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

• cclusion

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
• cclusion 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 [CI95 1.3-3.3] p=0.0085 Fishers exact)

CATCH results

• 10% (52/510) of patients had an intracranial
• cclusion.
• 19% (10/52) of patients with intracranial
• cclusion had early neurological deterioration

versus 2% (9/447) in patients without

• cclusion, 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
• utcome; (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

Informed Consent Process (cont.)

• Obtain subjects voluntary consent to participate
• If subject is unable to sign, but can indicate verbal/non-

verbal approval, consent in the presence of a witness will be obtained

• Study allows use of signed informed consent,

verbal/nonverbal consent, or consent provided by a Legally Authorized Representative

• Signed copy of consent should be provided to the

subject, with the original remaining on file at the site

• Consent process should be adequately documented in

the sites records

• On-going process during the time of subjects study

participation

Participating Sites:

• Calgary
• Vancouver
• Ottawa
• Montreal - CHUM/ Greenfield park
• Victoria
• Edmonton
• Quebec City
• Sunnybrook

Study Drug Administration

• An estimated weight will be used to calculate a weight

adjusted dose.

• There will be 2 dose tiers at 0.1mg/kg and 0.25mg/kg.

(25pts/tier)

• Advancement to the second dose tier will be dependent upon

safe completion of the 1st dose tier and approval of the DSMB.

• Temperature Requirements for Tenecteplase: Store

unreconstituted product at 2-30° C. If not used immediately, reconstituted product in the vial at 2-8 °C and use within 8 hours.

Study Drug Administration 2

• 2 signatures will be required to ensure proper dosing and minimize

any errors.

• TNK-tPA will be administered as a single intravenous bolus over 1-2
• minutes. Study drug must be given within 90 minutes of the CTA.
• TNK-tPA will be given in ER by the treating Investigator.

Prohibited Meds and Procedures:

• No antiplatelet agent, other antithrombotic medicines should be

given within the first 24 hours (+/- 6h) of the treatment.

• Patients should not undergo endovascular thrombectomy or

repeat thrombolysis.

• If the patient deteriorates, and the treating physician decides

to pursue endovascular thrombectomy, this is a Protocol Violation…….expect MANY FORMS!

Schedule of Assessments

Baseline 4-8 hour Day 1 Day 2 Day 5 or D/C Day 30 Day 90

Informed consent

X

History and examination

X

NIHSS

X X X X X X X

mRS

X X X

HSSS

X

Barthel Index

X X X X

CT head or MRO

X X

CTA COW

X X

Full Emergency Stroke Labs

X

Creatinine and CBC

X

ECG

X X

Adverse Event

X X X X X X

Study Drug

X

Site Monitoring

• It is paramount that the trial is performed in accordance with all

regulatory requirements; it is vital that No Protocol Violations

• ccur; No Protocol Waivers will be granted.
• An external independent monitor will ensure the completeness and

accuracy of information collected. There is a potential for Health Canada to perform an audit.

• This trial must be treated as a clinical trial, like all other industry
• trials. All study material will be stored and archived for 25 years.

Where are we at?

• Calgary only site up and running.
• 8 patients enrolled.
• No drug related SAE’s
• 4/8 patients recanalised (1 patient no fu

imaging).

• Plan is to apply to CIHR in March 2014 for

phase 3 RCT.

Questions??

• At any time if there are issues call the

monitoring number:

• 1-855-4TEMPO1 (1-855-483-6761)