Thrombolysis in Pediatric Stroke (TIPS)
Condition: Stroke
MeSH terms: Stroke
Intervention: Tissue plasminogen activator (Activase®)
Intervention description: 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.
Intervention MeSH terms: Plasminogen; Tissue Plasminogen Activator
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 2 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Stroke; Childhood; Thrombolysis

Summary:

      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 ischemic stroke (AIS) to
      determine the maximal safe dose of intravenous Tissue Plasminogen Activator (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.
    

Eligibility criteria:

        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)