A Trial to Assess the Efficacy and Safety of OTR4132-MD in Patients with Acute Ischemic Stroke (MATRISS-II)

MATRISS-II. Matrix Therapy to Reduce Ischemic Stroke Sequelae-II. a Randomized-double Blinded- Placebo Controlled Trial to Assess the Efficacy and Safety of OTR4132-MD in Patients with Acute Ischemic Stroke

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Cerebrovascular Accident; Endovascular Thrombectomy
• Intervention / Treatment: Device: OTR4132; Device: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Frederic SEDEL, MD, PhD; Phone Number: +33 (0)1 83 62 78 91; Email: frederic.sedel@otr3.com
• Study Contact Backup: Name: Martin Inizan; Phone Number: +33 (0)1 83 62 78 91; Email: martin.inizan@otr3.com

Study Locations

• France
  • Bordeaux, France, 33076
    • Centre Hospitalier Universi-taire de Bordeaux-Hôpital Pellegrin
    • Contact: Xaiver barreau, MD, PhD; Phone Number: 000; Email: xavier.barreau@chu-bordeaux.fr
  • Brest, France, 29609
    • Centre hospitalier universi-taire de Brest (Cavale Blanche)
    • Contact: Serge Timsit, MD, PhD; Phone Number: 000; Email: serge.timsit@chu-brest.fr
  • Créteil, France, 94000
    • CHU Henri-Mondor
    • Contact: Erwa Khalsoum, MD; Phone Number: 000; Email: erwah.kalsoum@aphp.fr
  • Fort de France, France, 97261
    • Centre Hospitalier Universitaire de Martinique
    • Contact: Christina IOSIF, MD; Phone Number: 000; Email: CHRISTINA.IOSIF@chu-martinique.fr
  • Grenoble, France, 38043
    • Centre Hospitalier Universitaire Grenoble Alpes
    • Contact: Olivier Detante, MD, PhD; Phone Number: 999; Email: odetante@chu-grenoble.fr
  • Lille, France, 59000
    • Centre Hospitalier Régional Universitaire de Lille- Hôpital Roger Salengro
    • Contact: Lucie DELLASCHIAVA, MD; Phone Number: 000; Email: lucie.dellaschiava@chu-lille.fr
  • Marseille, France, 13385
    • Hôpitaux Universitaires De Marseille Timone-AP-HM
    • Contact: Laurent SUISSA, MD; Phone Number: 000; Email: laurent.suissa@ap-hm.fr
  • Nancy, France, 54000
    • Centre Hospitalier Régional Universitaire de Nancy
    • Contact: René Anxionnat, MD; Phone Number: 000; Email: r.anxionnat@chru-nancy.fr
  • Nantes, France, 44093
    • UIC Imagerie et Neurovasculaire CHU de Nantes
    • Contact: Romain BOURCIER, MD; Phone Number: 000; Email: Romain.BOURCIER@chu-nantes.fr
  • Paris, France, 75013
    • Hôpital de la Pitié Salpêtrière - AP-HP
    • Contact: Charlotte ROSSO; Phone Number: 000; Email: charlotte.rosso@gmail.com
  • Paris, France, 75019
    • Hôpital Fondation Adolphe de Rothschild Service de neuro-vasculaire
    • Contact: Michael OBADIA, MD; Phone Number: 000; Email: mobadia@for.paris
  • Paris, France, France
    • GHU Paris Psychiatrie & Neurosciences
    • Contact: David CALVET, MD; Phone Number: 000; Email: d.calvet@ghu-paris.fr
  • Pointe-à-Pitre, France, 97159
    • Centre Hospitalier Universitaire de la Guadeloupe
    • Contact: Anne LANDAIS, MD; Phone Number: 000; Email: anne.landais@chu-guadeloupe.fr
  • Strasbourg, France, 67200
    • Hopital de Hautepierre
    • Contact: Valérie WOLFF, MD; Phone Number: 000; Email: valerie.wolff@chru-strasbourg.fr
  • Suresnes, France, 92150
    • Hôpital Foch
    • Contact: Bertrand LAPERGUE, MD; Phone Number: 000; Email: b.lapergue@hopital-foch.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Saline solution	Device: Placebo; saline solution
Experimental: OTR4132; 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.	Device: OTR4132; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-Adjusted 24-Hour NIHSS	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	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in modified Rankin scale (mRS) at 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).	3 months
Changes in total lesion volume from baseline to 3 months (MRI)	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	3 months
The rate of Intracranial hemorrhage at 24-hour	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	24 hours
Barthel Index at 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	3 months

Collaborators and Investigators

• Sponsor: Organ, Tissue, Regeneration, Repair and Replacement
• Collaborators: Euraxi Pharma
• Investigators: Principal Investigator: Olivier Detante, MD, Centre Hospitalier Universitaire Grenoble Alpes

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: November 20, 2024
• First Submitted That Met QC Criteria: November 20, 2024
• First Posted (Actual): November 22, 2024

Study Record Updates

• Last Update Posted (Estimated): November 26, 2024
• Last Update Submitted That Met QC Criteria: November 22, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: randomized controlled trial; ischemic stroke; neuroprotective agents; RGTA; OTR4132; endovacular thrombectomy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Ischemic Stroke; Stroke; Ischemia
• Other Study ID Numbers: MATRISS-II; 2024-A01526-41 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No