TEMPO-1: TNK-tPA Evaluation for Minor Ischemic Stroke With Proven Occlusion

• Sponsor: University of Calgary (Other)
• Overall Status: Completed
• CT.gov ID: NCT01654445
• Collaborator: Vancouver General Hospital (Other), Ottawa Hospital Research Institute (Other), Hopital Charles Lemoyne (Other), Université de Sherbrooke (Other), Vancouver Island Health Authority (Other), CHU de Quebec-Universite Laval (Other)
• Enrollment: 50
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This trial will enroll patients that have been diagnosed with a transient ischemic attack (TIA) or minor stroke that has occurred within the past 12 hours. Anyone diagnosed with a minor stroke faces the possibility of long-term disability and even death, regardless of treatment. Stroke symptoms such as weakness, difficulty speaking and paralysis may improve or worsen over the hours or days immediately following a stroke. The purpose of this research trial is to study the effects of a clot-dissolving drug, tenecteplase (TNK-tPA), as a treatment for patients who arrive within twelve hours from stroke onset. This study is attempting to see if TNK-tPA given through a vein in the arm (intravenous) to patients is a safe treatment for stroke patients. Neither the safety nor the effectiveness of this treatment has been proven yet.

This trial will be conducted at several site in Canada.

Dr Michael Hill and Dr. Shelagh Coutts are the Principal Investigators of this trial, coordinated at the University of Calgary, Foothills Medical Centre.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: Tenecteplase	Phase 2

Detailed Description

The primary objective of TEMPO-1 is 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. Up to 80% of ischemic stroke is minor and initially non-disabling. These patients present with a transient ischemic attack (TIA) or minor stroke.An overwhelming majority are not treated with thrombolysis as they are considered "too good to treat" by most physicians.

TEMPO-1 will enroll patients within a 12 hour time window with a NIHSS score of <6 and an ASPECTS >5. Patients must have an intracranial occlusion on CTA. Study drug must be administered within 90 minutes from the first slice of CTA. This is an open- label, multi-centre trial, dose- escalated trial. A total of 50 patients will be enrolled, 25 per tier. There will two dose tiers at 0.1 mg/kg and 0.25 mg/kg. Advancement to the second dose-tier will be dependent upon safe completion of the 1st dose tier and the approval of the DSMB.

Patients will undergo a study CT angiogram of the intracranial circulation between 4-8 hours after treatment to determine the biological effect of the drug - whether the occluded artery has recanalized or not. Patients will be assessed at 24 and 48 hours, and at Days 5, 30, and 90.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Prospective, Two Cohort, Dose-escalation, Safety and Feasibility Study of Thrombolysis for Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion Using TNK-tPA
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TNK-tPA Tenecteplase This is an open-label trial, all patients will receive tenecteplase.	Drug: Tenecteplase; Tenecteplase will be given to the patient as an intravenous bolus over 1- 2 minutes within 90 minutes of the first slice of the CTA. This is an open-label trial, all patients will receive tenecteplase, either tier 1 or tier 2 dosage.; Other Names: TNK-tPA

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Serious Bleeding Events [Up to 12 weeks]

   The primary safety outcome will be the rate of expected serious adverse events associated with study drug. This will be defined as the number patients with at least one SAE divided by the number of patients enrolled by dose-tier. Thus, the unit of analysis will be the patient and not the SAE.

Secondary Outcome Measures

1. Number of Patients With NIHSS 0 and mRS 0 and Barthel Index > 90 [90 days]

   Complete neurological and functional recovery at 90 days defined as: NIHSS 0 and mRS 0 iii)Complete neurological and functional recovery at 90 days defined as: a. NIHSS 0-1 and mRS 0-1 and Barthel Index > 90 NIHSS = National Institutes of Health Stroke Scale. This integer scale ranges 0-42 and is a quantitative measure of the neurological examination. mRS = modified Rankin Scale. This integer scale ranges from 0-6 and is a criterion-based quantitative measure of functional neurological disability. BI = Barthel Index. This scale range from 0-100 (in increments of 5 points) and is a summative categorical score measuring activities of daily living.

