Cerebral InfarctionPhase 2TIASNCT02101606
Penumbral Based Novel Thrombolytic Therapy in Acute Ischemic Stroke
A Phase 2 study testing Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg) in people with Cerebral Infarction and Brain Ischemia, run by University of Alberta at 1 site in Canada.
Trial summary
Rationale The only proven therapy for acute stroke is tPA within 4.5 hours of symptom onset. This is the standard of care for patients presenting to our hospital within that time frame. Thrombolysis outside the 4.5 hour window is considered only on experimental or compassionate grounds. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cerebral Infarction, Brain Ischemia, Stroke
- What is being tested?
- Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- Oct 2009to Nov 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Acute ischemic stroke patients, within 24 hours of symptom onset. In cases where onset time can not be established, including symptoms upon waking, it will be considered to be the time when the patient was last known to be well.
- All patients will be 18 years or older.
- Baseline NIHSS must be 4-18 inclusive.
- Blood pressure (BP) must be ≤180 mmHg systolic and ≤105 mmHg diastolic at the time of enrolment. Treatment of higher systolic BP is permitted, prior to enrolment.
- Female patients of child-bearing potential will have a negative pregnancy test prior to enrollment.
- NCCT Inclusion Criteria: ASPECT scores of the NCCT will be assessed prior to enrolment. An ASPECT score of >6 will be required for inclusion in the trial. Patients with an ASPECT score of ≤6 will be considered screening failures and no further imaging will be conducted.
- MRI Inclusion Criteria: Patients will have an MR mismatch score of >2. This will be defined as a minimum of 3 ASPECTS regions with evidence of hypoperfusion visible on MTT maps, associated with normal diffusion as demonstrated by DWI. This will ensure that all patients have more than 20% mismatch by volume. In cases where PWI demonstrates oligemia in the ACA or PCA territories, patients will be treated only if diffusion abnormality volumes are 50% of the MTT deficits by visual inspection.
- CTP Inclusion Criteria: Patients will have a CTP mismatch score of >2. This will be defined as a minimum of 3 ASPECTS regions with evidence of hypoperfusion, visible on MTT maps, associated with normal CBV. This will ensure that all patients have more than 20% mismatch by volume.
Who cannot join
- Patients with contraindications to both MRI and CT perfusion will be excluded. MRI Exclusion Criteria: Patients with metallic implants and any past sensitivity to gadolinium contrast media will be excluded from MRI. Due to recent reports of nephrogenic systemic fibrosis associated with gadolinium exposure in individuals with pre-existing renal failure, patients with Creatinine > 160 μmol/l or Glomerular Filtration Rate (GFR) <60 ml/min will also be excluded.72 Patients with metallic implants of any kind, pacemakers or other foreign bodies will be excluded from MRI, as will those with excessive claustrophobia.
- CT Perfusion Exclusion Criteria: Patients with any past sensitivity to iodinated contrast media, serum creatinine >160 μmol/l or Glomerular Filtration Rate (GFR) <50 ml/min will be excluded from CT perfusion imaging. Patients taking metformin will be eligible, but metformin will be withheld for 48 hours after imaging to avoid possible metabolic acidosis.
- Thrombolysis Exclusion Criteria: Patients who have suffered a prior ischemic stroke within 30 days of the presenting event or who have any history of intracranial hemorrhage will be excluded. Patients with a known secured or unsecured cerebral aneurysm or vascular malformation will be ineligible. An inability to control systolic BP > 180 mmHg, or diastolic BP > 105 mmHg with IV anti-hypertensive medications will result in exclusion. Patients with a known coagulopathy or evidence of active bleeding will be excluded. Surgical procedures, biopsy, subclavian venous or arterial puncture, trauma, gastrointestinal or genitourinary bleeding within 14 days of the event will all result in exclusion. Patients treated with IV heparin within the previous 24 hours and an abnormal PTT will be excluded, as will those taking oral anticoagulants, resulting in an INR >1.4. A platelet count <100 000, venous glucose either < 3 mmol/l or >18 mmol/l will all result in exclusion.
Trial locations and contacts
1 site in 1 country.
About this study
Rationale The only proven therapy for acute stroke is tPA within 4.5 hours of symptom onset. This is the standard of care for patients presenting to our hospital within that time frame. Thrombolysis outside the 4.5 hour window is considered only on experimental or compassionate grounds. Tenecteplase (TNK) is a genetically modified variant of tPA that has many theoretical advantages in acute stroke. Studies show that systemic plasminogen activation is higher after tPA administration, relative to TNK and this is associated with an increased risk of bleeding events. Imaging cerebral blood flow (CBF) with MRI (perfusion weighted imaging-PWI) and CT perfusion (CTP) can be performed routinely with standard clinical scanners. Patients with evidence of large volumes of tissue with low CBF, that is also structurally intact, as demonstrated by either normal signal on Diffusion weighted imaging (DWI) or normal cerebral blood volume (CBV) are considered to have penumbral patterns. Patients with penumbral patterns appear to be the ideal candidates for thrombolytic therapy, regardless of time from onset.
