Stroke, AcutePhase 2PATISNCT02327793
Perfusion and Antihypertensive Therapy in Acute Ischemic Stroke
A Phase 2 study testing Nitroglycerin and Labetalol in people with Stroke, Acute, run by University of Alberta at 1 site in Canada.
Trial summary
The purpose of this study is to provide a description of blood flow changes in the brain after blood pressure lowering drugs are given. This information will be used by physicians to guide blood pressure lowering therapy in stroke patients in the future. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Stroke, Acute
- What is being tested?
- Nitroglycerin and Labetalol
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 65 participants
- Where
- 1 siteCanada
- Study dates
- Jun 2009to Aug 2015
- 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 within 72 hours of symptom onset. In cases where onset time can not be established, it will be considered to be the time when the patient was last known to be well.
- 18 years or older.
- Patients with Partial Anterior Circulation Infarcts (PACI; Oxfordshire Stroke Classification Project; OSCP) will be included.
- Patients with Posterior Circulation Infarcts (POCI) will be included only if there is evidence of cortical infarction in the territory of the posterior cerebral artery or its branches, including the occipital and mesial temporal lobes.
Who cannot join
- Patients with a contraindication to the BP lowering protocol (i.e. known extracranial/intracranial arterial stenosis, high-grade stenotic valvular heart disease, or severe renal failure) will be ineligible, as will those with a definite indication for BP reduction (i.e. hypertensive encephalopathy, or aortic dissection).
- Patients with contraindications to MRI will be excluded, including metallic implants and any past sensitivity to gadolinium contrast media.
- 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.
- Patients with renal artery stenosis will be excluded from this study, irrespective of renal function.
- Due to the possibility that oxygen therapy may confound CBF measurements, patients requiring >4 lpm to keep Sp02 ≥92% by nasal cannulae will be excluded.
- Patients with a suspected hemodynamic stroke mechanism will be ineligible. This will include patients with known or suspected hypotensive periods and/or a watershed territory of cerebral infarction seen on CT or MRI.
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- Due to the possibility of increased susceptibility to BP reduction in patients with raised intracerebral pressure (ICP), those with evidence of significant mass effect secondary to acute infarction, including any degree of midline shift and/or ventricular compression will be ineligible. For the same reason, patients with head and eye deviation or other clinical evidence of a Total Anterior Circulation Infarct (TACI; OSCP) will also be ineligible.
- Due to technical difficulties associated with PWI in the posterior fossa, patients with brainstem and cerebellar strokes will be excluded.
- Patients with known sensitivity to nitroglycerin/labetalol/adhesives in nitroglycerin patches/ACE inhibitors/Angiotensin Receptor Blockers will be excluded.
- Amplification of the vasodilatory effects of topical nitroglycerin by phosphodiesterase inhibitors such as sildenafil or tadalafil can result in severe hypotension. Patients who have used either of these drugs within 12 h of initial assessment will therefore be excluded.
Trial locations and contacts
1 site in 1 country.
About this study
The purpose of this study is to provide a description of blood flow changes in the brain after blood pressure lowering drugs are given. This information will be used by physicians to guide blood pressure lowering therapy in stroke patients in the future.
Read the detailed description
Objective: To elucidate the inter-relationships between blood pressure (BP), cerebral blood flow (CBF) and oxygen metabolism in acute ischemic stroke in order to establish rational acute hypertension treatment thresholds.
Background: Management of acute hypertension in the first 48 hours after stroke is controversial and lends itself to competing rationales. Early reduction of BP may improve outcome by reducing the rate of hemorrhagic transformation and edema formation in early infarcts. Conversely, early BP reduction might reduce CBF and extend the infarct. Natural history studies have demonstrated that patients with higher BP at presentation have elevated early mortality rates, but causality has not been established. Consensus-based guidelines for acute BP management are not based on physiological data or sound evidence. The investigators propose to start addressing this clinical dilemma with a non-randomized controlled study of serial measurements of CBF and oxygen metabolism in acute stroke patients with 3 different levels of acute blood pressure representing 3 different potential treatment thresholds.
Hypothesis: The investigators hypothesize that the volume and severity of oligemia in at risk tissue will not increase with BP reduction in acute stroke patients.
Specific Aims:
- Determine the effect of mean arterial pressure (MAP) decreases on CBF.
- Determine the relationship between infarct volume change over time and MAP.
- Determine the frequency of hemorrhagic transformation and its relationship to MAP.
