TEMPO-1 TNK-tPA evaluation for minor ischemic stroke with proven - PowerPoint PPT Presentation

TEMPO-1 – TNK-tPA evaluation for minor ischemic stroke with proven occlusion Shelagh Coutts and Carol Kenney

Background • Up to 80% of ischemic stroke is minor and initially non-disabling. • Most are not treated with thrombolysis as they are considered “too good to treat. • Many physicians feel that the risks of thrombolysis outweigh the benefits for general use of tPA in this population.

Large vessel occlusion • Minor stroke patients with large vessel occlusion are at the highest risk of deterioration when thrombolysis is withheld. • “too good to treat population” :34/241 patients (14%) had large artery occlusion. 44%(15/34) of patients with occlusion had poor outcome versus 21%(44/207) of patients with no occlusion, • RR = 2.1 [CI 95 1.3-3.3] p=0.0085 Fishers exact)

CATCH results • 10% (52/510) of patients had an intracranial occlusion. • 19% (10/52) of patients with intracranial occlusion had early neurological deterioration versus 2% (9/447) in patients without occlusion, p<0.0001. • More patients with intracranial occlusion are disabled at the time of 90 day follow up (31% versus 13%, p=0.0016).

CATCH Timing • 93% of patients with arterial occlusion presented under 12h and 7% presented after 12h. • Poor outcome risk is equal before 12h or after 12h or before or after 6 hours. • No cut point at which there was a reduced risk for disability. • We chose 12 hours as the cut off for treatment.

TNK (Tenectaplase) • Genetically engineered, mutant tissue plasminogen activator • Advantages compared to TPA (alteplase): – Higher fibrin specificity – More resistant to plasminogen activator – Longer serum half life – Simple bolus injection – Lower rate of systemic bleeding with similar ICH rates in acute MI (ASSENT 2 trial) Tanswell et al. 2002

Pilot dose- escalation study of Tenectaplase in Acute ischemic stroke ( Haley et al., 2005) • 88 patients with acute ischemic stroke treated with TNK within 3 hour of onset • Open label dose escalation study conducted in tiers of 25 patients (0.1, 0.2, 0.4, 0.5 mg/kg) • Primary outcome: symptomatic ICH at 36 hours • Clinical outcome at 24 hours and 3 months

Results- Haley et al. 2005 • N=88 patients enrolled • Study closed when 2/13 of 0.5 mg dose had symptomatic ICH resulting in death • Main Findings: – No symptomatic ICH in the lower dose groups – mRS similar at 3 months between three groups and historical NINDS rates – Trend for 0.1 mg/kg to have best clinical results at 24h and highest rate minimal disability at 3 months

Dose tier analysis – Parsons 2012 NEJM • 0.25 mg/kg vs. TPA: – improvement in all imaging outcomes – Improved 3 month outcome : 72 vs. 40 % (p=0.02) but lower dose group had better 24 h NIHSS • 0.25 vs. 0.1 mg/kg: – Higher mean reperfusion (88.1 vs. 69.3% ) and recanalization (96 vs. 78%) rates – Better clinical outcome: 24 hours and excellent recovery at 90 days

TEMPO Study Design • A Phase 2, prospective, two cohort, dose- escalation, safety and feasibility study. • The primary outcome will be subject safety defined by serious adverse events associated with the treatment. • Secondary outcomes include: (1) clinical outcome; (2) feasibility of enrolment; (3) recanalization of the target arterial occlusive lesion defined by CTA 4-8 hours after treatment.

Study Objectives • To demonstrate the safety and feasibility of using TNK-tPA (tenecteplase), a thrombolytic agent that is relatively novel to the treatment ischemic stroke but well-established in the treatment of myocardial infarction, to treat minor ischemic stroke patients with proven acute symptomatic occlusions.

SAE’s included in main outcome • Symptomatic intracranial hemorrhage (NIHSS worsening of 2 or more). • Major extracranial hemorrhage • Life-threatening angioedema defined as severe airway obstruction requiring intubation. • Life-threatening thrombolysis associated hypotension defined as a drop in blood pressure that requires inotropic support.

