Imatinib in Acute Ischaemic Stroke

Acute Ischaemic Stroke Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03639922
• Other study ID #: I-StrokeII2016
• Secondary ID: 2017-000075-85
• Status: Recruiting
• Phase: Phase 3
• Start date: October 1, 2018
• Est. completion date: June 2023

Study information

• Verified date: September 2020
• Source: Karolinska Institutet
• Contact: Niaz Ahmed, MD PhD
• Phone: + 46 8-517 72026
• Email: niaz.ahmed[@]ki.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1260
• Est. completion date: June 2023
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Ischaemic Stroke
• Cerebral Infarction
• Ischemia
• Stroke

Intervention

Drug:
• Imatinib 400mg
2 tablets of Imatinib 400mg per day for 6 days
• Placebo Oral Tablet
2 tablets of placebo per day for 6 days

Locations

Country	Name	City	State
Sweden	Mälarsjukhuset Eskilstuna	Eskilstuna
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Hässleholms sjukhus	Hässleholm
Sweden	Centralsjukhuset Karlstad	Karlstad
Sweden	Centralsjukhuset Kristianstad	Kristianstad
Sweden	Skånes Universitetssjukhus Lund	Lund
Sweden	Skånes Universitetssjukhus Malmö	Malmö
Sweden	Skaraborgs sjukhus Skövde	Skövde
Sweden	Capio S:t Görans Hospital	Stockholm
Sweden	Danderyds sjukhus	Stockholm
Sweden	Karolinska Universitetssjukhuset Huddinge	Stockholm
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
Sweden	Södersjukhuset	Stockholm
Sweden	Sundsvalls Sjukhus	Sundsvall
Sweden	Umeå University Hospital	Umeå
Sweden	Uppsala Akademiska Sjukhus	Uppsala
Sweden	Västmanlands sjukhus Västerås	Västerås

Sponsors (1)

Lead Sponsor	Collaborator
Niaz Ahmed

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Functional independency at 3 months as measured by modified Rankin Scale (mRS) Score 0-2.	For a positive outcome, patients in the active group treated with Imatinib 800 mg per day will have statistically significant higher functional independency compared to the control group treated with placebo.	3 months post treatment
Secondary	Change in mRS score at 3 months compared to baseline	For a positive outcome, patients treated with Imatinib will have a favorable shift of the scale.	At baseline and 3 months post treatment
Secondary	Frequency (%) of ICH on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
Secondary	Grade of ICH (COED 1-3) on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
Secondary	Frequency (%) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
Secondary	Grade (COED 1-3) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
Secondary	Serious and non-serious adverse events		3 months post teatment
Secondary	Mortality at 3 months.		3 months post treatment