Study Design: A 3 group non-randomized controlled study. After informed consent, all patients will undergo MRI scanning including diffusion and perfusion-weighted imaging (DWI and PWI). Patients with MAP <100 mmHg will not receive hypertension treatment. Patients with moderate hypertension (MAP 100-120 mmHg) will be treated with transdermal nitroglycerin (0.2 mg/h) for 48 hours. Patients with severe hypertension (MAP >120 mmHg) will also be treated with intravenous labetalol, to a target of <120 mmHg. Two hours after the baseline scan, MRI will be repeated. Any clinical or radiographic evidence of exacerbated oligemia associated with BP reduction will result in immediate discontinuation of all anti-hypertensive therapy. The effectiveness of BP control will be evaluated using a weighted mean average of MAP over 72 hours. All patients will be re-imaged with MRI on day 3 to assess for hemorrhagic transformation. The primary endpoint is the change in objectively measured hypoperfused tissue volume between the baseline and 2 hour scans. Hypoperfused tissue will be determined as the volume of voxels with CBF ≤18 ml/100g/min, a previously validated measurement independent of observer variability. Sample size is based on power calculations required to detect a 10% change in oligemic tissue volume (which would be sufficient to result in exacerbation of ischemic injury) following MAP reduction.
Preliminary Work: First, the investigators surveyed Canadian stroke neurologists about their current BP management practices. Indications for acute BP therapy in acute stroke varied from 180 to 240 mmHg systolic, and few clinicians even considered diastolic or MAP treatment thresholds. Physicians based a generally conservative approach on the absence of evidence. Second, the investigators assessed the feasibility of serial MRI and MAP treatment protocols. To date, 9 patients have been imaged with repeat MRI, within 2 hours of the initial exam, confirming that the CBF≤18 ml/100g/min measures of at risk tissue volume can be used to monitor cerebral perfusion. Four patients were treated with our BP management protocol and imaged serially. MAP decreased in all 4 patients 2 hours after treatment. Increases in hypoperfused tissue volume (CBF≤18 ml/100g/min) following MAP reduction were generally mild (<10%). Of note, after BP reduction, the patient with the lowest initial MAP (96 mmHg) had a marked decline in CBF and large increase in volume of at risk tissue. Third, the investigators determined that decreases in CBF were always associated with increases in oxygen extraction, which appeared to protect tissue from infarct expansion because DWI lesion volumes remained stable. The variations in current practice and demonstration that reductions in MAP can lead to decreases CBF, potentially increasing the risk of adverse stroke-related outcomes justifies studies to determine appropriate treatment thresholds.
Significance: The precise relationship between CBF and MAP in acute stroke must be elucidated prior to developing treatment thresholds for testing in a large randomized controlled trial. A serial perfusion study, with careful monitoring of MAP is a critical step in developing a rational BP management protocol. These findings will also help elucidate the mechanisms for poor outcome in patients with both high and low MAP at onset.
- Conditions
- Stroke, Acute
- Being tested
- Nitroglycerin, Labetalol
- Keywords
- Perfusion, Blood pressure
- Medical subject headings
- Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitroglycerinDrug
LabetalolDrug
| Study group | Role | What they receive |
|---|---|---|
| Mean Arterial Pressure <100 mmHg | No intervention | Patients with mean arterial pressure <100 mmHg at the time of the perfusion weighted magnetic resonance imaging will not be treated. After 15 minutes of the baseline perfusion imaging a repeat perfusion weighted magnetic resonance imaging would be performed. |
| Mean Arterial Pressure 100-120 mmHg | Experimental | Patients with mean arterial pressure between 100-120 mmHg at the time of the perfusion weighted magnetic resonance imaging will be treated with sublingual 0.3 mg nitroglycerin. A repeat blood pressure would be assessed at 5min, 10min, 15min and 20 min of nitroglycerin administration. After a sustained drop of blood pressure (>10% of the baseline reading) as defined by two reading 5minutes apart, a perfusion weighted magnetic resonance imaging will be performed. Receives: Drug: Nitroglycerin |
| Mean Arterial Pressure >120 mmHg | Experimental | Patients with mean arterial pressure >120 mmHg at the time of the perfusion weighted magnetic resonance imaging will be treated with intravenous 10-20mg labetalol injection. A repeat blood pressure would be assessed at 5min, 10min, 15min and 20 min of labetalol injection. After a sustained drop in blood pressure (>10% of the baseline reading) as defined by two reading 5minutes apart, a perfusion weighted magnetic resonance imaging will be performed. Receives: Drug: Labetalol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Volume of Hypoperfused Tissue
Change in the volume of hypoperfused tissue, defined as that having a CBF <19 ml/100g/min, between the acute and the post treatment initiation perfusion weighted scans.