Study Hypotheses
Read more
- The primary aim of this study is to demonstrate the feasibility and safety of TNK based thrombolysis in ischemic stroke patients presenting 4.5-24 hours after symptom onset.
- It is hypothesized that treatment with TNK in patients with penumbral patterns will be associated with reperfusion, early neurological improvement and penumbral tissue salvage.
Study Design The study is planned as an open label feasibility and safety study of acute treatment with TNK in ischemic stroke patients with penumbral patterns evident on advanced MRI or CT perfusion sequences.
Study Outcomes The primary outcome of this study is a safety endpoint, specifically the frequency of symptomatic hemorrhagic transformation evident on MRI or CT images on 24 h or day 5 scans. The ECASS II system for rating hemorrhagic transformation will be applied to all GRE/SWI images
Significance Current treatment paradigms have not permitted success of tPA to be extended beyond narrow and limiting therapeutic window of 4.5 hours. Clearly, more effective patient selection criteria are required. Penumbral imaging is biologically plausible, practical and has been shown to be predictive of outcome. Application of these imaging techniques to the acute stroke population is the most promising strategy for extending the therapeutic window and for introducing superior thrombolytic agents.
- Conditions
- Cerebral Infarction, Brain Ischemia, Stroke
- Being tested
- Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg)
- Keywords
- Acute Stroke, Cerebral Stroke, Brain Ischemia, Perfusion Imaging, MRI, Diffusion Weighted, MRI, Perfusion Weighted
- Medical subject headings
- Cerebral Infarction, Brain Ischemia, Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg)Drug
TNK will be administered within 30 minutes once MRI and CTP inclusion criteria are determined to have been met.
| Study group | Role | What they receive |
|---|---|---|
| Tenecteplase | Experimental | Not described Receives: Drug: Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of symptomatic hemorrhagic transformation evident on MRI or CT
The ECASS II system for rating hemorrhagic transformation will be applied to all GRE / SWI / CT images
Measured: 2-5 days post treatment
Secondary outcomes (2)
Imaging: Change in volume of hypoperfused tissue at follow up perfusion imaging
The primary efficacy endpoint is the change in volume of hypoperfused tissue, defined as that having a Tmax delay of >4s, between the acute and 24 hour post-treatment PWI or CTP scans. It is hypothesized that the perfusion deficit volume will decrease significantly between the two scans.
Measured: At 24 hours follow up perfusion scan
Clinical: Clinical improvement as shown by change in NIHSS
All follow-up neurological examinations and scoring will be performed during face-to-face examinations in the Stroke Clinic or, if necessary, in the facility where the patient is at that time. Day 90 is the standard time point for measuring outcome in stroke trials, as most patients destined to improve will have had the bulk of their neurological recovery by then. All clinical assessments will be done by study personnel certified in NIHSS administration and blinded to image analysis. All adverse events, including those related to imaging procedures will be recorded
Measured: At 24 h, 3, 30 and 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2014 (estimated)
- Study startOct 2009
- Primary completionNov 2017
- Study completionNov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cerebral InfarctionStudies of the same condition, open and under way.
- More trials run by University of AlbertaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alberta
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ken Butcher, University of Alberta
- Investigators
- Kenneth Butcher, MD, PhD, Principal investigator, University of Alberta
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02101606
- Sponsor's protocol ID
- Pro00009050
- Acronym
- TIAS
- Status last verified
- Apr 2018
- First submitted
- 28 Mar 2014
- Last updated
- 6 Apr 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Penumbral Based Novel Thrombolytic Therapy in Acute Ischemic Stroke
- ClinicalTrials.gov ID
- NCT02101606
- Acronym / sponsor ID
- TIAS / Pro00009050
- Conditions
- Cerebral Infarction, Brain Ischemia, Stroke
- Keywords
- Acute Stroke, Cerebral Stroke, Brain Ischemia, Perfusion Imaging, MRI, Diffusion Weighted, MRI, Perfusion Weighted
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- University of AlbertaUniversity, hospital or other
- Study start
- Oct 2009
- Primary completion
- Nov 2017 (actual)
- Study completion
- Nov 2017 (actual)
- First posted
- 2 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Rationale The only proven therapy for acute stroke is tPA within 4.5 hours of symptom onset. This is the standard of care for patients presenting to our hospital within that time frame. Thrombolysis outside the 4.5 hour window is considered only on experimental or compassionate grounds. Tenecteplase (TNK) is a genetically modified variant of tPA that has many theoretical advantages in acute stroke. Studies show that systemic plasminogen activation is higher after tPA administration, relative to TNK and this is associated with an increased risk of bleeding events. Imaging cerebral blood flow (CBF) with MRI (perfusion weighted imaging-PWI) and CT perfusion (CTP) can be performed routinely with standard clinical scanners. Patients with evidence of large volumes of tissue with low CBF, that is also structurally intact, as demonstrated by either normal signal on Diffusion weighted imaging (DWI) or normal cerebral blood volume (CBV) are considered to have penumbral patterns. Patients with penumbral patterns appear to be the ideal candidates for thrombolytic therapy, regardless of time from onset.
