Clinical trial NCT03639922: Imatinib in Acute Ischaemic Stroke
Official title: Imatinib in Acute Ischaemic Stroke: A Phase 3, Randomized, Double-blind, Placebo Controlled, Parallel-arm Efficacy Trial of Imatinib in Acute Ischaemic Stroke
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Ischaemic Stroke
Keywords: acute ischaemic stroke
Imatinib
blood-brain-barrier
trombectomy
iv trombolysis
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2018-08-21
Enrollment: 1260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized, double-blind, placebo-controlled, parallel-arm
Primary purpose: TREATMENT

Brief summary: A clinical trial comparing treatment with Imatinib to placebo when administered within 8 hours of stroke onset for 6 days, in addition to conventional stroke treatment after acute ischaemic stroke.

Detailed description: The study aims to investigate if Imatinib reduces intracerebral haemorrhage and oedema in stroke patients after IV thrombolysis and/or trombectomy. Two important complications of ischaemic stroke and its acute treatment are haemorrhage into the infarcted tissue and cerebral oedema. Leading to worsening functional outcome in survivors. Both are caused by a disruption of the blood brain barrier (BBB) by ischemia of the brain vascular endothelium and associated cells involved in maintaining the BBB. Imatinib can reduce the damage to the BBB and hence reduce the formation of oedema and haemorrhage.

The study is a phase III randomised, double-blind placebo-controlled parallel-arm trilal of patents with acute ischaemic stroke. Assessing the Clinical variables at baseline and after 3 months.

Primary objective:

To investigate if Imatinib (800 mg / day) treatment initiated within 8 hours of symptom onset and given for 6 days improves functional outcome at three months after acute ischaemic stroke

Secondary objective:

1. Investigate if Imatinib treatment improves functional outcome at three months in acute ischaemic stroke patients treated with iv thrombolysis
2. Investigate if Imatinib treatment improves neurological outcome at three months after acute ischaemic stroke
3. Investigate if Imatinib treatment improves neurological outcome at three months in acute ischaemic stroke patients treated with iv thrombolysis
4. Investigate if Imatinib reduces the frequency and grade of ICH in patients with acute ischaemic stroke treated with iv thrombolysis
5. Investigate if Imatinib reduces the frequency and grade of cerebral oedema in patients with acute ischaemic stroke treated with iv thrombolysis
6. Examine serious and non-serious adverse events in patients treated with Imatinib
7. Investigate if Imatinib reduces mortality at 3 months after acute ischaemic stroke
8. Investigate if Imatinib reduces mortality at 3 months in acute ischaemic stroke patients treated with iv thrombolysis

Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis of acute ischaemic stroke with a neurological deficit corresponding to 6 points or higher on the NIHSS score

   1. at the time of randomization if no recanalisation therapy performed
   2. prior to iv thrombolysis therapy alone or prior to thrombectomy alone if performed
   3. prior to iv thrombolysis if both iv thrombolysis and thrombectomy performed Ischaemic stroke is defined as an event characterised by sudden onset of acute focal neurological deficit, presumed to be caused by cerebral ischaemia and an imaging scan excluding any intracranial haemorrhage.
2. Age 18-85 years
3. Patients should be randomized as soon as possible but not later than 8 hours of symptom onset.

   1. If the patient receives iv thrombolysis alone, patient should be randomized and study drug should be given within one hour after completion of iv thrombolysis infusion
   2. If the patient receives endovascular thrombectomy (with or without prior iv thrombolysis), patient should be randomized within two hours after completion of endovascular thrombectomy and study drug given as soon as possible after randomization.
4. iv thrombolysis, if performed, is done in agreement with European Stroke Organisation guidelines and has been initiated within 4.5 hours of stroke onset (see below separate criteria for indications / contraindications)
5. Endovascular thrombectomy, if performed, is done in agreement with recently published American Stroke Association guidelines, and fulfilling the following criteria

   1. Confirmed diagnosis on Computed Tomography Angiography (CTA) or Magnetic Resonance Angiography (MRA) of acute occlusion of either of the first two segments of the Middle Cerebral Artery (M1 or M2), terminal Carotid Artery, first segment of the Anterior Cerebral Artery (A1), or Basilar Artery, consistent with the clinical symptoms.
   2. thrombectomy has been initiated within 8 hours of symptom onset (defined as start with femoral artery (groin) puncture)
6. Patient is competent to make a decision and has provided informed consent with regard to participation in the study, retrieval and storage of data and follow up procedures

