Thrombolysis in Pediatric Stroke (TIPS)

• Sponsor: Seattle Children's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01591096
• Collaborator: The Hospital for Sick Children (Other), Medical College of Wisconsin (Other), University of Texas at Austin (Other), Alberta Children's Hospital (Other), McMaster University (Other)
• Enrollment: 1
• Locations: 15
• Arm: 1
• Actual Duration (Months): 14
• Patients Per Site: 0.1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Drug: Tissue plasminogen activator (Activase®)	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Thrombolysis in Pediatric Stroke (TIPS)
• Actual Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Tissue plasminogen activator All patients will receive study drug.

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.; Other Names: Genentech as Activase®

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

2. 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University and Lucile Packard Children's Hospital at Stanford	Palo Alto	California	United States	94304
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Columbia University Medical Center	New York	New York	United States	10032
6	Cleveland Clinic	Cleveland	Ohio	United States	44195
7	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15244
8	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
9	Children's Medical Center at Dallas	Dallas	Texas	United States	75390-9063
10	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
11	University of Texas Medical School at Houston	Houston	Texas	United States	77030
12	The University of Utah and Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
13	Seattle Children's Hospital	Seattle	Washington	United States	98105
14	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
15	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1E2

Sponsors and Collaborators

• Seattle Children's Hospital
• The Hospital for Sick Children
• Medical College of Wisconsin
• University of Texas at Austin
• Alberta Children's Hospital
• McMaster University

Investigators

• Principal Investigator: Catherine Amlie-Lefond, MD, Seattle Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Catherine Amlie-Lefond, Associate Professor of Neurology, Seattle Children's Hospital
• ClinicalTrials.gov Identifier: NCT01591096
• Other Study ID Numbers: 1R01NS065818
• First Posted: May 3, 2012
• Last Update Posted: May 25, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Catherine Amlie-Lefond, Associate Professor of Neurology, Seattle Children's Hospital: Stroke; Childhood; Thrombolysis
• Additional relevant MeSH terms: Stroke; Plasminogen; Tissue Plasminogen Activator

Study Results

Participant Flow

Pre-assignment Detail	1 patient was recruited for the study, however, they did not receive the intervention due to an AE

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
Overall Participants	1
Age (Count of Participants)
<=18 years	1 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Region of Enrollment (Count of Participants)
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Symptomatic Intracranial Hemorrhage
Description	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

Outcome Measure Data

Analysis Population Description

Data cannot be reported in the data table as no data was collected

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
Measure Participants	0

2. Secondary Outcome

Title	Pharmacokinetics of tPA
Description	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

Outcome Measure Data

Analysis Population Description

Data cannot be reported in the data table as no data was collected

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
Measure Participants	0

3. Secondary Outcome

Title	Pharmacokinetics of tPA
Description	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

Outcome Measure Data

Analysis Population Description

Data cannot be reported in the data table as no data was collected

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Arm/Group Title	Tissue Plasminogen Activator
Arm/Group Description	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.
All Cause Mortality
	Tissue Plasminogen Activator
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Tissue Plasminogen Activator
	Affected / at Risk (%)	# Events
Total	1/ (NaN)
Cardiac disorders
Hypoventilation, bradycardia	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	Tissue Plasminogen Activator
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

Limitations/Caveats

Early termination due to lack of participant accrual.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.