 24 hours.
Subjects must remain in shock for at least 1 hour after the patency of the IRA is confirmed.
Randomization cannot occur sooner than 1 hour after de

Exclusion Criteria

Patients will be excluded from participation in the study if ANY of the following criteria apply at the time of randomization:
1. Suspected or documented infection; or
2. Other causes of shock state (e.g., septic, hypovolemic, hemorrhagic, anaphylactic shock); or
3. Shock secondary to acute severe mitral regurgitation (MR) and/or mitral apparatus rupture; or
4. Other severe underlying valvular heart disease, e.g. aortic stenosis, mitral stenosis or aortic insufficiency; or
5. Cardiogenic shock due to predominant RV failure or severe RV dysfunction of any cause; or
6. Cardiogenic shock secondary to rupture of the ventricular septum or ventricular free wall; or
7. Cardiogenic shock secondary due solely to bradyarrhythmia or tachyarrhythmia; or
8. Aortic dissection; or
9. Serum creatinine > 3.0 mg/dl (>264 µmol/L); or
10. End-stage renal disease requiring dialysis; (including peritoneal dialysis); or
11. Adult respiratory distress syndrome (ARDS); or
12. Brain damage that precludes survival despite normalized cardiovascular status; or
13. Irreversible multi-system failure; for example a persistent pH <7.1, or acute liver failure; or
14. Intra-thoracic or abdominal surgical procedure within 30 days, unless procedure was coronary artery bypass grafting (CABG); or
15. Primary pulmonary hypertension; or
16. Age <18 years; or
17. Requirement for emergency coronary artery bypass grafting (CABG); or
18. IRA occlusion; or
19. Concurrent or prior participation in another clinical trial of an investigational drug in which the last dose of study drug was administered within 5 half-lives of that drug; or
20. Prior enrollment in this study; or
21. CS as a consequence of PCI (iatrogenic shock) if the IRA cannot be demonstrated as patent; or
22. Rapid resolution of cardiogenic shock between randomization and study drug administration. (The following are clinical examples of resolving shock; an SBP improvement of >20 mm Hg between randomization and initiation of study drug; a reduction of 25% or more in the dose of vasopressors administered). If there are signs of resolving shock, a 1-hour observation period for signs of further improvement should be undertaken. At the end of this hour, if SBP =100 mm Hg on vasopressors, no study drug should be given.
23. A positive pregnancy test in women who are of child-bearing potential and are not surgically sterile; or women who are breast feeding.