An Open, Study to Assess the Safety of RGTA® (OTR4132) in Patients With Acute Ischemic Stroke (AIS)

Study Overview
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Brief Summary
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RGTA® (ReGeneraTing Agent) are synthetic polysaccharides mimicking extra-cellular matrix scaffold elements and protective agents called Heparan Sulphates (HSPGs). OTR4132-MD is provided as a sterile injectable medical device. OTR4132-MD is indicated in anterior circulation acute ischemic stroke (AIS) patients re-vascularized (TICI score 2b - 3) by combined thrombolysis and endovascular thrombectomy within 6 hours of symptoms onset.

Detailed Description
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The promising results of OTR4132-MD in the treatment of acute ischemic stroke in animal studies and the excellent results of biocompatibility tests reported in the Investigator's Brochure allowed to design a clinical investigation in humans named MATRISS. As this is a First-In-Man (FIM) study assessing OTR4132-MD, it is designed as a single ascending dose (SAD) to evaluate the safety, tolerability of a single intra-arterial injection of OTR4132-MD in AIS patients treated with combined thrombolysis and thrombectomy. The FIM will include up to 18 patients in up to five dose groups. Each group will comprise 3 subjects. This FIM study will also monitor a dose response relationship in humans: lesion volume change throughout the study period. Patients will be given a single intra-arterial injection of OTR4132-MD with a predefined dose of OTR4132. In the first dose group, the OTR4132 dose is 0.20 mg. The results of this study will serve as a groundwork for the design of a pivotal study in the intended patient population.

Official Title
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An Open, Multi-centre Study to Assess the Safety and Tolerability of RGTA® (OTR4132) in Patients With Acute Ischemic Stroke (AIS)

Conditions
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Stroke, Acute

Intervention / Treatment
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* Device: OTR4132MD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients for this study will be included if all of the following conditions are met: Age 18 to 80 years Acute ischemic stroke in anterior circulation territory, identified by magnetic resonance imaging (MRI) Occlusion of anterior circulation i.e. internal carotid artery or proximal middle cerebral artery (MCA) (M1, M1/M2) Volume of the lesion estimated below two third of the MCA territory Intravenous (IV) thrombolysis performed according to European Stroke Organization (ESO) guidelines Intravenous Alteplase (1h infusion) terminated at least 40min before effective thrombectomy; or Intravenous Tenecteplase (bolus) terminated at least 120min before effective thrombectomy Endovascular thrombectomy initiated within 6 hours of stroke onset Angiography after endovascular treatment: TICI grade 2b - 3 Baseline NIHSS (National Institute of Health Stroke Score), including hand testing 11 and 25 at screening No significant pre-stroke disability (pre-baseline modified Rankin Score (mRS) 0-1) Able to follow neuro-rehabilitation programme Patient* or legally authorized representative (family member, trusted person or physician) if patient unable to give consent has signed informed consent. Patients unable to give consent at baseline will go through a deferred consent procedure to continue the study (Section 12: Subject Information and Informed Consent) Exclusion Criteria: Eligible patients for this study will not be included if any of the following conditions are present: Previous symptomatic stroke Pre-existing medical, neurological or psychiatric disease that would confound the neurological evaluation Contra-indication to MRI Evidence of intracranial haemorrhage (ICH) At the discretion of the investigator, patients with co-morbidities associated with a 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 History of allergy or anaphylactic reactions to any of the ingredients of OTR4132-MD or heparinoids Severe renal failure with glomerular filtration rate (GFR) < 30 mL/min 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 Increased risk of haemorrhage (such as medical history of significant bleeding disorders, major surgery or significant trauma in the past 3 months, any history of central nervous damage or suspected intracranial haemorrhage, symptoms suggestive of subarachnoid haemorrhage, even if the MRI is normal, international normalized ratio (INR)>1.3 or activated partial thromboplastin time (aPTT)>ULN (upper limit of normal) Suspected cerebral vasculitis based on medical history and imaging Occlusions in multiple vascular territories Evidence of intracranial tumour Evidence of any prior intracranial intervention (i.e. neurosurgery, endovascular intervention) Worsening of medical or neurological conditions or per-procedures complications Any other serious, advanced, or terminal illness (investigator judgment) Pregnant or breastfeeding or women without an adequate contraceptive method Current participation in another investigation drug or device study The patient is not a member or beneficiary of a social security scheme

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: open study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OTR4132MD<br>one medical device (10mL) of one of the 5 available concentrations (20 μg/mL, 50 μg/mL, 100 μg/mL, 150 μg/mL, 200 μg/mL) will be administrated as a one shot-dose to the patient. The respective total dose of OTR4132 received by a patient will be one of the following: 0,20 mg, 0,50 mg, 1 mg, 1,5 mg and 2 mg. | Device: OTR4132MD<br>* According to Regulation (EU) 2017/745(MDR), OTR4132-MD is an implantable medical device, for short term use which is specifically intended for use in direct contact with systemic circulation system. OTR4132-MD is by definition intended to come into contact with the patient when being injected. It is administered through intra-arterial injection, in an one-shot dose and the majority of the product is eliminated within 24 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of severe adverse events device related and dose limiting | Severe adverse events | 7 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival rates | survival rates | 24 hours, 7 Days, 30 Days, 90 Days | 
| All cause death | All cause death | 24 hours, 7 Days, 30 Days, 90 Days | 
| Stroke related death | Stroke related death | 24 hours, 7 Days, 30 Days, 90 Days | 
| Rate of device related adverse events (AEs) and serious adverse events (SAEs) | rate of device related adverse events | 24 hours, 7 Days, 30 Days, 90 Days | 
| Rate of adverse events (AEs) and serious adverse events (SAEs) procedure related | Rate of AEs and SAEs propcedure related | 24 hours, 7 Days, 30 Days, 90 Days | 
| Symptomatic intracranial haemorrhage | Intracranial haemorrhage | 24 hours, 7 Days, 30 Days, 90 Days | 
| Brain oedema on 24-hour follow-up imaging | brain oedema | 24 hours | 
| New ischaemic lesions | Ischaemic lesions in new territories on 24-hours follow-up imaging | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, FIM, OTR3