IV vs. IA tPA (Activase) in Acute Ischemic Stroke With CTA Evidence of Major Vessel Occlusion
IV vs. IA tPA (Activase) in Acute Ischemic Stroke With CTA Evidence of Major Vessel Occlusion
Stroke is the third leading cause of death in the United States, responsible for 158,488
 deaths in 1998 (American Heart Association). Nationwide, each year, an estimated 600,000 to
 750,000 people suffer a new or recurrent stroke. Cerebral infarction comprises 80% of all
 strokes and is the result of a complex series of cellular metabolic events that occur rapidly
 after interruption of blood flow to a region of the brain. The extent of the brain damage is
 dependent on the duration and severity of the cerebral ischemia. Acute thrombus formation or
 migration is the principal cause of blood flow interruption in at least 75% of cerebral
 infarctions. In several animal models of focal cerebral ischemia, restoration of cerebral
 blood flow within two to six hours after initial occlusion has been associated with smaller
 volumes of cerebral infarction and improved functional outcome. An effective way of
 dissolving the thrombus is by administration of recombinant tissue plasminogen activator or
 Activase (Alteplase, rt-PA), which promotes the proteolytic action of plasmin from
 plasminogen at the site of a clot. In this study, the drug, Activase, will be administered in
 subjects with acute ischemic stroke (AIS) intravenously (IV) or by local intra-arterial (IA)
 injection. The use of the intravenous administration within 3 hours of stroke symptom onset
 is FDA approved whereas the intra-arterial administration, despite evidence of potential
 benefit, is not currently FDA approved. Although not FDA approved, this study will evaluate
 the effectiveness of IA thrombolysis with Activase, used in AIS because of its higher rate of
 recanalization , potential expansion of the time window out to 6 hours, and lower doses of
 thrombolytic agent used compared with systemic or intravenous Activase. The study is designed
 to test the feasibility and provide preliminary safety data regarding the relative benefits
 and risks of IA Activase as compared to IV Activase when administered per the NINDS rt-PA
 stroke study protocol, i.e. randomized within 3 hours of onset of symptoms of ischemic stroke
 then treated within 3 hours in the IV Activase arm and within 4 hours in the IA Activase arm.
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.

 Study Treatment Activase will be administered IV or IA based on random assignment. The IV
 administration will be in accordance to the FDA approved guidelines based on the NINDS rt-PA
 stroke study. The IA administration is considered investigational and will be in accordance
 to the ongoing IMS-2 study.

 Cathetrization and Intra-arterial Alteplase protocol: A sheath will be placed in the femoral
 artery by a 1-wall puncture and arteriography performed by standard technique. If the
 suspected distribution of ischemia is the carotid artery, injection of the common carotid
 artery for examination of the carotid bifurcation as well as for intracranial examination
 will be performed. If the suspected arterial distribution is vertebral or basilar artery,
 selective injection of both vertebral arteries will be performed. Arteriographic examination
 of the remainder cerebral vessels will be performed if examination of collateral flow to the
 brain is deemed essential for determining treatment strategies. Five thousand units of
 heparin will be administered IV as a bolus at the beginning of the procedure. No post bolus
 IV heparin will be administered. Per standard neurointerventional procedure, a heparin flush
 solution (eg, 1000 U in 500 mL) normal saline at ~2 U of heparin/min) will be used through
 the access sheath and continued till the sheath is removed.

 After performing diagnostic cerebral arteriogram, a 3F, tapered, variable-stiffness, end-hole
 microcatheter will be passed over a micro-guide wire to the level of occlusion. One milligram
 of Activase will be injected beyond the thrombus and the catheter retracted into the proximal
 thrombus where an additional one milligram of Activase will be injected. A maximum of 22 mg
 of Activase will be administered in pulse spray fashion at a rate of 1mg every 6 minutes up
 to 10 mg/hr for 2 hrs till the maximum dose is reached or a TIMI 3 flow is noted on
 arteriographic examination. Repeat arteriography will be performed every 15 minutes using
 isosmolar contrast during the intra-arterial administration to assess recanalization. If the
 vessel is not patent the intra-arterial administration is continued. If the vessel is
 partially recanalized, the infusion catheter is introduced further into the vessel for
 thrombus access. If the arterial catheter cannot be introduced into the thrombus, the
 Activase will be administered proximal to the thrombus as described above. The subject's
 neurological function will be evaluated every 15 minutes during the IA procedure, including
 level of consciousness, speech examination, cranial nerve examination, and upper extremity
 motor and sensory function.

