Thrombolysis in Pediatric Stroke (TIPS)

OBJECTIVES:

1. To determine the maximal safe dose of intravenous (IV) tPA among three doses (0.75. 0.9,
1.0 mg/kg) for children age 2-17 years within 4.5 hours from onset of acute AIS.

2. To determine the pharmacokinetics of tPA and its inhibitor, plasminogen activator
inhibitor in these children.

3. To measure the 3-month neurological outcome in children treated with IV tPA.

TRIAL DESIGN:

Thrombolysis in Pediatric Stroke (TIPS) is a five-year multi-center international safety and
dose-finding study of intravenous (IV) tPA in children with acute AIS to determine the
maximal safe dose of intravenous (IV) tPA among three doses (0.75. 0.9, 1.0 mg/kg) for
children age 2-17 years within 4.5 hours from onset of acute AIS.

An adaptive dose finding method will be applied to escalate across the three dose levels
within two age groups: 2-10 years (prepubertal) and 11-17 years. Dose will be escalated based
on safety (absence of excess toxicity) with at least 3 children treated at each dose level.
Intracranial hemorrhage following stroke can occur even in the absence of thrombolytic
therapy, but the risk is increased by the use of thrombolytics.

Primary endpoint toxicity is defined as SICH or severe hemorrhage within 36 hours of tPA
administration, defined as any of the following:

1. PH2 (parenchymal hemorrhage within 36 hours after tPA administration involving > 30% of
the infarcted area), regardless of whether or not it is associated with clinical
deterioration, OR,

2. Any intracranial hemorrhage which is judged to be the most important cause of
neurological deterioration. Neurological deterioration is guided by a minimum of change
of 2 or more points on the PedNIHSS from the lowest PedNIHSS. At the time of each
PedNIHSS assessment, the site PI or co-PI will review the patient's course with the care
team to ensure that all changes in neurologic status, including improvements since the
last assessment by the study team, are captured, OR,

3. Any hemorrhage that results in the need for transfusion, need to discontinue study drug,
surgical evacuation of hemorrhage, or death.

TIPS will determine the pharmacokinetics of tPA and its inhibitor, plasminogen activator
inhibitor, including free tPA, PAI-1, and tPA antigen in children receiving IV tPA for acute
AIS. In addition, TIPS will measure the 3-month neurological outcome in children treated with
IV tPA.

TRIAL POPULATION:

TIPS will enroll a maximum of 18 children age 2-10 years and maximum of 18 children age 11-17
years within 4.5 hours of the onset of acute AIS. On MRA or CTA they will have partial or
complete occlusion of the artery, consistent with focal impairment of the arterial flow, that
correlates with the clinical deficit.

TIPS STUDY INTERVENTION:

Investigation labeled tPA will be obtained for all sites by the Core Pharmacy as commercially
available recombinant tPA (Genentech as Activase®) for IV administration. The Bayesian method
of toxicity probability intervals will be used to select one of the following three dose
tiers (0.75, 0.9, 1.0 mg/kg) of IV tPA. The dose escalation for the two age groups (2-10,
11-17 years) will be performed independently. The maximum dose for each tier will be reached
at a weight of 90 kg.

To be eligible for TIPS, a patient must meet the following Inclusion Criteria:

1. Age 2 to 17 years inclusive.

2. Clinical presentation consisting of clearly defined acute onset of neurological
deficit in a pattern consistent with arterial territory ischemia.

3. Clinically significant deficit as defined by a PedNIHSS score of ≥ 6 and ≤ 24 felt to
be due to acute stroke that is not improving at the time of initiation of tPA
administration

4. Time of symptom onset within 4.5 hours of initiation of treatment for IV tPA. Time of
symptom onset is defined as time the patient was last seen awake and at neurological
baseline.

