Efficacy of Imatinib in Acute Ischemic Stroke: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-506178-11-00
- Protocol
- I-Stroke II
- Sponsor
- Karolinska Institutet
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3, randomized, double-blind, placebo-controlled, parallel-arm efficacy trial is to evaluate whether **Imatinib** treatment, administered at a dosage of 800 mg per day within 8 hours of symptom onset and continued for 6 days, enhances the functional outcome at three months following an acute ischemic stroke. This is clinically relevant as improving functional outcomes can significantly impact the quality of life and independence of stroke survivors.
Secondary objectives include:
- Investigating if Imatinib treatment improves functional and neurological outcomes at three months in acute ischemic stroke patients, both with and without intravenous thrombolysis.
- Assessing whether Imatinib reduces the frequency and severity of intracerebral hemorrhage (ICH) and cerebral edema in patients treated with intravenous thrombolysis.
- Examining the incidence of serious and non-serious adverse events in patients receiving Imatinib.
- Determining if Imatinib reduces mortality at three months post-stroke, both in the general acute ischemic stroke population and specifically in those treated with intravenous thrombolysis.
Participants
The clinical trial focuses on individuals diagnosed with **acute ischemic stroke**, aiming to assess the efficacy of Imatinib treatment. The study population includes both male and female participants aged between 18 and 89 years. Participants are required to have a clinical diagnosis of acute ischemic stroke with a neurological deficit of 6 points or higher on the NIHSS score. The trial does not involve a vulnerable population. Participants must be randomized within specific time frames following symptom onset or awakening in the case of wake-up strokes. The trial population was selected based on specific inclusion criteria, including the ability to provide informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of **Imatinib** in patients with **acute ischemic stroke**. The trial aims to determine if treatment with Imatinib, administered at a dose of 800 mg per day, initiated within 8 hours of symptom onset and continued for 6 days, can improve functional outcomes at three months post-stroke. The study is structured as a parallel-arm trial, with participants randomly assigned to receive either Imatinib or a placebo. The trial is expected to run from June 1, 2018, to December 31, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-89 years), clinical diagnosis of acute ischemic stroke, and the ability to provide informed consent. Following randomization, the study drug will be administered as soon as possible, adhering to specific timelines related to prior treatments like intravenous thrombolysis or endovascular thrombectomy. Follow-up visits will occur at 24 hours, 7 days, and 3 months post-treatment to assess neurological outcomes, functional independence, and any adverse events. The end-of-study visit will coincide with the 3-month follow-up, where the primary endpoint, a change in the modified Rankin Scale (mRS) score, will be evaluated.
Participant involvement is expected to last approximately 3 months, from the initial screening to the final follow-up visit. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or the occurrence of serious adverse events. The trial's primary endpoint is the favorable shift in the mRS score at 3 months in the Imatinib group compared to the placebo group. Secondary endpoints include functional independence, neurological outcomes, frequency of intracerebral hemorrhage and cerebral edema, adverse events, and mortality at 3 months.
Treatment
The clinical trial involves the administration of **Imatinib**, a film-coated tablet, as the experimental medication. The active substance is **Imatinib**, a chemical compound, administered orally. The dosage is set at 800 mg per day, with a maximum daily dose of 800 mg and a total maximum dose of 4800 mg over the treatment period. The treatment is administered for a maximum of 6 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
In addition to the experimental medication, a placebo is used as a comparator treatment. The placebo is provided in two forms: a tablet placebo and a powder for concentrate for solution for infusion. The tablet placebo is administered orally, while the powder for concentrate is intended for intravenous infusion. These placebo treatments are designed to match the experimental medication in appearance and administration route to maintain the double-blind nature of the trial.
Another formulation of **Imatinib** is used in the trial, specifically the **Imatinib 400 mg powder for concentrate for solution for infusion**. This formulation contains **Imatinib Mesilate** as the active substance and is administered intravenously. The maximum daily dose for this formulation is also 800 mg, with a total maximum dose of 1600 mg over a 2-day treatment period. This formulation is used to assess the efficacy of intravenous administration compared to oral administration.
Additional non-experimental substances used in the trial include a combination of Sodium Chloride, Mannitol, L-Methionine, Potassium dihydrogen phosphate, and Riboflavin. These substances are not active treatments but may be used as part of the infusion solution to maintain consistency in the administration process.
Furthermore, the trial includes the use of excipients such as Lactose Monohydrate, Hypomellose 2910, Magnesium Stearate, Colloidal Silicon Dioxide, and Quinoline Yellow. These excipients are used in the formulation of the tablets and do not have therapeutic effects but are necessary for the production and stability of the pharmaceutical forms used in the trial.