Study Hypotheses
- The primary aim of this study is to demonstrate the feasibility and safety of TNK based thrombolysis in ischemic stroke patients presenting 4.5-24 hours after symptom onset.
- It is hypothesized that treatment with TNK in patients with penumbral patterns will be associated with reperfusion, early neurological improvement and penumbral tissue salvage.
Study Design The study is planned as an open label feasibility and safety study of acute treatment with TNK in ischemic stroke patients with penumbral patterns evident on advanced MRI or CT perfusion sequences.
Study Outcomes The primary outcome of this study is a safety endpoint, specifically the frequency of symptomatic hemorrhagic transformation evident on MRI or CT images on 24 h or day 5 scans. The ECASS II system for rating hemorrhagic transformation will be applied to all GRE/SWI images
Significance Current treatment paradigms have not permitted success of tPA to be extended beyond narrow and limiting therapeutic window of 4.5 hours. Clearly, more effective patient selection criteria are required. Penumbral imaging is biologically plausible, practical and has been shown to be predictive of outcome. Application of these imaging techniques to the acute stroke population is the most promising strategy for extending the therapeutic window and for introducing superior thrombolytic agents.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Tenecteplase | Experimental | Drug: Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Acute ischemic stroke patients, within 24 hours of symptom onset. In cases where onset time can not be established, including symptoms upon waking, it will be considered to be the time when the patient was last known to be well.
- All patients will be 18 years or older.
- Baseline NIHSS must be 4-18 inclusive.
- Blood pressure (BP) must be ≤180 mmHg systolic and ≤105 mmHg diastolic at the time of enrolment. Treatment of higher systolic BP is permitted, prior to enrolment.
- Female patients of child-bearing potential will have a negative pregnancy test prior to enrollment.
Key exclusion criteria (3 listed)
- Patients with contraindications to both MRI and CT perfusion will be excluded. MRI Exclusion Criteria: Patients with metallic implants and any past sensitivity to gadolinium contrast media will be excluded from MRI. Due to recent reports of nephrogenic systemic fibrosis associated with gadolinium exposure in individuals with pre-existing renal failure, patients with Creatinine > 160 μmol/l or Glomerular Filtration Rate (GFR) <60 ml/min will also be excluded.72 Patients with metallic implants of any kind, pacemakers or other foreign bodies will be excluded from MRI, as will those with excessive claustrophobia.
- CT Perfusion Exclusion Criteria: Patients with any past sensitivity to iodinated contrast media, serum creatinine >160 μmol/l or Glomerular Filtration Rate (GFR) <50 ml/min will be excluded from CT perfusion imaging. Patients taking metformin will be eligible, but metformin will be withheld for 48 hours after imaging to avoid possible metabolic acidosis.
- Thrombolysis Exclusion Criteria: Patients who have suffered a prior ischemic stroke within 30 days of the presenting event or who have any history of intracranial hemorrhage will be excluded. Patients with a known secured or unsecured cerebral aneurysm or vascular malformation will be ineligible. An inability to control systolic BP > 180 mmHg, or diastolic BP > 105 mmHg with IV anti-hypertensive medications will result in exclusion. Patients with a known coagulopathy or evidence of active bleeding will be excluded. Surgical procedures, biopsy, subclavian venous or arterial puncture, trauma, gastrointestinal or genitourinary bleeding within 14 days of the event will all result in exclusion. Patients treated with IV heparin within the previous 24 hours and an abnormal PTT will be excluded, as will those taking oral anticoagulants, resulting in an INR >1.4. A platelet count <100 000, venous glucose either < 3 mmol/l or >18 mmol/l will all result in exclusion.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg)TNK will be administered within 30 minutes once MRI and CTP inclusion criteria are determined to have been met. | Drug | Tenecteplase |
Primary outcome
Frequency of symptomatic hemorrhagic transformation evident on MRI or CT
Time frame: 2-5 days post treatment
The ECASS II system for rating hemorrhagic transformation will be applied to all GRE / SWI / CT images
2 secondary outcomes
Imaging: Change in volume of hypoperfused tissue at follow up perfusion imaging
Time frame: At 24 hours follow up perfusion scan
Clinical: Clinical improvement as shown by change in NIHSS
Time frame: At 24 h, 3, 30 and 90 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kenneth Butcher, MD, PhD principal investigator
University of Alberta
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tenecteplase (TNK) (0.25 mg/kg, to maximum of 25mg) in people with Cerebral Infarction and Brain Ischemia, run by University of Alberta at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of symptomatic hemorrhagic transformation evident on MRI or CT (time frame: 2-5 days post treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2018.