Stroke
Conditions
Keywords
Stroke, Childhood, Thrombolysis
Brief 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.
Detailed description
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.
Interventions
DRUGTissue plasminogen activator (Activase®)
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.
Sponsors
The Hospital for Sick Children
Medical College of Wisconsin
University of Texas at Austin
Alberta Children's Hospital
McMaster University
Seattle Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Intracranial Hemorrhage | 36 hours | Any PH 2 OR, Any intracranial hemorrhage which is judged to be the most important cause of neurological deterioration (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, Any hemorrhage that results in the need for transfusion, need to discontinue study drug, surgical evacuation of hemorrhage, or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of tPA | 24 hours | 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. |
Countries
Canada, United States
Participant flow
Pre-assignment details
1 patient was recruited for the study, however, they did not receive the intervention due to an AE
Participants by arm
| Arm | Count |
|---|---|
| Tissue Plasminogen Activator All patients will receive study drug.
Tissue plasminogen activator (Activase®): 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. | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Tissue Plasminogen Activator |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Region of Enrollment United States | 1 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 1 / — |
Outcome results
Primary
Symptomatic Intracranial Hemorrhage
Any PH 2 OR, Any intracranial hemorrhage which is judged to be the most important cause of neurological deterioration (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, Any hemorrhage that results in the need for transfusion, need to discontinue study drug, surgical evacuation of hemorrhage, or death.
Time frame: 36 hours
Population: Data cannot be reported in the data table as no data was collected
Secondary
Pharmacokinetics of tPA
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.
Time frame: 24 hours
Population: Data cannot be reported in the data table as no data was collected
Secondary
Pharmacokinetics of tPA
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.
Time frame: 24 hours
Population: Data cannot be reported in the data table as no data was collected