Other Outcome Measures

1. Number of Patients With Recanalization 4-8 Hours Post-treatment [4-8 hours]

   Recanalization defined on follow-up 4-8 hour CTA as a modified arterial occlusive lesion (mAOL) score 0-1.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Acute ischemic stroke in an adult patient (18 years of age or older)

2. Onset (last-seen-well) time to treatment time < 12 hours.

3. Minor stroke defined as a baseline NIHSS < 6 at the time of randomization. Patients must have a demonstrable neurological deficit on physical neurological examination.

4. 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.

5. 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.

6. Informed consent from the patient or surrogate.

7. Patients can be treated within 90 minutes of the CT/CTA being completed.

Exclusion Criteria:

1. 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.

2. Large acute stroke >1/3 MCA territory or ASPECTS<5 visible on baseline CT scan.

3. 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.

4. Clinical history, past imaging and clinical judgment suggest that the intracranial occlusion is chronic.

5. Patient is a candidate for and should receive standard of care IV tPA.

6. 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.

7. 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.

8. Patient cannot complete follow-up due to co-morbid non-fatal illness or is visiting the host sites city and cannot return for follow-up.

9. Pregnancy.

10. Patient is actively taking dual antiplatelet medication (aspirin & clopidogrel) in the last 48 hours.

11. International normalized ratio > 1.4

12. Standard thrombolysis exclusions (Taken from Canadian guidelines1)

NOTES: NIHSS = National Institutes of Health Stroke Scale ACA = anterior cerebral artery MCA = middle cerebral artery ICA = internal cerebral artery PCA = posterior cerebral artery VB = vertebrobasilar TICI = thrombolysis in cerebral ischemic scale CT = computed tomography NCCT = non-contrast CT CTA = CT angiography ASPECTS = Alberta Stroke Program Early CT Score IV = intravenous tPA = tissue plasminogen activator ED = Emergency Department

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Calgary	Calgary	Alberta	Canada	T2N 2T9

Sponsors and Collaborators

• University of Calgary
• Vancouver General Hospital
• Ottawa Hospital Research Institute
• Hopital Charles Lemoyne
• Université de Sherbrooke
• Vancouver Island Health Authority
• CHU de Quebec-Universite Laval

Investigators

• Principal Investigator: Michael D Hill, MD,MSc FRCPC, University of Calgary
• Principal Investigator: Shelagh B Coutts, MD,FRCPC, University of Calgary

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 6, 2012

More Information

Additional Information:

• TEMPO-1 site

Publications

None provided.

• Responsible Party: Dr. Michael Hill, PI, University of Calgary
• ClinicalTrials.gov Identifier: NCT01654445
• Other Study ID Numbers: Version 2.2, Aug 28,2013
• First Posted: Jul 31, 2012
• Last Update Posted: Nov 25, 2020
• Last Verified: Nov 1, 2020

• Keywords provided by Dr. Michael Hill, PI, University of Calgary: Minor stroke
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia; Tenecteplase

Study Results

Participant Flow

Recruitment Details	Patients were recruited from July 2012 through July 2014
Pre-assignment Detail	All patients were treated with study drug.

Arm/Group Title	Tenecteplase 0.1 mg/kg	Tenecteplase 0.25 mg/kg
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase	25 patients treated with 0.25 mg/kg intravenous tenecteplase
Period Title: Overall Study
STARTED	25	25
COMPLETED	25	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tenecteplase 0.1 mg/kg	Tenecteplase 0.25 mg/kg	Total
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase	25 patients treated with 0.25 mg/kg intravenous tenecteplase	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 40%	9 36%	19 38%
>=65 years	15 60%	16 64%	31 62%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	72	71	71
Sex: Female, Male (Count of Participants)
Female	13 52%	11 44%	24 48%
Male	12 48%	14 56%	26 52%
Region of Enrollment (participants) [Number]
Canada	25 100%	25 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Serious Bleeding Events
Description	The primary safety outcome will be the rate of expected serious adverse events associated with study drug. This will be defined as the number patients with at least one SAE divided by the number of patients enrolled by dose-tier. Thus, the unit of analysis will be the patient and not the SAE.
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Tenecteplase 0.1 mg/kg	Tenecteplase 0.25 mg/kg
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase	25 patients treated with 0.25 mg/kg intravenous tenecteplase
Measure Participants	25	25
Number [Participants]	0 0%	1 4%