 If the subject did not have an occlusion on the initial arteriogram in the vascular territory
 appropriate for the subject's symptoms, no Activase will be administered, and the procedure
 terminated (these subjects will be included in the overall analysis). If the subject has a
 significant stenosis or occlusion of the internal carotid, vertebral or basilar arteries, the
 stenosis/occlusion is traversed with the microcatheter to approach a distal occlusive
 thrombus. The use of Activase(IV) in an acute ischemic stroke is standard of care. IA
 Activase is being performed clinically, but is not standard of care. Intravenous Activase
 protocol: is essentially identical to the NINDS rt-PA stroke study. In accordance with the
 protocol, AIS subjects will be treated with IV Activase within 180 minutes from symptom
 onset. Symptom onset is defined in the usual manner as the last time at which the subject was
 known to be asymptomatic. A total dose of 0.9 mg/kg body weight (max 90 mg) will be
 administered, 10% of it given as IV push over 1 minute and the remainder 90% as an IV
 infusion over 1 hour.

 One week, one month, and three months after receiving Activase IV or IA the subject will
 spend 10 to 20 minutes talking to a doctor and being examined to check recovery from the
 stroke. In addition, 60 days after receiving the study drug, the study coordinator will
 contact the subject by phone to ask questions about overall feeling of health. This telephone
 contact is expected to take about five minutes. One follow-up visit after the subject has
 left the hospital is standard care for someone who has had a stroke. Other visits and the
 telephone call are for research purposes only.

 Outcome Measures

 Primary Efficacy Outcome Measures

 The following primary efficacy outcome measures will be evaluated:

 -  Feasibility of enrolling 12 subjects with major vessel occlusion within 1 year and
 random 1:1 assignment to treatment with IV (N=6) and IA (N=6) IA Activase using the
 following criteria: - Time to clinical and radiological assessments

 -  Time to IA Activase treatment

 -  Proportion of subjects receiving timely assessments and treatment

 -  Preliminary safety assessment: 24 hour symptomatic ICH

 -  Resources utilized and risk-benefit of IA Activase treatment.

 Secondary Outcome Measures

 The following secondary efficacy outcome measures will be evaluated:

 -  90-day efficacy outcome including NIHSS, modified Rankin Scale and Barthel's Index.

 -  24-h recanalization (TIMI 2/3) on MRA or CTA

 -  Major extracranial bleed (defined under section 3.3.3) and asymptomatic intracranial
 hemorrhage
Inclusion Criteria:Subjects will be eligible if the following criteria are met:

 -  Ability to provide written informed consent and comply with study assessments for the
 full duration of the study.

 -  Age > 18 years

 -  NIHSS ≥ 4 or isolated aphasia or isolated hemianopsia

 Exclusion Criteria:

 -  NIHSS >30

 -  Coma

 -  Rapidly improving symptoms

 -  History of stroke in the last 6 weeks

 -  Seizure at onset

 -  Subarachnoid Hemorrhage (SAH ) or suspected SAH

 -  Any history of Intracrannial Hemorrhage (ICH)

 -  Neoplasm

 -  Septic embolism

 -  Surgery, biopsy, trauma or LP in last 30 days

 -  Head trauma in the last 90 days

 -  Bleeding diathesis, or INR >1.7 or PTT >1.5 times baseline or platelet <100K

 -  SBP >180 or DBP ≥100 despite treatment with 3 doses of IV Labetalol (10-20 mg Q10")

 -  Lacunar stroke syndrome

 -  CT: Hemorrhage, tumor (except small meningioma), significant mass effect, midline
 shift, acute hypodensity or >1/3 MCA territory sulcal effacement

 -  Radiological contrast hypersensitivity

 -  Angiographic: Dissection, lack of access, lack of occlusion, or nonatherosclerotic
 arteriopathy