Efficacy
The efficacy of **Imatinib** in the treatment of acute ischaemic stroke will be assessed through a phase 3, randomised, double-blind, placebo-controlled, parallel-arm clinical trial. The primary endpoint for evaluating efficacy is the change in the modified Rankin Scale (mRS) score at 3 months, with a favourable shift in the scale expected in the Imatinib group compared to the placebo group. Secondary endpoints include functional independence at 3 months, as measured by an mRS score of 0-2, neurological outcomes at 24 hours, 7 days, or discharge if earlier, and at 3 months. Additionally, the frequency and grade of intracerebral hemorrhage (ICH) and cerebral oedema on post-treatment imaging scans in patients undergoing IV thrombolysis and/or endovascular thrombectomy will be evaluated, along with serious and non-serious adverse events and mortality at 3 months.
Measurements will be collected at specified timepoints, including 24 hours, 7 days, or discharge if earlier, and at 3 months post-treatment. The modified Rankin Scale, a validated tool for assessing the degree of disability or dependence in daily activities, will be used to evaluate functional outcomes. Imaging scans will be employed to assess ICH and cerebral oedema. The trial aims to determine if Imatinib treatment, initiated within 8 hours of symptom onset and administered for 6 days, improves functional outcomes at three months following an acute ischaemic stroke.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Clinical diagnosis of acute ischaemic stroke with a neurological deficit corresponding to 6 points or higher on the NIHSS score.performed b) prior to iv thrombolysis therapy alone or prior to thrombectomy alone if performed c) 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.
- Age 18-89 years
- Patients should be randomised as soon as possible but not later than 8 hours of symptom onset/ last known well or patients who present with a wake up stroke (WUS) who can be randomised within 6 hours from awakening provided the other criteria are met. a) If the patient receives iv thrombolysis alone, patient should be randomised and study drug should be given withinone hour after completion of iv thrombolysis infusion b) If the patient receives endovascular thrombectomy (with or without prior iv thrombolysis), patient should be randomised within two hours after completion of endovascular thrombectomy and study drug given as soon as possible after randomisation.
- iv thrombolysis, if performed, is done in agreement with European Stroke Organisation (ESO) guidelines 2021* and has been initiated within 4.5 hours of stroke onset (see below separate criteria for indications / contraindications)
- Endovascular thrombectomy, if performed, is done in agreement with ESO guidelines 2019**, and fulfilling the following criteria a) 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 or first segment of the Posterior Cerebral Artery (P1), consistent with the clinical symptoms. b) thrombectomy has been initiated within 8 hours of symptom onset/last known well or within 6 hours of WUS (defined as start of Arterial puncture)
- 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
- 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
- Known significant pre-stroke disability (mRS ≥2)
- 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.
- Acute pancreatitis
- Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
- Ongoing treatment with chemotherapy
- Drugs which may increase the plasma concentration of Imatinib -– ketokonazol, itrakonazol, erythromycin and claritomycin
- Drugs which may decrease the plasma concentration of Imatinib: Dexametason, phenytoin, karbamazepin, rifampizin, phenobarbital, fosphenytoin, primidon, Hypericum perforatum (Johannesört, St John’s wort)
- Female patients with childbearing potential, if pregnancy cannot be excluded by pregnancy test (urine point-of-care pregnancy test).
- Patient is participating in other interventional study
- Additional Exclusion criteria for patients treated with intravenous thrombolysis (IVT):
- 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.
- Patients receiving oral anticoagulants, e.g. warfarin sodium (INR>1.7) or direct oral anticoagulation: dabigatran (aPTT>40s), apixaban, rivaroxaban.
- Platelet count below 100,000/mm3. Significant bleeding disorder at present or within the past 6 months, known haemorrhagic diathesis
- History or evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage
- 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.
- 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
- Major surgery or significant trauma in the past 10 days
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Sweden | Not Yet Recruiting | 01 Jun 2018 | 680 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IMATINIB | Test | — | ORAL | 800 | 6 | SUB25387 |
Imatinib placebo, powder for concentrate for solution for infusion | Placebo | N/A | — | — | — | N/A |
Imatinib 400 mg powder for concentrate for solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 800 | 2 | PRD10826978 |
Tablet placebo | Placebo | N/A | — | — | — | N/A |
Sodium Chloride, Mannitol, L-Methionine, Potassium dihydrogen phosphate, Riboflavin | Placebo | N/A | — | — | — | N/A |
Lactose Monohydrate, Hypomellose 2910, Magnesium Stearate, Colloidal Silicon Dioxide, Quinoline Yellow | Placebo | N/A | — | — | — | N/A |