2. Secondary Outcome

Title	Number of Patients With NIHSS 0 and mRS 0 and Barthel Index > 90
Description	Complete neurological and functional recovery at 90 days defined as: NIHSS 0 and mRS 0 iii)Complete neurological and functional recovery at 90 days defined as: a. NIHSS 0-1 and mRS 0-1 and Barthel Index > 90 NIHSS = National Institutes of Health Stroke Scale. This integer scale ranges 0-42 and is a quantitative measure of the neurological examination. mRS = modified Rankin Scale. This integer scale ranges from 0-6 and is a criterion-based quantitative measure of functional neurological disability. BI = Barthel Index. This scale range from 0-100 (in increments of 5 points) and is a summative categorical score measuring activities of daily living.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

All enrolled participants

Arm/Group Title	Tenecteplase 0.1 mg/kg	Tenecteplase 0.25 mg/kg
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase	25 patients treated with 0.25 mg/kg intravenous tenecteplase
Measure Participants	25	25
NIHSS = 0 at 90d	15 60%	19 76%
mRS = 0 at 90d	10 40%	14 56%
Barthel Index > 90 at 90d	22 88%	22 88%

3. Other Pre-specified Outcome

Title	Number of Patients With Recanalization 4-8 Hours Post-treatment
Description	Recanalization defined on follow-up 4-8 hour CTA as a modified arterial occlusive lesion (mAOL) score 0-1.
Time Frame	4-8 hours

Outcome Measure Data

Analysis Population Description

2 patients in each tier had missing data on this outcome.

Arm/Group Title	Tenecteplase 0.1 mg/kg	Tenecteplase 0.25 mg/kg
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase	25 patients treated with 0.25 mg/kg intravenous tenecteplase
Measure Participants	23	23
Number [Participants]	9 36%	12 48%

Adverse Events

Time Frame	90 days from the date of enrolment
Adverse Event Reporting Description	Symptomatic intracranial hemorrhage
Arm/Group Title	Tenecteplase 0.1 mg/kg		Tenecteplase 0.25 mg/kg
Arm/Group Description	25 patients treated with 0.1 mg/kg intravenous tenecteplase		25 patients treated with 0.25 mg/kg intravenous tenecteplase
All Cause Mortality
	Tenecteplase 0.1 mg/kg		Tenecteplase 0.25 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		1/25 (4%)
Serious Adverse Events
	Tenecteplase 0.1 mg/kg		Tenecteplase 0.25 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		1/25 (4%)
Nervous system disorders
symptomatic intracerebral hemorrhage	0/25 (0%)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Tenecteplase 0.1 mg/kg		Tenecteplase 0.25 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/25 (48%)		8/25 (32%)
Cardiac disorders
Atrial fibrillation	3/25 (12%)	3	0/25 (0%)	0
Nervous system disorders
Asymptomatic intracerebral hemorrhage	1/25 (4%)	1	1/25 (4%)	1
Headache	5/25 (20%)	5	3/25 (12%)	3
Renal and urinary disorders
Urinary tract infection	1/25 (4%)	1	2/25 (8%)	2
Skin and subcutaneous tissue disorders
Bruising/hematoma	0/25 (0%)	0	2/25 (8%)	2
Vascular disorders
Carotid revascluarization (CEA or CAS)	2/25 (8%)	2	0/25 (0%)	0

Limitations/Caveats

TEMPO-1 was a phase 2 study with a limited sample size. The program was designed to assess feasibility and safety and not efficacy. A further larger phase 3 study is planned. Only selected adverse events are presented here. All SAEs are reported.

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.