Secondary outcomes Multiple but include: • Asymptomatic or minor bleeding • Complete neurological recovery • Recanalization on follow up CT at 4-8 hours.

Selecting Patients • The principles of patient selection are based upon the broad criteria of: – Minor stroke presentation with a diagnosis of an ischemic stroke syndrome – Minor initial symptoms that would not normally warrant use of thrombolytic medication in the judgment of the treating neurologist. – Imaging proof of an intracranial occlusion relevant to the presenting symptoms • No region of well-defined hypodensity on the NCCT consistent with the presenting symptoms or consistent with the suspected pathophysiology of the presenting symptoms (ie. fractured embolus to the MCA) that suggests well-evolved infarction, judged to be potentially prone to bleeding.

Inclusion criteria Acute ischemic stroke in an adult patient (18 years of age or older) • Onset (last-seen-well) time to treatment time < 12 hours. • Minor stroke defined as a baseline NIHSS < 6 at the time of • randomization. Patients must have a demonstrable neurological deficit on physical neurological examination. Any acute intracranial occlusion (MCA, ACA, PCA, VB territories) • defined by non-invasive acute imaging (CT angiography) that is neurologically relevant to the presenting symptoms and signs. An acute occlusion is defined as TICI 0 or TICI 1 flow. Pre-stroke independent functional status in activities of daily living • with pre-stroke estimated modified Barthel Index of 90 or greater AND premorbid mRS 0 or 1 . Informed consent from the patient or surrogate. • Patients can be treated within 90 minutes of the CT/CTA being • completed.

Exclusion criteria Hyperdensity on NCCT consistent with any intracranial hemorrhage. • Any clinical suspicion of any intracranial hemorrhage even in the absence of visible blood on baseline brain imaging. Large acute stroke >1/3 MCA territory or ASPECTS<5 visible on • baseline CT scan. Core of established infarction. No area of grey matter hypodensity • at a similar or lesser density to white matter or in the judgment of the enrolling neurologist is consistent with a subacute ischemic stroke > 12 hours of age. Clinical history, past imaging and clinical judgment suggest that the • intracranial occlusion is chronic. Patient is a candidate for and should receive standard of care IV tPA. •

Exclusion criteria Stroke occurring as an in-patient. An in-patient is a person who has • been officially admitted to the hospital to a ward bed. A patient in the ED who has not been formally admitted is still considered to be an outpatient. Patient has a severe or fatal or disabling illness that will prevent • improvement or follow-up or such that the treatment would not likely benefit the patient. Patient cannot complete follow-up due to co-morbid non-fatal • illness (such as psychiatric illness) or is visiting the host sites city and cannot return for follow-up. Pregnancy. • Patient is actively taking dual antiplatelet medication (aspirin & • clopidogrel) in the last 48 hours. International normalized ratio ³ 1.4 •

Exclusion criteria Standard thrombolysis exclusions (Taken from Canadian guidelines) Historical • – History of intracranial hemorrhage – Stroke or serious head or spinal trauma in the preceding three months – Recent major surgery in the preceding three months. – Arterial puncture at a non-compressible site in the previous seven days – Any other condition that could increase the risk of hemorrhage after TNK-tPA administration

Exclusion criteria • Clinical – Symptoms suggestive of subarachnoid hemorrhage. – Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with Post-ictal Todd's paralysis or focal neurological signs due to severe hypo- or hyperglycemia. – Hypertension refractory to antihypertensive medication such that target blood pressure <185/110 cannot be achieved before treatment .

Exclusion criteria • Laboratory – Elevated activated partial-thromboplastin time. – Platelet count below 100,000 per cubic millimeter. – Active use of any standard or novel anticoagulant therapy with full anticoagulant dosing. [DVT prophylaxis dosing shall not prohibit enrolment]. Active use means that the patient has taken at least one dose of drug within 5 half-lives of the drug.

Enrolment/Informed Consent • Subjects voluntarily confirm their willingness to participate in the study • Sign informed consent form, after subjects are informed of all aspects of the study relevant to their decision to participate • Consent process is documented by a written, signed and dated informed consent form • Give the subject adequate information • Allow subject to consider all available options • Respond to subject questions • Ensure subject comprehends information