5. Radiological confirmation of an acute arterial ischemic stroke in one of two ways:

- MRI confirmation, consisting of acute infarction with restricted diffusion in an
arterial territory consistent with the clinical syndrome plus MRA showing partial
or complete occlusion in an intracranial artery corresponding to the infarct
location, OR,

- CT and CT angiogram confirmation, consisting of normal head CT or early
hypodensity in an arterial territory consistent with the clinical syndrome plus
CT angiogram showing partial or complete occlusion in an intracranial artery
corresponding to the infarct location.

6. Baseline neuroimaging (CT or MRI) with no evidence of intracranial hemorrhage
(including HI-1, HI-2, PH-1 or PH-2). If no head CT scan is done, the pre-tPA MRI must
include Gradient-recalled ECHO (GRE) imaging or Susceptibility Weighted Imaging (SWI)
sequences.

7. Children with seizures at or following onset of stroke may be included, as long as the
clinical picture is consistent with the documented arterial occlusion.

3.4.1.2.2. Patients with the following Exclusion Criteria will not be eligible for TIPS:

Safety Related exclusion criteria:

1. Patients in whom time of symptom onset is unknown.

2. Pregnancy

3. Clinical presentation suggestive of subarachnoid hemorrhage (SAH), even if head CT or
head MRI scan is negative for blood.

4. Patient who would decline blood transfusion if indicated

5. History of prior intracranial hemorrhage

6. Known cerebral arterial venous malformation, aneurysm, or neoplasm

7. Persistent Systolic Blood Pressure > 15% above the 95th percentile for age while
sitting or supine

8. Glucose < 50 mg/dl (2.78 mmol/l) or > 400 mg/dl (22.22 mmol/l)

9. Bleeding diathesis including platelets < 100,000, PT > 15 sec (INR > 1.4) or elevated
PTT > upper limits of the normal range.

10. Clinical presentation consistent with acute myocardial infarction (MI) or post-MI
pericarditis that requires evaluation by cardiology prior to treatment

11. Stroke, major head trauma, or intracranial surgery within the past 3 months

12. Major surgery or parenchymal biopsy within 10 days (relative contraindication)

13. Gastrointestinal or urinary bleeding within 21 days (relative contraindication)

14. Arterial puncture at noncompressible site or lumbar puncture within 7 days (relative
contraindication). Patients who have had a cardiac catheterization via a compressible
artery are not excluded.

15. Patient with malignancy or within 1 month of completion of treatment for cancer

16. Patients with an underlying significant bleeding disorder. Patients with a mild
platelet dysfunction, mild von Willebrand Disease or other mild bleeding disorders are
not excluded.

Stroke related exclusions:

1. Mild deficit (PedNIHSS < 6) at start of tPA infusion

2. Severe deficit suggesting very large territory stroke, with pre-tPA PedNIHSS > 25,
regardless of the infarct volume seen on neuroimaging

3. Stroke suspected to be due to subacute bacterial endocarditis, moyamoya, sickle cell
disease, meningitis, bone marrow, air or fat embolism

4. Previously diagnosed primary angiitis of the central nervous system (PACNS) or
secondary CNS vasculitis. Focal cerebral arteriopathy (FCA) of childhood is not a
contraindication.

Neuro-imaging related exclusions:

1. Intracranial hemorrhage (HI-1, HI-2, PH-1 or PH-2) on pretreatment head MRI or head CT

2. Intracranial dissection (defined as at or distal to the opthalmic artery)

3. Large infarct volume, defined by the finding of acute infarct on MRI involving 1/3 or
or more of the complete MCA territory involvement, regardless of the pre-tPA PedNIHSS
score due to increased risk of ICH.78, 79

Drug Related exclusions:

1. Known allergy to recombinant tissue plasminogen activator

2. Patient on anticoagulation therapy must have INR ≤ 1.4

3. Patient who received heparin within 4 hours must have aPTT in normal range

4. LMWH within past 24 hours (aPTT and INR will not reflect LMWH effect)