Measured: 15-30 minutes
Secondary outcomes (1)
Time-to-Treatment
Patients treated within 12 hours will be compared to those treated 12-24 hours after symptom onset.
Measured: 15-30 minutes
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Dec 2014 (estimated)
- Study startJun 2009
- Primary completionJul 2015
- Study completionAug 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Stroke, AcuteStudies 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
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 65 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
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02327793
- Sponsor's protocol ID
- PATIS Version 1.0
- Acronym
- PATIS
- Status last verified
- Oct 2017
- First submitted
- 24 Dec 2014
- Last updated
- 26 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Perfusion and Antihypertensive Therapy in Acute Ischemic Stroke
- ClinicalTrials.gov ID
- NCT02327793
- Acronym / sponsor ID
- PATIS / PATIS Version 1.0
- Conditions
- Stroke, Acute
- Keywords
- Perfusion, Blood pressure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- University of AlbertaUniversity, hospital or other
- Study start
- Jun 2009
- Primary completion
- Jul 2015 (actual)
- Study completion
- Aug 2015 (actual)
- First posted
- 30 Dec 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.
The purpose of this study is to provide a description of blood flow changes in the brain after blood pressure lowering drugs are given. This information will be used by physicians to guide blood pressure lowering therapy in stroke patients in the future.
Detailed description
Objective: To elucidate the inter-relationships between blood pressure (BP), cerebral blood flow (CBF) and oxygen metabolism in acute ischemic stroke in order to establish rational acute hypertension treatment thresholds.
Background: Management of acute hypertension in the first 48 hours after stroke is controversial and lends itself to competing rationales. Early reduction of BP may improve outcome by reducing the rate of hemorrhagic transformation and edema formation in early infarcts. Conversely, early BP reduction might reduce CBF and extend the infarct. Natural history studies have demonstrated that patients with higher BP at presentation have elevated early mortality rates, but causality has not been established. Consensus-based guidelines for acute BP management are not based on physiological data or sound evidence. The investigators propose to start addressing this clinical dilemma with a non-randomized controlled study of serial measurements of CBF and oxygen metabolism in acute stroke patients with 3 different levels of acute blood pressure representing 3 different potential treatment thresholds.
Hypothesis: The investigators hypothesize that the volume and severity of oligemia in at risk tissue will not increase with BP reduction in acute stroke patients.
Specific Aims:
- Determine the effect of mean arterial pressure (MAP) decreases on CBF.
- Determine the relationship between infarct volume change over time and MAP.
- Determine the frequency of hemorrhagic transformation and its relationship to MAP.
Study Design: A 3 group non-randomized controlled study. After informed consent, all patients will undergo MRI scanning including diffusion and perfusion-weighted imaging (DWI and PWI). Patients with MAP <100 mmHg will not receive hypertension treatment. Patients with moderate hypertension (MAP 100-120 mmHg) will be treated with transdermal nitroglycerin (0.2 mg/h) for 48 hours. Patients with severe hypertension (MAP >120 mmHg) will also be treated with intravenous labetalol, to a target of <120 mmHg. Two hours after the baseline scan, MRI will be repeated. Any clinical or radiographic evidence of exacerbated oligemia associated with BP reduction will result in immediate discontinuation of all anti-hypertensive therapy. The effectiveness of BP control will be evaluated using a weighted mean average of MAP over 72 hours. All patients will be re-imaged with MRI on day 3 to assess for hemorrhagic transformation. The primary endpoint is the change in objectively measured hypoperfused tissue volume between the baseline and 2 hour scans. Hypoperfused tissue will be determined as the volume of voxels with CBF ≤18 ml/100g/min, a previously validated measurement independent of observer variability. Sample size is based on power calculations required to detect a 10% change in oligemic tissue volume (which would be sufficient to result in exacerbation of ischemic injury) following MAP reduction.
