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Imatinib in Acute Ischaemic Stroke

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ClinicalTrials.gov Identifier: NCT03639922
Recruitment Status : Recruiting
First Posted : August 21, 2018
Last Update Posted : August 14, 2019
Sponsor:
Information provided by (Responsible Party):
Niaz Ahmed, Karolinska Institutet

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.

Condition or disease Intervention/treatment Phase
Acute Ischaemic Stroke Drug: Imatinib 400mg Drug: Placebo Oral Tablet Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1260 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized, double-blind, placebo-controlled, parallel-arm
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: The study is double-blind, only after the study is completed or terminated the treatments will be made available, or if requested by the data safety board, or if requested by treating clinician in association with possible SAE/SUSAR
Primary Purpose: Treatment
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
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Functional independency at 3 months as measured by modified Rankin Scale (mRS) Score 0-2. [ Time Frame: 3 months post treatment ]
    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.


Secondary Outcome Measures :
  1. Change in mRS score at 3 months compared to baseline [ Time Frame: At baseline and 3 months post treatment ]
    For a positive outcome, patients treated with Imatinib will have a favorable shift of the scale.

  2. Frequency (%) of ICH on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy. [ Time Frame: 1 day post treatment start ]
  3. Grade of ICH (COED 1-3) on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy. [ Time Frame: 1 day post treatment start ]
  4. Frequency (%) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy. [ Time Frame: 1 day post treatment start ]
  5. Grade (COED 1-3) of cerebral oedema on post-treatment imaging scan in patients undergoing IV thrombolysis and or endovascular thrombectomy. [ Time Frame: 1 day post treatment start ]
  6. Serious and non-serious adverse events [ Time Frame: 3 months post teatment ]
  7. Mortality at 3 months. [ Time Frame: 3 months post treatment ]


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03639922


Contacts
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Contact: Niaz Ahmed, MD PhD + 46 8-517 72026 niaz.ahmed@ki.se
Contact: Marie Westman, PhD + 46 8-517 75034 marie.westman@sll.se

Locations
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Sweden
Mälarsjukhuset Eskilstuna Not yet recruiting
Eskilstuna, Sweden, 633 49
Contact: Christina Widhe Qvist, MD       christina.widhe.qvist@dll.se   
Sahlgrenska Universitetssjukhuset Not yet recruiting
Göteborg, Sweden, 413 45
Contact: Jan-Erik Karlsson, MD       Jan-erik.karlsson@vgregion.se   
Centralsjukhuset Kristianstad Recruiting
Kristianstad, Sweden, 291 85
Contact: Axel Andersson, MD       axel.p.andersson@skane.se   
Skånes Universitetssjukhus Lund Not yet recruiting
Lund, Sweden, 221 85
Contact: Jesper Pettersson, MD       jesper.pettersson@skane.se   
Skånes Universitetssjukhus Malmö Not yet recruiting
Malmö, Sweden, 205 02
Contact: Jesper Pettersson, MD       jesper.pettersson@skane.se   
Skaraborgs sjukhus Skövde Recruiting
Skövde, Sweden, 541 42
Contact: Björn Cederin, MD       bjorn.cederin@vgregion.se   
Capio S:t Görans Hospital Not yet recruiting
Stockholm, Sweden, 112 81
Contact: Ulrika Löfmark Höjeberg       ulrika.lofmark@capiostgoran.se   
Södersjukhuset Recruiting
Stockholm, Sweden, 118 83
Contact: Mihaela Romanitan       mihaela.romanitan@sodersjukhuset.se   
Karolinska Universitetssjukhuset Huddinge Recruiting
Stockholm, Sweden, 141 86
Contact: Konstantinos Kostulas, MD       konstantinos.kostulas@sll.se   
Karolinska Universitetssjukhuset Solna Recruiting
Stockholm, Sweden, 171 76
Contact: Christina Sjöstrand       christina.sjostrand@ki.se   
Danderyds sjukhus Recruiting
Stockholm, Sweden, 182 88
Contact: Ann-Charlotte Laska, MD       ann-charlotte.laska@ds.se   
Sundsvalls Sjukhus Not yet recruiting
Sundsvall, Sweden, 856 43
Contact: Fredrik Björk, MD       fredrik.bjorck@rvn.se   
Uppsala Akademiska Sjukhus Recruiting
Uppsala, Sweden, 751 85
Contact: Lars Sjöblom       Lars.sjoblom@akademiska.se   
Västmanlands sjukhus Västerås Not yet recruiting
Västerås, Sweden, 721 89
Contact: Andreas Ranhem, MD       andreas.ranhem@ltv.se   
Sponsors and Collaborators
Niaz Ahmed
Investigators
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Study Director: Niaz Ahmed, MD PhD Karolinska Institutet

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Responsible Party: Niaz Ahmed, Sponsor, Coordinating investigator, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT03639922     History of Changes
Other Study ID Numbers: I-StrokeII2016
2017-000075-85 ( EudraCT Number )
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Niaz Ahmed, Karolinska Institutet:
acute ischaemic stroke
Imatinib
blood-brain-barrier
trombectomy
iv trombolysis
Additional relevant MeSH terms:
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Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action