Acute Myocardial Infarction With HyperOxemic Therapy II (AMIHOT II)

The AMIHOT II clinical trial is designed as a focused study of a promising patient subset from the completed AMIHOT study. A brief synopsis of the AMIHOT experience is provided below, followed by a description of the AMIHOT II study.

The pivotal AMIHOT clinical study for the TherOx® Aqueous Oxygen (AO) System in treating post acute myocardial infarction (AMI) patients was approved by FDA on January 10, 2002 under IDE G980257/S011. The study objective was to determine whether the adjunctive administration of AO Therapy immediately after successful PCI in a group of patients presenting less than 24 hours from AMI symptom onset improves left ventricular function and reduces the area of infarction, with no increased incidence of 30-day Major Adverse Cardiac Events (MACE) when compared to a control group receiving only PCI standard-of-care treatment. 30-day MACE comprises the combined incidence of death, reinfarction, target vessel revascularization, and stroke.

Two hundred eighty-nine (289) patients were enrolled from January 16, 2002 through December 24, 2003, including 20 run-in subjects and 269 randomized patients. Three independent biomarkers (infarct size reduction, regional wall motion score improvement at three months, and reduction in ST segment elevation) were designated as co-primary endpoints to evaluate the effectiveness of AO Therapy. The study was designed to demonstrate superiority of the AO Therapy group as compared to controls for each of these endpoints, and to demonstrate non-inferiority of the AO Therapy group as compared to Control with respect to 30-day MACE. The study population was comprised of qualifying AMI patients treated with either PCI alone or with AO Therapy as an adjunct to successful PCI within 24 hours of symptom onset.

The observed 30-day MACE rates were comparable between the AO Therapy and Control groups. The AMIHOT trial results revealed positive trends for the overall study population in favor of the AO Therapy test group in each of the three co-primary endpoints. These favorable results did not demonstrate the required level of statistical significance to claim superiority. However, an examination of a pre-specified patient subset, anterior AMI subjects treated within six hours of symptom onset, showed promising results after analysis of the surrogate endpoint data, forming the basis for this IDE supplement that requests approval to conduct a new trial focused on this further defined patient population.

TherOx has designed a follow-up clinical trial focused on these anterior AMI subjects treated within six hours, utilizing a Bayesian statistical design that incorporates both the existing AMIHOT data, and the new proposed AMIHOT II study data, into a hierarchical model for combined analysis.

The key differences between the proposed AMIHOT II study and the previously conducted AMIHOT trial are:

• Focused target patient population - anterior AMI subjects revascularized within six hours of symptom onset. (AMIHOT included patients revascularized within 24 hours of symptom onset, irrespective of location of infarct.)
• Single effectiveness endpoint - infarct size reduction as measured by 14-day Tc-99m Sestamibi SPECT imaging. (AMIHOT included 3 co-primary endpoints)
• Non-inferiority comparison of 30-day MACE rates within a 6% safety delta (AMIHOT proposed an 8% delta.)
• Randomization scheme - AMIHOT II will be randomized on a 2.8:1 (AO Therapy Group: Control Group) basis, as compared to the (1:1) randomization used in AMIHOT.

The method of administration of AO Therapy and the basic design of the AO System and AO Cartridge have not changed since the approval was granted by FDA to conduct the AMIHOT trial. The IDE number for the AMIHOT II clinical proposal is consistent with AMIHOT (G980257).