Safety Study of Allogeneic Mesenchymal Precursor Cell Infusion in Myocardial Infarction

This was a prospective, double-blind, randomized, placebo-controlled study that was designed to enroll approximately 225 participants with de novo anterior STEMI due to a lesion involving the proximal-mid LAD coronary artery who undergo primary PCI at approximately 45 clinical study sites. However, due to difficulty in consenting participants and operationalizing the protocol under the emergency environment of an acute STEMI, it became clear that a major protocol amendment would be required. Accordingly, the protocol was adjusted to randomize 105 participants (35 per treatment group) at 25 clinical study sites. This 53% reduction in participants from the original protocol allowed preliminary evaluations of safety and feasibility.

Potential participants who were in the midst of experiencing an acute anterior wall STEMI, where increased time to coronary revascularization is known to correlate with the extent of subsequent myocardial necrosis, were approached by a study site investigator prior to PCI to determine the participant's interest to participate in a stem cell investigational trial. This required the patient to sign an informed consent permitting both the PCI procedure and participation in the trial. Participants who agreed to participate in the AMICI study and had a successful and uneventful PCI and stenting of the culprit LAD lesion performed were then randomized to one of the three treatment groups. The randomization and treatment assignment were obtained using an interactive voice-response system (IVRS/interactive web response system [IWRS]). The following stratification for duration of cardiac ischemia was performed to ensure balanced randomization across the treatment groups:

• ≤2 hours
• >2 hours to ≤6 hours
• >6 to ≤12 hours

Eligible participants received intracoronary delivery of the assigned treatment infused via a microcatheter into the stented culprit artery.

After approximately 50% of the intracoronary infusion of investigational treatment was completed, an angiographic determination of coronary flow was performed. The following guidelines were used to determine if the remaining investigational agent should be infused:

The study infusion should have been continued if TIMI 2 or TIMI 3 flow was present in the absence of ALL of the following;

• Sustained hypotension not responsive to fluid administration;
• Clinical signs/symptoms indicating an acute cerebrovascular event;
• Re-elevation of ST-segments if previously resolved with PCI;
• Onset of the participant's symptoms of myocardial ischemia unresponsive to appropriate interventions;
• Two episodes of sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) requiring cardioversion (infusion can continue if a single episode of sustained VT/VF requiring cardioversion occurred).

Feasibility of the infusion of the investigational agent was assessed by measurement of TIMI flow and perfusion (1) immediately prior to, (2) during (after approximately 50% of total investigational agent volume infused) and (3) following the investigational agent infusion after successful PCI and stenting. There was no evidence of clinically important coronary microvascular obstruction related to infusion of the investigational agent.

If, for any reason, the site investigator withdrew a randomized participant prior to infusion of the investigational agent, the reason for early termination and data from the screening visit were entered into the eCRF by the study site. The participant did not remain in the study. If for any reason, a participant's study infusion was halted due to safety considerations, the participant remained in the study. A participant who prematurely withdrew from the study remained in the study for long-term safety follow-up.

Evaluation for safety was performed for up to 24 months post infusion for all non-Swedish sites. Participants enrolled in Sweden who consented for additional follow-up underwent safety assessments at 36, 48, and 60 months post-infusion of investigational agent. All participants were to have cardiac imaging using cardiac magnetic resonance imaging [cMRI] and 2D-echocardiography, Holter monitoring, clinical evaluations, and laboratory testing as outlined in the study protocol.

An independent Data Monitoring Safety Board (DSMB) reviewed all relevant acute peri-procedural data, serious adverse events (SAE), other adverse events (AE), and efficacy data (if requested) periodically until participant enrolment was closed.