Endovascular Thrombectomy, Ischemic Cerebrovascular Accident
Conditions
Keywords
OTR4132, RGTA, neuroprotective agents, randomized controlled trial, ischemic stroke, endovacular thrombectomy
Brief summary
The MaTRISS 2 study is a phase 2 randomized, double-blinded and placebo-controlled trial aimed at recruiting 60 subjects (30 placebo and 30 active) from 15 stroke centers in France. The main objective will be to assess the efficacy of OTR4132-MD in patients with anterior ischemic stroke after endovascular thrombectomy. One dose will be tested (2 mg) against placebo. The main outcomes will be NIHSS (neurological score) at 24 hours, rate of intracranial hemorrhages at 24 hours, MRI lesion volume at 3 months and neurological scores at 3 months.
Detailed description
* The aim of the study is to confirm previous safety and encouraging efficacy data obtained from the MATRISS first-in man study and animal studies. . This is a prospective double-blinded placebo-controlled trial. The trial will recruit 60 subjects (30 per group) with anterior circulation acute ischemic stroke (AIS) re-vascularized (TICI score 2b - 3) by endovascular thrombectomy. Subjects will be followed for 3 months after a single administration of OTR4132-MD or placebo. * The study is double blinded and there is no way to distinguish the active product from the placebo. Neither the treating nor evaluating physicians, nor the patients, will be informed of the allocation of the treatment before database lock and the end of the trial. * The use of a placebo is justified by the absence of any neuroprotector approved in France in this indication so there is no comparator. The administration of OTR4132-MD or Placebo will be done in addition to the best standard of care and does not result in any additional po-tentially harmful procedure. * The study will include 60 patients (30 in the active group and 30 in the placebo group) which is considered sufficient to demonstrate superiority of treatment over placebo with a 5% risk two-sided level (see sample size calculation). * The study will evaluate a single dose of OTR4132-MD (2 mg) over Placebo. This dose has been selected as the highest and safest dose tested in the previous MATRISS dose-escalation study. * A 3 months-follow-up period is estimated sufficient to evaluate the residual disability and is recommended in the guideline "Points to consider on clinical investigation of medicinal products for the treatment of acute stroke" (EMA, 2001, CPMP/EWP/560/98). * A Data Safety Monitoring Board (DSMB) will be set up. It will consist of three medical experts in neurology and stroke trials. Other relevant expertise will be consulted if deemed neces-sary. The members of the committee will review interim blinded safety and efficacy study da-ta. Unblinding procedures will be set up in individual cases if deemed necessary.
Interventions
DEVICEOTR4132
OTR4132 is a new ReGeneraTing Agent (RGTA®) which is a polymer of glucose (α-1,6 bounds, i.e. dextran backbone) engineered to mimic heparan sulphate (HS) in all three mechanical functions (extracellular matrix scaffold element, protector of matrix pro-teins and cellular communication peptides storage sites) but differ from HS by their resistance to glycanases. OTR4132 allows a restoration of the matrix architecture which secondarily facilitates cell survival and recovery at the site of injury.