Exclusion Criteria:

General

1. Imaging scans show signs of large current infarction as defined by more than 1/3 of the Middle Cerebral Artery territory or ½ of other vascular territories
2. ) Known significant pre-stroke disability (mRS ≥2)
3. Severe comorbidities such as advanced dementia (estimate pre-stroke if otherwise healthy), terminal illness, and other severe medical conditions with anticipated life expectancy less than 6 months.
4. Acute pancreatitis
5. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
6. Ongoing treatment with chemotherapy
7. Drugs which may increase the plasma concentration of Imatinib - ketokonazol, itrakonazol, erythromycin and claritomycin
8. Drugs which may decrease the plasma concentration of Imatinib: Dexametason, phenytoin, karbamazepin, rifampizin, phenobarbital, fosphenytoin, primidon, Hypericum perforatum (Johannesört, St John's wort)
9. Female patients with childbearing potential, if pregnancy cannot be excluded by pregnancy test (urine point-of-care pregnancy test).
10. Patient is participating in other interventional study

Additional Exclusion criteria for patients treated with intravenous thrombolysis (IVT)

1. Severe stroke as assessed clinically by NIHSS\>25
2. Administration of heparin within the previous 48 hours preceding the onset of stroke with an elevated activated thromboplastin time (aPTT) at presentation, or corresponding low-molecular heparin.
3. Patients receiving oral anticoagulants, e.g. warfarin sodium (INR\>1.7) or direct oral anticoagulation: dabigatran ( aPTT\>40s), apixaban, rivaroxaban.
4. Platelet count below 100,000/mm3. Significant bleeding disorder at present or within the past 6 months, known haemorrhagic diathesis.
5. History or evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage
6. Systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg, in spite of repeated doses of i.v. medication to reduce blood pressure below these limits.
7. History of the following conditions: prior ischemic stroke within 3 months, intra-axial neoplasm, intracranial or spinal surgery within the prior 3 months, recent severe head trauma within 3 months or unruptured intracranial aneurysm\>5 mm.
8. Major surgery or significant trauma in the past 10 days

Primary outcomes:
measure: Functional independency at 3 months as measured by modified Rankin Scale (mRS) Score 0-2.
timeFrame: 3 months post treatment
Secondary outcomes:
measure: Change in mRS score at 3 months compared to baseline
timeFrame: At baseline and 3 months post treatment
measure: Frequency (%) of ICH on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.
timeFrame: 1 day post treatment start
measure: Grade of ICH (COED 1-3) on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.
timeFrame: 1 day post treatment start
measure: Frequency (%) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.
timeFrame: 1 day post treatment start
measure: Grade (COED 1-3) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.
timeFrame: 1 day post treatment start
measure: Serious and non-serious adverse events
timeFrame: 3 months post teatment
measure: Mortality at 3 months.
timeFrame: 3 months post treatment
Other outcomes:
Locations:
city: Eskilstuna
country: Sweden
facility: Mälarsjukhuset Eskilstuna
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Hässleholm
country: Sweden
facility: Hässleholms sjukhus
city: Karlstad
country: Sweden
facility: Centralsjukhuset Karlstad
city: Kristianstad
country: Sweden
facility: Centralsjukhuset Kristianstad
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus Lund
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus Malmö
city: Skövde
country: Sweden
facility: Skaraborgs sjukhus Skövde
city: Stockholm
country: Sweden
facility: Capio S:t Görans Hospital
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Stockholm
country: Sweden
facility: Danderyds sjukhus
city: Sundsvall
country: Sweden
facility: Sundsvalls Sjukhus
city: Umeå
country: Sweden
facility: Umeå University Hospital
city: Uppsala
country: Sweden
facility: Uppsala Akademiska Sjukhus
city: Västerås
country: Sweden
facility: Västmanlands sjukhus Västerås
Study officials:
affiliation: Karolinska Institutet
name: Niaz Ahmed, MD PhD
role: STUDY_DIRECTOR
References: