IV vs. IA tPA (Activase) in Acute Ischemic Stroke With CTA Evidence of Major Vessel Occlusion

DESCRIPTION OF THE STUDY This is a randomized, controlled, single center feasibility and preliminary safety study to determine the clinical efficacy of Activase administered locally, IA, in the course of an angiogram, as compared with Activase systemic IV infusion, in subjects with a ischemic stroke due to major vessel occlusion (M1, M2, terminal ICA, basilar or vertebral) detected by CT angiography, within 3 hours of symptoms onset. IV Activase (0.9 mg kg-1, maximum 90 mg) will be administered as per the NINDS protocol and IA Activase (2 mg bolus, followed by 10 mg hr-1 for 2 hours or TIMI 3 recanalization, whichever is earlier, maximum total dose 22 mg) will be administered as per the protocol used in the IMS-2 study with administration initiated within 4 hours from symptom onset and completed within 6 hours from symptom onset. The subject will be randomized following CT angiography after the demonstration of complete occlusion or minimal perfusion of symptom-related M1 segment and/or M2, distal ICA, vertebral artery or basilar artery. The primary analysis will be focused on feasibility of such a trial in terms of time-frame, preliminary safety analysis (the proportion of symptomatic intracranial hemorrhages) and preliminary risk-benefit ratio of IA Activase when compared with IV Activase. Secondary analyses will include the proportion of subjects exhibiting significant neurological improvement, reduction in disability and recanalization on a MRA or CTA. The sample size for this feasibility trial was estimated taking into account that it will be done in a single center, involve a major investment in time, personnel, and equipment required. IA thrombolysis as compared to IV thrombolysis, should be justified only with evidence of a superior clinical efficacy. A larger multicenter feasibility trial will need to be planned to determine safety and estimate sample size for an efficacy trial. An outside, independent safety monitor will assess the safety of the treatment arms.

A majority of clinical trials involving AIS conducted since the NINDS Activase stroke study have yielded negative results, emphasizing the point that recanalization and not neuroprotection can lead to clinical improvement. A recent randomized clinical trial (PROACT) showed the efficacy (recanalization and clinical improvement) of IA thrombolysis with Prourokinase for acute ischemic stroke <6 h from symptom onset, due to occlusion of proximal MCA. Although not FDA approved, IA thrombolysis with Activase, used in AIS is attractive because of higher rates of recanalization, potential extension of the time window out to 6 hours from symptom onset, and lower doses of thrombolytic agent used compared with systemic or IV Activase and a possible lower rate of symptomatic ICH (5-7%) compared with IA Pro-UK (10.9%). Support for use of IV Activase comes mainly from the NINDS study, whereas that for IA Activase comes from the PROACT study and a metanalysis of several anecdotal series. However, these two therapeutic approaches have never been compared in a randomized controlled trial. IA Activase may be used in AIS due to major vessel occlusion, whereas IV Activase may be used independent of the presence or absence of major vessel occlusion. CT angiography can rapidly detect major vessel occlusion and hence candidacy for IA thrombolysis. An ongoing pilot (IMS-2 trial) assessing the use of combination of IV and IA thrombolysis and comparing it with historical control has one draw-back in that the subjects are being subjected to a dual risk of hemorrhage by IV (6%) + IA (5-7%) Activase.

The rationale for the study design is as follows:

• Random assignment: to reduce treatment assignment bias.
• Controlled: the appropriate control group being the FDA approved IV Activase administration.
• Open label: as intra-arterial and intravenous administration is difficult to blind observers because of the difference in route of administration that is obvious to the observer and the subject. Sham intra-arterial stick that can be used to camouflage the information, may be extremely dangerous in the intra-venous group.
• Blinded 90-day assessment: to remove assessment bias.

Method of Treatment Assignment Block randomization (1:1) will be used to assign equal numbers of subjects to the IV and IA arms. In the preliminary feasibility study twelve subjects will be randomly assigned to receive IV (N=6) and IA (N=6) Activase. The treatment will remain open label to the treating physician. A physician blinded to the treatment arm will assess the 90-day outcomes.