Preliminary Work: First, the investigators surveyed Canadian stroke neurologists about their current BP management practices. Indications for acute BP therapy in acute stroke varied from 180 to 240 mmHg systolic, and few clinicians even considered diastolic or MAP treatment thresholds. Physicians based a generally conservative approach on the absence of evidence. Second, the investigators assessed the feasibility of serial MRI and MAP treatment protocols. To date, 9 patients have been imaged with repeat MRI, within 2 hours of the initial exam, confirming that the CBF≤18 ml/100g/min measures of at risk tissue volume can be used to monitor cerebral perfusion. Four patients were treated with our BP management protocol and imaged serially. MAP decreased in all 4 patients 2 hours after treatment. Increases in hypoperfused tissue volume (CBF≤18 ml/100g/min) following MAP reduction were generally mild (<10%). Of note, after BP reduction, the patient with the lowest initial MAP (96 mmHg) had a marked decline in CBF and large increase in volume of at risk tissue. Third, the investigators determined that decreases in CBF were always associated with increases in oxygen extraction, which appeared to protect tissue from infarct expansion because DWI lesion volumes remained stable. The variations in current practice and demonstration that reductions in MAP can lead to decreases CBF, potentially increasing the risk of adverse stroke-related outcomes justifies studies to determine appropriate treatment thresholds.
Significance: The precise relationship between CBF and MAP in acute stroke must be elucidated prior to developing treatment thresholds for testing in a large randomized controlled trial. A serial perfusion study, with careful monitoring of MAP is a critical step in developing a rational BP management protocol. These findings will also help elucidate the mechanisms for poor outcome in patients with both high and low MAP at onset.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Mean Arterial Pressure <100 mmHg | No intervention | –Patients with mean arterial pressure <100 mmHg at the time of the perfusion weighted magnetic resonance imaging will not be treated. After 15 minutes of the baseline perfusion imaging a repeat perfusion weighted magnetic resonance imaging would be performed. |
| Mean Arterial Pressure 100-120 mmHg | Experimental | Drug: NitroglycerinPatients with mean arterial pressure between 100-120 mmHg at the time of the perfusion weighted magnetic resonance imaging will be treated with sublingual 0.3 mg nitroglycerin. A repeat blood pressure would be assessed at 5min, 10min, 15min and 20 min of nitroglycerin administration. After a sustained drop of blood pressure (>10% of the baseline reading) as defined by two reading 5minutes apart, a perfusion weighted magnetic resonance imaging will be performed. |
| Mean Arterial Pressure >120 mmHg | Experimental | Drug: LabetalolPatients with mean arterial pressure >120 mmHg at the time of the perfusion weighted magnetic resonance imaging will be treated with intravenous 10-20mg labetalol injection. A repeat blood pressure would be assessed at 5min, 10min, 15min and 20 min of labetalol injection. After a sustained drop in blood pressure (>10% of the baseline reading) as defined by two reading 5minutes apart, a perfusion weighted magnetic resonance imaging will be performed. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Acute ischemic stroke within 72 hours of symptom onset. In cases where onset time can not be established, it will be considered to be the time when the patient was last known to be well.
- 18 years or older.
- Patients with Partial Anterior Circulation Infarcts (PACI; Oxfordshire Stroke Classification Project; OSCP) will be included.
- Patients with Posterior Circulation Infarcts (POCI) will be included only if there is evidence of cortical infarction in the territory of the posterior cerebral artery or its branches, including the occipital and mesial temporal lobes.
Key exclusion criteria (10 listed)
- Patients with a contraindication to the BP lowering protocol (i.e. known extracranial/intracranial arterial stenosis, high-grade stenotic valvular heart disease, or severe renal failure) will be ineligible, as will those with a definite indication for BP reduction (i.e. hypertensive encephalopathy, or aortic dissection).
- Patients with contraindications to MRI will be excluded, including metallic implants and any past sensitivity to gadolinium contrast media.
- 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.
- Patients with renal artery stenosis will be excluded from this study, irrespective of renal function.
- Due to the possibility that oxygen therapy may confound CBF measurements, patients requiring >4 lpm to keep Sp02 ≥92% by nasal cannulae will be excluded.
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 |
|---|---|---|
| Nitroglycerin | Drug | Mean Arterial Pressure 100-120 mmHg |
| Labetalol | Drug | Mean Arterial Pressure >120 mmHg |
Primary outcome
Change in Volume of Hypoperfused Tissue
Time frame: 15-30 minutes
Change in the volume of hypoperfused tissue, defined as that having a CBF <19 ml/100g/min, between the acute and the post treatment initiation perfusion weighted scans.
1 secondary outcome
Time-to-Treatment
Time frame: 15-30 minutes
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 26 Oct 2017.
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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.
The record lists no contact. Use the official record to reach the sponsor.
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 Nitroglycerin and Labetalol in people with Stroke, Acute, 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 4 inclusion and 10 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 26 Oct 2017. 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?
Change in Volume of Hypoperfused Tissue (time frame: 15-30 minutes). 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 26 Oct 2017.