Imatinib in Acute Ischaemic Stroke

Imatinib in Acute Ischaemic Stroke: A Phase 3, Randomized, Double-blind, Placebo Controlled, Parallel-arm Efficacy Trial of Imatinib in Acute Ischaemic Stroke

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Ischaemic Stroke
• Intervention / Treatment: Drug: Imatinib 400mg; Drug: Placebo Oral Tablet

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

• Study Type: Interventional
• Enrollment (Anticipated): 1260
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Niaz Ahmed, MD PhD; Phone Number: + 46 8-517 72026; Email: niaz.ahmed@ki.se
• Study Contact Backup: Name: Marie Westman, PhD; Phone Number: + 46 8-517 75034; Email: marie.westman@sll.se

Study Locations

• Sweden
  • Eskilstuna, Sweden, 633 49
    • Not yet recruiting
    • Mälarsjukhuset Eskilstuna
    • Contact: Christina Widhe Qvist, MD; Email: christina.widhe.qvist@dll.se
  • Göteborg, Sweden, 413 45
    • Recruiting
    • Sahlgrenska Universitetssjukhuset
    • Contact: Jan-Erik Karlsson, MD; Email: Jan-erik.karlsson@vgregion.se
  • Hässleholm, Sweden, 28151
    • Recruiting
    • Hässleholms sjukhus
    • Contact: Magnus Esbjörnsson, DR; Email: Magnus.Esbjornsson@skane.se
  • Karlstad, Sweden, 65185
    • Recruiting
    • Centralsjukhuset Karlstad
    • Contact: Felix Andler; Email: Felix.Andler@regionvarmland.se
  • Kristianstad, Sweden, 291 85
    • Recruiting
    • Centralsjukhuset Kristianstad
    • Contact: Axel Andersson, MD; Email: axel.p.andersson@skane.se
  • Lund, Sweden, 221 85
    • Not yet recruiting
    • Skånes Universitetssjukhus Lund
    • Contact: Jesper Pettersson, MD; Email: jesper.pettersson@skane.se
  • Malmö, Sweden, 205 02
    • Not yet recruiting
    • Skånes Universitetssjukhus Malmö
    • Contact: Jesper Pettersson, MD; Email: jesper.pettersson@skane.se
  • Skövde, Sweden, 541 42
    • Recruiting
    • Skaraborgs sjukhus Skövde
    • Contact: Björn Cederin, MD; Email: bjorn.cederin@vgregion.se
  • Stockholm, Sweden, 141 86
    • Recruiting
    • Karolinska Universitetssjukhuset Huddinge
    • Contact: Linda Säll, MD; Email: linda.sall@sll.se
  • Stockholm, Sweden, 112 81
    • Recruiting
    • Capio S:t Görans hospital
    • Contact: Ulrika Löfmark Höjeberg; Email: ulrika.lofmark@capiostgoran.se
  • Stockholm, Sweden, 118 83
    • Recruiting
    • Södersjukhuset
    • Contact: Mihaela Romanitan; Email: mihaela.romanitan@sodersjukhuset.se
  • Stockholm, Sweden, 171 76
    • Recruiting
    • Karolinska Universitetssjukhuset Solna
    • Contact: Magnus Thorén, MD; Email: magnus.thoren@sll.se
  • Stockholm, Sweden, 182 88
    • Recruiting
    • Danderyds Sjukhus
    • Contact: Ann-Charlotte Laska, MD; Email: ann-charlotte.laska@ds.se
  • Sundsvall, Sweden, 856 43
    • Not yet recruiting
    • Sundsvalls sjukhus
    • Contact: Fredrik Björk, MD; Email: fredrik.bjorck@rvn.se
  • Umeå, Sweden, 90185
    • Not yet recruiting
    • Umeå University Hospital
    • Contact: Elias Johansson; Email: elias.johansson@umu.se
  • Uppsala, Sweden, 751 85
    • Recruiting
    • Uppsala Akademiska Sjukhus
    • Contact: Lars Sjöblom; Email: Lars.sjoblom@akademiska.se
  • Västerås, Sweden, 721 89
    • Recruiting
    • Västmanlands sjukhus Västerås
    • Contact: Andreas Ranhem, MD; Email: andreas.ranhem@ltv.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Imatinib; Imatinib 400mg (2 tablets of 400mg) per day for 6 days	Drug: Imatinib 400mg; 2 tablets of Imatinib 400mg per day for 6 days
PLACEBO_COMPARATOR: Placebo; 2 placebo tablets per day for 6 days	Drug: Placebo Oral Tablet; 2 tablets of placebo per day for 6 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Frequency (%) of ICH on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
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
Frequency (%) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy.		1 day post treatment start
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
Serious and non-serious adverse events		3 months post teatment
Mortality at 3 months.		3 months post treatment

Collaborators and Investigators

• Sponsor: Niaz Ahmed
• Investigators: Study Director: Niaz Ahmed, MD PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2018
• Primary Completion (ANTICIPATED): December 1, 2022
• Study Completion (ANTICIPATED): June 1, 2023

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 17, 2018
• First Posted (ACTUAL): August 21, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 16, 2020
• Last Update Submitted That Met QC Criteria: September 14, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Imatinib; acute ischaemic stroke; blood-brain-barrier; trombectomy; iv trombolysis
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: I-StrokeII2016; 2017-000075-85 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No