DEVICEPlacebo
saline solution
Sponsors
Organ, Tissue, Regeneration, Repair and Replacement
Euraxi Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 18 and 85 years 2. Acute ischemic stroke in anterior circulation territory, identified by magnetic resonance imaging (MRI). 3. Occlusion of anterior circulation i.e. carotid artery (ICA) or proximal middle cerebral artery (MCA) (M1 and/or M2 segment) 4. Endovascular thrombectomy (with or without previous intravenous thrombolysis) 5. Recanalization confirmed by angiography after endovascular treatment: TICI grade 2b - 3 6. NIHSS (National Institute of Health Stroke Scale/Score) ≥ 11 7. Pre-stroke modified Rankin Score (mRS): 0 or 1 8. Patient\* or legally authorized representative (family member or trusted person if patient unable to give consent) or independent physician (if patient unable to give consent and if an authorized representative cannot be reached) has signed informed consent. * Patients unable to give consent at baseline will go through a deferred consent procedure to continue the study
Exclusion criteria
1. Previous symptomatic stroke with permanent sequelae 2. Pre-existing medical, neurological, or psychiatric disease that would confound the neurological evaluation 3. Contraindication to MRI 4. Stroke lesion not visible on MRI 5. History of allergy or anaphylactic reactions to any of the ingredients of OTR4132-MD or heparinoids 6. History of hypersensitivity or anaphylactic reactions to iodinated contrast media 7. Intracranial tumor at inclusion 8. Pregnant or breastfeeding women 9. Severe renal failure with glomerular filtration rate (GFR) \< 30 mL/min 10. Severe uncontrolled arterial hypertension e.g. systolic blood pressure \> 185 mmHg or diastolic blood pressure \> 110 mmHg, or intravenous medication necessary to reduce blood pressure 11. Life expectancy of less than 3 months or co-morbidities that could influence the study results or would complicate assessment of outcomes (e.g. dementia, psychiatric disease) or would make clinical follow-up difficult 12. Increased risk of hemorrhage (for instance medical history of significant bleeding disorders, major surgery or significant trauma in the past 3 months, any history of suspected intracranial hemorrhage, symptoms suggestive of subarachnoid hemorrhage, even if the MRI is normal, international normalized ratio (INR)\>1.3 or activated partial thromboplastin time (aPTT)\>ULN (upper limit of normal) 13. Suspected cerebral vasculitis based on medical history and imaging 14. Occlusions in multiple vascular territories 15. Evidence of any prior intracranial intervention (i.e. neurosurgery, endovascular intervention) 16. Worsening of medical or neurological conditions or per-procedures complications 17. Any other serious, advanced, or terminal illness (investigator judgment) 18. Current participation in another therapeutic investigation (drug or device) 19. The patient is not a member or beneficiary of the French social security system
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-Adjusted 24-Hour NIHSS | 24 hours | The NIH Stroke Scale (NIHSS) is based on the collection of 15 clinical neurological items. It allows for an accurate and rapid assessment of observed deficits. A large number of publications have shown that the NIHSS score at 24 hours is the best prognostic factor for long-term functional disability and is closely correlated with disability scores at 3 months. An NIHSS score between 1 and 4 means a minor stroke, between 5 and 15, a moderate stroke, above 15 points, a severe stroke. The maximum score is 42 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in modified Rankin scale (mRS) at 3 months | 3 months | The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire. The Modified Rankin Score (mRS) is the most widely used outcome measure in stroke clinical trials. Standardized interviews to obtain a mRS score are recommended at 3 months (90 days) following hospital discharge. The mRS will be used as a continuous endpoint (change in mRS at 3 months and in a responder analysis (mRS 0-2 at 3 months). |
| Changes in total lesion volume from baseline to 3 months (MRI) | 3 months | Follow-up infarct volume is a more direct measure of biological effect of treatment. Infarct volume is less likely to be confounded by intervening comorbid illness, rehabilitation therapy, or non-stroke related pathology. volumetric analyses will be analyzed by an independent core laboratory |
| The rate of Intracranial hemorrhage at 24-hour | 24 hours | The rate of Intracranial hemorrhage at 24-hour based on Heidelberg classification is considered an important endpoint to assess the potential performance of OTR4132-MD in the repair of the blood brain barrier |
| Barthel Index at 3-months | 3 months | Modified Barthel Index (from 0 to 20) is a measure of physical disability used widely to assess behaviour relating to activities of daily living. It measures what patients do in practice. Assessment is made by anyone who knows the patient well. 100: normal \<99 represents slight dependency \<90 represents moderate disability \<60 represents severe disability \>20 represents total dependency |
Countries
France
Contacts
PRINCIPAL_INVESTIGATOROlivier Detante, MD
Centre Hospitalier Universitaire Grenoble Alpes
Outcome results
None listed